Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[N:8]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[NH2:19])[CH3:10])C=CC=CC=1.[NH4+].[OH-]>O>[NH2:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:9]1[NH:8][C:11]2[C:16]([CH:10]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(N)c(C(C)=NNc2ccccc2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N)c(-c2cc3ccccc3[nH]2)c1
Yield: 164.8 %

Procedure:
To polyphosphoric acid (30 ml) preheated to 110° C. was added 1.95 g 1-(2-amino-5-methoxyphenyl)ethanone phenylhydrazone in small portions under nitrogen. The reaction was maintained at 110°-120° C. for forty-five minutes. This mixture was poured directly into excess water and made basic with concentrated NH4OH. Extraction with CH2Cl2, drying (MgSO4) and concentration yielded 1.5 g 2-(2-amino-5-methoxyphenyl)-1H-indole as a solid, m.p. 97°-99° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.B(O)(O)[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(F)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (70 mg, 95%), MS (ISP) m/z=295.2 [(M+H)+], mp 271.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH3:22])=[O:20].Cl>C1COCC1>[CH3:22][O:21][C:19]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 198.7 %

Procedure:
A suspension of L-diphenylalanine (13.87 g, 57.5 mmol) in THF (100 ml), and saturated NaHCO3 (3 mL) stirred at 0° C. was treated with neat methyl chloroformate (11.81 g, 125 mmol) (slow addition), stirred at the same temperature for 10 min and then at room temperature for 14 h, made acidic by addition of 1M HCl and extracted with DCM, dried over MgSO4 filtered and concentrated to give title compound (17.1 g, 99% yield) as white solid. Used without further purification. MS: m/z=322.1 (MNa+).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H]>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Temperature: 25 °C

Procedure:
3.72 g (6.51 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL DCM were combined with 300 mg of 10% Pd/C and shaken at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][OH:25])[CH:20]=[C:21]([F:23])[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:24][O:25][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:15])([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CCN1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-ethyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:25]([C:27]([CH2:32][CH3:33])([CH2:30]O)[CH2:28]O)[CH3:26]>O1CCCC1>[CH2:16]([O:15][C:13]([C:8]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[C:9]=1[O:12][CH2:30][C:27]([CH2:32][CH3:33])([CH2:25][CH3:26])[CH2:28][O:11]2)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Reactant: CCC(CC)(CO)CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(c(C(=O)OCC)n1Cc1ccccc1)OCC(CC)(CC)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylic acid diethyl ester (2.6 g, 7.7 mmol), 2,2-diethyl-1,3-propanediol (1.1 g, 8.5 mmol), and PH02 (4.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 0° C. The reaction mixture was then allowed to warm to 25° C., stirred for 3 h, and then was refluxed for 21 h. The reaction mixture was then allowed to cool to 25° C. and was concentrated by rotary evaporator to remove the tetrahydrofuran. The residue was then diluted with diethyl ether and allowed to stand overnight to enable the tributylphosphine oxide to precipitate out. The tributylphosphine oxide was then removed by filtration and the remaining product was purified by chromatography on silica gel (eluant: ethyl acetate/hexane=3/1) to give 2-benzyl-6,6-diethyl-6, 7-dihydro-2H,5H-4,8-dioxa-2-aza-azulene-1,3-dicarboxylic acid diethyl ester as a colourless oil in 2.5 g (75%) yield as characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51](=O)[CH3:52])=[C:47]([OH:54])[C:46]=1[CH3:55])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:52]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[C:47]([OH:54])[C:46]=1[CH3:55])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCc2ccccc2)ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1O
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-benzyloxy-2-hydroxy-3-methyl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (73 mg, 10% yield). MS: 584.29 (M+H+); HPLC Procedure A, retention time=18.27 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([NH2:13])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1>C(O)C>[Si:1]([O:8][CH2:9][C:10]1([NH:13][CH2:15][C:16]2([OH:14])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(N)CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Yield: 18 %

Procedure:
To a solution of 1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanamine (10.09 mmol) in absolute ethanol (40 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9.61 mmol) in one portion. The reaction was heated at reflux for 20 h then cooled and evaporated onto silica. The solid was purified by flash chromatography (30-80% ethyl acetate in hexanes) to afford the title product (719 mg, 16% yield) as a colorless oil. MS(ES)+ m/e 415.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 105 °C

Procedure:
A flame-dried flask containing N2 inlet and magnetic stirrer was charged with 2.9 g (18 mmol) of 3,4-dichlorophenol, 6.2 g (45 mmol) of potassium carbonate and 50 mL of anhydrous DMF. With stirring, 2.08 g (15 mmol) of 2,5-difluorobenzonitrile (Aldrich Chem. Co.) was added and the mixture was heated overnight at 105° C., cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was reextracted with EtOAc and the combined organic layers were successively washed with 2N NaOH, water and saturated aqueous NaCl. After drying with MgSO4, the solvent was removed to give the title product as a light brown oil which slowly solidified, 3.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>ClCCl>[Si:32]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=3[F:31])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 21h (1.12 g, 2.38 mmol) in dichloromethane (20 mL) were added tert-butyldimethylsilyl chloride (0.54 g, 3.58 mmol) and imidazole (0.49 g, 7.16 mmol) in turn at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between dichloromethane (40 mL) and water (40 mL). The organic layer was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21i as yellow oil (1.37 g, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:33])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:31][CH3:32])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 78.1 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitro-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,4-diamine (Intermediate 159, 440 mg, 0.95 mmol), iron (319 mg, 5.71 mmol), NH4Cl (38.2 mg, 0.71 mmol), ethanol (15 mL) and water (5 mL) was heated at reflux for 1.5 h. After cooling, the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (20 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (321 mg, 78%) as a brown gum after trituration with diethyl ether; 1H NMR: 2.18 (6H, s), 2.37 (2H, t), 2.65 (3H, s), 2.91 (2H, t), 3.72 (3H, s), 4.57 (2H, br s), 6.77 (1H, s), 7.07 (1H, td), 7.22 (1H, d), 7.29 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s), 8.77-8.80 (1H, m); m/z: ES+ MH+ 433.36.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[N:32][CH:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:34]1[N:35]=[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:31]=[N:32][CH:33]=1)#[N:37]
Reactant: N#Cc1cncc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(C#N)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0513 g, 0.134 mmol) and 6-chloropyrazine-2-carbonitrile (0.0326 g, 0.234 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 300 watts, 120° C. for 30 minutes on the Biotage microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.66 (s, 1H), 8.35 (s, 1H), 8.22 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.75 (s, 2H), 3.90 (t, J=5.3, 2H), 3.74 (d, J=4.4, 4H), 3.50 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.81 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)[CH:3]=1.[CH3:15][Mg]Br.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]([OH:14])[CH3:15])[S:11][CH:12]=2)[CH:3]=1
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (160 mg, 0.72 mmol) in THF (3 mL) was added methylmagnesium bromide (3 M, 1 mL) at −78° C. and the resulting mixture was stirred at the temperature for 3 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 1-[4-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-ethanol
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Br)sc1Br)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Br)sc1Br)C2
Temperature: 90 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a mixture of 7-(2,5-dibromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.08 g) and aminoguanidine hydrochloride (24 mg) were added ethanol (1 ml) and concentrated hydrochloric acid (0.04 ml), and the mixture was stirred at 90° C. for 12 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dibromothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 124) (0.09 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH2:27][OH:28]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[N:27][OH:28])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NO
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Solvent: CO
Solvent: O
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=NO)ccn23)ccc1F
Temperature: 60 °C

Procedure:
A suspension of 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (260 mg, 0.8 mmol) in methanol (3 ml) was treated with hydroxylamine (0.13 ml of a 50 wt. % solution in water) then heated at 60° C. for 3 h. The reaction was cooled to 0° C., the solid collected by filtration and washed with a little cold methanol to afford 2′-fluoro-5′-[7-(hydroxyiminomethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in dichloromethane (5 ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.1 mmol) and triethylamine (0.31 ml, 2.3 mmol) then heated at reflux for 2 h. The reaction was cooled, diluted with dichloromethane then washed with water, brine, dried over anhydrous sodium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane/methanol/conc. ammonia (99:0.9:0.1) afforded a solid which was recrystallised from acetonitrile to furnish 3-(2′-cyano-6-fluorobiphenyl-3-yl)imidazo[1,2-α]pyrimidine-7-carbonitrile as a yellow powder (160 mg, 63% over 2 steps): δH (400 MHz, DMSO) 7.64-7.72 (3H, m), 7.78-7.81 (1H, m), 7.89 (1H, ddd, J 7, 7 and 1), 7.94-7.99 (2H, m), 8.05 (1H dd, J 8 and 2), 8.43 (1H, s), 9.36 (1H, d, J 7); m/z (ES+) 340 (M++H).
Reaction SMILES: [CH3:1]N(C)C1(C2C=CC=CC=2)CCC(=O)CC1.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][OH:29].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>[OH-].[Na+]>[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH2:1][O:29][CH2:28][CH2:27][C:21]2=1
Reactant: Cc1ccc2[nH]cc(CCO)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2[nH]c3c(c2c1)CCOC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Dimethylamino-4-phenylcyclohexanone (325 mg, 1.5 mmoles) and 2-(5-methyl-1H-indol-3-yl)-ethanol (“5-methyltryptophol”, 262 mg, 1.5 mmoles) were initially introduced into abs. MC (10 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.3 ml, 1.55 mmoles) was then added very rapidly. The mixture was stirred at room temperature for 24 hours. For working up, 1 M NaOH (20 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×20 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The suspended solid was filtered out with suction. One of the two possible diastereoisomers of 1,143-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained (430 mg, m.p. 259-270° C.). 350 mg of this were dissolved in hot ethanol (300 ml), and a similarly hot solution of citric acid (300 mg, 1.56 mmoles) in ethanol (10 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 hours. The resulting solid was filtered out with suction. It was possible to obtain the hemicitrate of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole in this way in a yield of 380 mg (white solid, m.p. 243-265° C.).
Reaction SMILES: C([OH:3])C.[C:4]([OH:13])(=[O:12])[C@@H:5]([C@H:7]([C:9]([OH:11])=[O:10])[OH:8])[OH:6]>O>[C:9]([CH:7]([CH:5]([C:4]([O-:13])=[O:12])[OH:6])[OH:8])([O-:11])=[O:10].[OH2:3]
Reactant: CCO
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 70 °C
Reaction time: 72 h

Procedure:
In 50 volume parts of water are dissolved 19 parts of TRH monohydrate and 7.5 parts of L-tartaric acid, and while the solution is warmed to 70°C, ethanol is added in installments. Immediately after a slight turbidity is observed, the temperature is gradually brought down to room temperature, at which temperature the solution is allowed to stand for 3 days. Then, the solution is cooled to 10°C and allowed to stand for 2 days to allow crystallization to be completed. The crystals thus obtained are harvested by filtration, washed with hot ethanol and dried under reduced pressure at 50°C for 1 hour and at 80°C for 5 hours. The described procedure yields 18 parts of TRH tartrate-water as crystals melting at 127°C-130°C. [α]D 24 =-49.90°(c=1.05 in water)
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:4]([O:22][CH:23]([F:25])[F:24])[CH:3]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[F:25][CH:23]([F:24])[O:22][C:4]1[CH:3]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([NH:34][C@@H:35]3[CH2:43][C@H:42]4[N:38]([CH2:39][CH2:40][CH2:41]4)[C:37]([CH3:44])([CH3:45])[CH2:36]3)[C:31]([F:46])=[CH:30][N:29]=2)[CH:21]=[CH:20][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2OC(F)F)CC1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCNCC4)c(OC(F)F)c3)ncc2F)C[C@@H]2CCCN21
Yield: 58.3 %

Procedure:
The general displacement procedure described herein was used with tert-butyl 4-(4-amino-2-(difluoromethoxy)phenoxy)piperidine-1-carboxylate (113 mg, 0.3 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (106 mg, 0.3 mmol) and pTsOH.H2O (42 mg, 0.2 mmol) in IPA (3 mL) at reflux to give the product (91 mg, 55% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 85:15) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:25][CH:26]([CH2:31]OS(C)(=O)=O)[C:27]([O:29][CH3:30])=[O:28]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)COS(C)(=O)=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: COC(=O)C(C)Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Yield: 38.6 %

Procedure:
Following the general method as outlined in Example 6 Step 1, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 683 mg; 2.00 mmol) and methyl 2-methyl-3-((methylsulfonyl)oxy)propanoate (588 mg; 3.00 mmol), 341 mg (39%) of the title compound was obtained as a colorless oil after purification by a silica gel chromatography (petroleum ether/EtOAc=3/1 to 2/1).