Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=O)[C:11]=2[N:10]=1.[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1>>[CH3:29][C:26]1[S:25][C:24]([NH:23][C:18]([C:17]2[C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:3]=4[C:2]([F:21])([F:22])[F:1])[NH:13][C:12]=3[CH:14]=[CH:15][CH:16]=2)=[O:20])=[N:28][CH:27]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(O)c1cccc2[nH]c(-c3cnccc3C(F)(F)F)nc12
Product: Cc1cnc(NC(=O)c2cccc3[nH]c(-c4cnccc4C(F)(F)F)nc23)s1

Procedure:
2-(4-(Trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 119 was coupled to 2-amino-5-methylthiazole 171 using the same general amide coupling procedure shown above to afford N-(5-methylthiazol-2-yl)-2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 703). MS (ESI) calcd for C18H12F3N5OS: 403.07; found: 404 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.O.O.[C:37]1([S:43]([O-:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Na+].[OH-].[Na+].Cl>C(O)C.C(O)(C)C.CO.ClCCl>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][S:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:45])=[O:44])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (60 mg, 0.110 mmol) and sodium benzenesulfinate dihydrate (33.1 mg, 0.165 mmol, available from TCI Europe) in ethanol (0.8 ml) were heated under microwave irradiation to 100° C. for 30 mins then 150° C. for 20 mins. The mixture was treated with dichloromethane (3 ml) and methanol (3 ml) and absorbed onto Florisil. This was placed on top a silica cartridge (10 g) and eluted with 0-100% ethyl acetate/cyclohexane and then 0-20% methanol/ethyl acetate. Appropriate fractions were combined and concentrated to give a yellow solid, 33 mg. The solid was treated with isopropanol (1 ml) and 2M aqueous sodium hydroxide (0.999 ml, 1.998 mmol) and stirred at 20° C. for 22 h. The mixture was neutralised with 2M aqueous hydrochloric acid, blown to dryness and purified by Mass Directed Automated Preparative H PLC. Appropriate fraction was evaporated, then azeotroped with methanol to give the title compound as a white solid (8 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].S([O-])([O-])(=O)=O.CS[C:13]([NH2:25])=[NH+:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24].CS[C:28]([NH2:40])=[NH+:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][C:38]=1[CH3:39]>O>[CH3:39][C:38]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:33][S:32][CH2:31][CH2:30][N:29]=[C:28]([NH2:40])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:13]([NH2:25])=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24]
Reactant: NCCCN
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
1,3-Diaminopropane (0.37 g) was added to a solution of S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.93g) in water (10 ml) and the mixture was heated under reflux for 2 hours. Following concentration the residue was converted into the picrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (1.1 g) m.p. 114°-6°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:9]2)=[CH:5][CH:4]=1.C([Li])CCC.CN([CH:29]=[O:30])C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH:29]=[O:30])=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-4-phenylimidazole (2.00 g, 7.56 mmol) in THF (20 mL) cooled to −78° C. under nitrogen add dropwise a solution of n-butyl lithium (1.6 M hexane, 5.60 mL, 8.96 mmol). Stir the mixture at this temperature for 10 minutes then add DMF (1.43 mL, 18.5 mmol) dropwise, and continue stirring for 30 minutes. Add a saturated aqueous solution of NH4Cl (50 mL), raise the temperature to room temperature, and extract the aqueous layer with CH2Cl2 (150 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 9:1) to provide 1.75 g (79% yield). MS(ES+): m/z=293 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:34]([O-])=O>[Pd].CO.O1CCCC1.[H][H]>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C[C@@H](c1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 3-[(S)-1-(4′-amino-3′-nitro-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.50 g) and 10% palladium on carbon (0.10 g) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was shaken in hydrogen atmosphere (3 bar) at room temperature for 3.5 h. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to afford the title compound as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClCCl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3s2)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (7.0 g) and 2-chlorobenzthiazole (5.26 g) were dissolved in dichloromethane to ensure good mixing. The solvent was then evaporated and the residue fused at 130° C. for 16 hours. The cooled reaction mixture was subjected to chromatography on silica (chloroform:methanol 10:1) to give the title compound as an oil (8.5 g). This was treated with maleic acid in isopropanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]benzthiazole dimaleate, m.p. 113° C. (decomp) (recrystallised from ethylacetate and isopropanol-ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](Cl)(Cl)=[O:11]>C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]=[C:10]=[O:11])[CH:8]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)cc1N=C=O
Yield: 90.4 %

Procedure:
A solution of 16.5 grams of 5-bromo-2-methyl aniline and 100 ml. of ethylacetate was added with stirring to a solution of 20 grams of phosgene and 300 ml. of ethylacetate kept at 5° C. After the addition was completed, phosgene was bubbled through the mixture while refluxing for one-half hour. The reaction mixture was purged with nitrogen, then the solvent was removed in vacuo to obtain 17 grams of 5-bromo-2-methylphenylisocyanate. This material was dissolved in 150 ml. of chloroform and added cautiously to a solution of 18.2 grams of 3-chloropropylamine hydrochloride, 150 ml. of chloroform, and 20 ml. of triethylamine. The mixture was refluxed for one-half hour, then cooled and shaken with water. The precipitated solid was separated by filtration. Recrystallization from ethylacetate afforded N-[3-(chloropropylamino)propyl]-N'-(5-bromo-2-methylphenyl)urea, m.p. 145°-148° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([F:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[CH2:4][C@@H:3]1[OH:12].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>CN(C=O)C>[F:8][C@H:7]1[C@H:2]2[NH:1][C:13](=[S:14])[O:12][C@H:3]2[CH2:4][C@H:5]([CH2:10][OH:11])[C@H:6]1[OH:9]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H]1[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]1O
Solvent: CN(C)C=O
Product: OC[C@H]1C[C@@H]2OC(=S)N[C@@H]2[C@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of (1S,2S,3S,4R,5R)-2-amino-3-fluoro-5-(hydroxymethyl)cyclohexane-1,4-diol (480 mg, 2.68 mmol) in DMF (5 mL) at room temperature was added thiocarbonyldiimidazole (549 mg, 3.08 mmol). The mixture was stirred at room temperature for 1.5 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 10%-35 MeOH in DCM to give the product (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazole-2(3H)-thione (494 mg, 83%) as a pale yellow solid. 1H NMR (500 MHz, MeOD) δ 4.74-4.77 (m, 1H), 4.56 (ddd, J=52.8 Hz, 3.8 Hz, 1.7 Hz, 1H), 3.98 (ddd, J=23.3 Hz, 7.0 Hz, 3.9 Hz, 1H), 3.59-3.64 (m, 2H), 3.45 (ddd, J=29.6 Hz, 10.6 Hz, 1.5 Hz, 1H), 2.22-2.27 (m, 1H), 1.95-2.02 (m, 1H), 1.69-1.75 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24](O)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:24](=[O:28])[C@@H:25]([OH:26])[CH3:27])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CC(O)C(=O)O
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (600 mg) was reacted with lactic acid via General Procedure B to give (S)-1-(4-((2-chloro-4morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (36.6 g) in N,N-dimethylformamide (500 mL) were added benzyl bromide (50.0 mL) and potassium carbonate (66.3 g), and the mixture was stirred overnight at 60° C. The reaction mixture was poured into water and the resulting mixture was extracted with a mixture of ethyl acetate and n-hexane (1:1). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (200 mL), and the resulting mixture was stirred for 30 minutes at 50° C. The reaction mixture was concentrated and the residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from isopropanol (50 mL)/n-hexane (200 mL) to give the title compound (31.99 g) having the following physical data.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]([C:27]1[N:28]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[S:30][CH:31]=1)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[Br:21][C:20]([Br:24])=[CH:25][C:27]1[N:28]=[C:29]([CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]2)[S:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C=C(Br)Br)cs2)CC1
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a solution of triphenylphosphine (7.08 g, 27 mmol) in anhydrous dichloromethane (11 ml) was added dropwise a solution of carbon tetrabromide (4.3 g, 13 mmol) in anhydrous dichloromethane (5 ml) at 10° C., and the mixture was stirred at the same temperature for 15 mins. Stirring was stopped, the supernatant of the reaction mixture was collected, and a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.0 g, 3.4 mmol) in anhydrous dichloromethane (11 ml) was added dropwise at 10° C. After stirring at 5-10° C. for 40 mins, triethylamine (4 ml) and saturated aqueous sodium hydrogen carbonate solution (0.5 ml) were added. The mixture was filtered through a Celite pad, and the insoluble material was washed with dichloromethane. The filtrate and washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to give tert-butyl 4-[4-(2,2-dibromovinyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.5 g, yield 97%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:13]=1[F:27]>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:13]=2[F:27])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(C(=O)Nc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: COc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2-fluoro-3-(3-fluorophenyl)-5-methoxy-benzamide (300 mg, 0.77 mmol, 1.0 eq) in THF (10 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 4 mL, 4.0 mmol, 5.2 eq) dropwise. The reaction mixture was heated to 60° C. and stirred for 1.5 h. The reaction was cooled to room temperature then quenched by addition of 1M HCl. The mixture was stirred at room temperature for 1.5 h, then extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a yellow oil (180 mg, 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.[C:20]([O:24][C:25](=O)[O:26]C(C)(C)C)([CH3:23])([CH3:22])[CH3:21].O>O1CCCC1>[CH2:1]([N:8]1[C@@H:9]([CH3:15])[CH2:10][N:11]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Agent: CN(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=S.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH:5]1([N:1]=[C:2]=[N:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: c1ccccc1
Reactant: NC(N)=S
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
They are heated to reflux into 200 ml benzene, 33 g of the thiourea obtained in the step G, together with 16 g dicyclohexyl carbodiimide for 5 hours. After achievement of the reaction, it is cooled, washed with water than with an aqueous solution of sodium carbonate and further with water. It is dried and concentrated to dryness under vacuum, the residue is taken up with 100 ml methanol and 20 ml water, then the pH value is adjusted to 1 with concentrated hydrochloric acid. The end of the reaction is followed by TLC on silica plates with chloroform 7--ethanol 3 (revelation UV and Iodoplatinate). It is neutralized after dilution with water using sodium carbonate then sodium hydroxide to obtain a pH value of 12. It is extracted with methylene chloride, the organic solution is washed with water, dried, filtered and concentrated to dryness. 37 g of raw product are produced which are washed with isopropyl ether and 24 g of the pure compound are obtained. The product is recrystallized from ethyl acetate containing a little methanol. MP=164.8°165.2° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:42][C:43](=O)[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Br:52]>C(Cl)Cl>[Br:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH2:45][O:44][C:43]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:25])=[O:42]
Reactant: O=C(OCc1ccccc1Br)ON1C(=O)CCC1=O
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (836 mg, 2.00 mmol, 1.0 eq.) and DIPEA (0.86 mL, 5.00 mmol, 2.5 eq.) in DCM (30 mL), carbonic acid 2-bromo-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (787 mg, 2.40 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. during 2 hours. The reaction was quenched with 1M aq. citric acid soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the previous mixture in EtOH (1.1 mL), conc. H2SO4 (0.10 mL) was added. The solution was stirred at r.t. during 3 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.
Reaction SMILES: [Na].[NH:2]1[C:6]([SH:7])=[CH:5][N:4]=[N:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27]Cl)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27][S:7][C:6]3[NH:2][N:3]=[N:4][CH:5]=3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: Sc1cnn[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnn[nH]3)c2CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Slurry 1H-[1,2,3]triazole-5-thiol sodium salt (465 mg, 3.78 mmol) in anhydrous DMF (20 mL). Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 3.4 mmol) in anhydrous DMF (10 mL) dropwise over 10 min under nitrogen. Stir at room temperature for 3 h. Quench by addition of saturated NH4Cl (100 mL). Extract with EtOAc (3×50 mL) and dry the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain 3-tert-butoxycarbonyl-7-chloro-6-(3H-[1,2,3]triazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.2 g, 90%) as a yellow oil suitable for use without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 55 mg (40%) product as a white solid. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH:35]=O)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([O:21]CC1C=C(C=O)C=C(Cl)C=1)=[O:20].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=[O:20]
Reactant: C1CCNC1
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cc(Cl)cc(C=O)c4)n3Cc3cc(Cl)cc(C=O)c3)n12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cc(Cl)cc(CN4CCCC4)c3)n12
Reaction time: 8 h

Procedure:
3-Chloro-5-formylbenzyl 6-(3-chloro-5-formylbenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (0.035 g, 0.067 mmol, from Example 131, Step 7) was suspended in DCM (4 mL) and pyrrolidine (0.03 g, 0.4 mmol, Aldrich) and sodium triacetoxyborohydride (0.2 g, 0.8 mmol, Aldrich) were added. After stirring overnight, the reaction mixture was made basic by the addition of 1N solution of NaOH, and the product was extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was stirred with 1.0 M solution of NaOH (2 mL, 2 mmol) and THF (2 mL) for 1.5 hours. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 18%). LCMS (M+H)+: 424.2.