Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][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)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 128 mg of (2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylacetic acid in 3 ml of dimethylformamide, 81 mg of carbonyldiimidazole was added and stirred for 30 minutes. Then 121 mg of 4-hydroxy-1-t-butoxycarbonylpiperidine and 10 mg of sodium hydride were added successively, followed by another 30 minutes' stirring. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to provide 121 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Cl)[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][O:18][C:17](=[O:19])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]([I:11])=[C:9]([NH:12][C:13](=[O:14])[CH3:15])[C:8]=1[I:16])[CH3:23]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To 175 mL of dry N,N-dimethylformamide (DMF) was added 63.6 g (0.100 mol) sodium diatrizoate and 14.7 g (0.120 mol) of ethylchloroacetate and the mixture was heated on a steam bath for 6 hr. The reaction was filtered while hot and the filtrate cooled to room temperature and diluted to 500 ml with water. The mixture was cooled and filtered and the collected solid washed with water. The solid was then dissolved in 350 ml hot DMF, filtered and added to an equal volume of water. The mixture was cooled, filtered, washed with water, and the solid dried at 100° C. overnight to afford 53.0 g (76% yield) of a white powder, mp 269.5°-270.5° C.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(-c2cc(C(=O)O)c(C)cc2C2CCC2)n[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)n[nH]1
Temperature: 30 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound 445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and 4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 30° C., and then diluted with 40 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (59.0% CH3CN up to 73.0% in 6 min, up to 100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 150 mg (72%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+.
Reaction SMILES: CN(C)[CH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[S:12](=C)[CH:11]=[N:10]3)[NH:5][C:4]1=[O:16].[CH2:18]([OH:20])[CH3:19]>C(OCC)C>[CH3:4][N:5]([C:6]1[CH:14]=[CH:13][C:9]([NH:10]/[CH:11]=[C:3]2\[C:4](=[O:16])[NH:5][C:6]3[C:14]\2=[C:13]2[S:12][CH:11]=[N:10][C:9]2=[CH:8][CH:7]=3)=[CH:8][CH:7]=1)[C:18](=[O:20])[CH3:19]
Reactant: C=S1C=Nc2ccc3c(c21)C(N(C)C)C(=O)N3
Reactant: CCO
Solvent: CCOCC
Product: CC(=O)N(C)c1ccc(N/C=C2\C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A mixture of 8-dimethylamino-methylene-6,8dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure E, 0.040 g, 0.163 mmol), 4-amino-N-methylacetanilide (0.040 g, 0.244 mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for 16 h. The reaction was diluted with ethanol and diethyl ether and the product collected by filtration to yield 0.038 g (64%) of the title compound. 1H NMR (DMSO-d6): δ 11.03 (d,1 H, J=12.3 Hz), 10.84 (s,1H), 9.23 (s,1H), 8.02 (d,1H, J=12.3 Hz), 7.78 (d,1H, J=8.4 Hz), 7.48 (d,2H, J=8.2 Hz), 7.35 (d,2H, J=8.2 Hz), 7.09 (d,1H, J=8.4 Hz), 3.11 (s,3H), 1.76 (s, 3H); ES-MS m/z 363 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:29]1([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:39][CH:38]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCCC2)cc1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: Clc1cccc(-c2ccc3cnc(Nc4ccc(N5CCCC5)cc4)nn23)c1
Yield: 16.1 %

Procedure:
7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004284 mol), N,N-Diisopropylethylamine (0.112 mL, 0.000643 mol) and 4-Pyrrolidin-1-yl-phenylamine (139 mg, 0.000857 mol) were dissolved in 2-Methoxyethanol (3.01 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 26.91 mg of [7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyrrolidin-1-yl-phenyl)-amine as a lyophilized powder. (M+H)=390.09. 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 7.84 (m, 1H), 7.76 (d, 2H, J=8.93 Hz), 7.48 (m, 2H), 7.34 (d, 2H, J=8.93 Hz), 7.21 (m, 1H), 7.18 (m, 1H), 3.66 (m, 4H), 2.25 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:14]([CH:15](C)C)=C(S([O-])(=O)=O)C=CC=2C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:14]([N:30]2[C:29](=[O:31])[C:28]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]3[C:26]2=[O:36])[CH3:15])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C(C)C)c1Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(COc1ccc([N+](=O)[O-])cc1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 77 g of 2-(4-nitrophenoxy)-1-methylethyl-p-toluenesulfonate, 45 g of potassium salt of phthalimide and N,N-dimethylformamide was heated at 110° C. for 3 hr. with stirring. The reaction mixture was extracted with ethyl acetate; the extract was washed consecutively with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure; the residue was dissolved in ethanol and left standing overnight in refrigirator. Crystals thus isolated were filtered off, dried, and yielded 38.5 g of N-{2-(4-nitrophenoxy)-1-methylethyl}phthalimide in crystalline form.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[OH-:29].[K+]>C(O)(C)(C)C>[F:15][C:13]1[CH:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[CH:19][CH:18]=2)[CH:10]=[C:9]([C:3]2([C:1]([NH2:2])=[O:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: [OH-]
Reactant: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C#N)CCOCC3)c2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Yield: 31.2 %

Procedure:
To a solution of 4-cyano-4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 25, 1.71 g, 4.36 mmol) in tert-butanol (20 ml) was added powdered potassium hydroxide (85%, 860 mg, 13 mmol). The resulting mixture was heated at reflux temperature for 4 h, cooled and concentrated in vacuo . Water (50 ml) was added and the precipitates were collected by filtration and washed with 50 ml of ethyl acetate. After drying in vacuo, 560 mg (31%) of the titled compound was obtained as a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]#[N:16])=[C:13]([S:17][CH3:18])[S:12][C:11]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35].O.Cl>C(Cl)Cl>[C:15]([C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH:37][CH:34]([CH3:36])[CH3:35])=[CH:5][CH:6]=2)=[C:11]([C:19]([OH:21])=[O:20])[S:12][C:13]=1[S:17][CH3:18])#[N:16]
Reactant: CSc1sc(C(=O)O)c(-c2ccc(C(=O)O)cc2)c1C#N
Reactant: CC(C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CSc1sc(C(=O)O)c(-c2ccc(C(=O)NC(C)C)cc2)c1C#N
Reaction time: 8 h
Yield: 27 %

Procedure:
Combine 3-(4-Carboxy-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (0.1 g, 1.0 eq) in CH2Cl2 (5.0 mL) and stir. Add carbonyldiimidazole (2.0 eq). Stir the mixture overnight. Add isopropylamine (1.0 eq) and stir overnight at room temperature. Add 1N HCl water solution. Filter the precipitate to provide the title compound (0.03 g, Yield 27%). MS (ES+, m/e): 361 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCCCCO)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 6-bromohexanol (1.28 g, 7.0 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 91%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
To a stirring solution of (2S)-2-hydroxy-4-methylvaleric acid (5.0 g) and benzyl bromide (4.95 ml) in DMF (50 ml) was added potassium carbonate (3.13 g) at room temperature. After being stirred for 12 hours, the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with water, 1N HCl and brine successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified with silica gel column chromatography (hexane-ethyl acetate as an eluent) to give benzyl (2S)-2-hydroxy-4-methylvalerate (8.2 g) as a colorless oil.
Reaction SMILES: [Na+].[C:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([S:16]([O-:19])(=O)=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].P(Cl)(Cl)([Cl:22])=O>CC(N(C)C)=O>[Cl:22][S:16]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:15]2)=[CH:10][CH:11]=1)(=[O:19])=[O:17]
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3.6 g (12.5 mmol) of compound 130 was added 100 mL of phosphorous oxychloride. Then, 4 mL of dimethylacetamide was added dropwise. The reaction was allowed to stir at ambient temperature for 5 hours and then was poured onto 2 L of ice. After the ice had melted, the solid precipitate was collected by vacuum filtration and was washed with water. After drying in vacuo, this provided 3.4 g of compound 131.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([Cl:16])[CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=O)C.O.[NH2:21][NH2:22]>C(O)C>[Cl:16][C:13]1[CH:12]=[C:11]([Cl:17])[C:10]([O:18][CH3:19])=[C:9]2[C:14]=1[CH:15]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:7]=[N:8]2
Reactant: NN
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1
Solvent: O
Solvent: CCO
Product: COc1c(Cl)cc(Cl)c2cc(C(=O)NN)cnc12
Yield: 79.5 %

Procedure:
A solution of 5,7-dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester 27 (404 mg, 1.35 mmol) and hydrazine monohydrate (1.0 g) in ethanol (10 ml) was heated under reflux for 5 hours. Upon cooling, a white crystalline solid was deposited. This was isolated via filtration, washed with ethanol, and dried, yielding the hydrazide 28 (307 mg, 80%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 10.32 (br, 1 H), 9.33 (d, J=2.4, 1 H), 8.89 (d, J=2.4, 1 H), 8.02 (s, 1 H), 4.66 (br, 2H), 4.06 (s, 3 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:30][CH:31](OC)OC)[C:12]([C:14]1[NH:15][CH:16]=[C:17]([C:19](=[O:29])[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])[CH:18]=1)=[O:13]>CC#N.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]1[CH:30]=[CH:31][C:18]2[C:17]([C:19](=[O:29])[C:20]3[C:21]([F:28])=[CH:22][C:23]([F:27])=[CH:24][C:25]=3[F:26])=[CH:16][NH:15][C:14]=2[C:12]1=[O:13]
Reactant: COC(CN(Cc1nc2ccccc2[nH]1)C(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1)OC
Solvent: CC#N
Solvent: O
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ccccc4[nH]3)ccc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A methanesulofonic acid 1.5 mL solution of the product from Step B (910 mg, 1.87 mmol) was stirred at 95° C. in an oil bath for 25 min. The reaction mixture was cooled to room temperature, diluted with MeCN—H2O (2:3) mixture (3 mL). The resulting solution was purified by reverse phase HPLC (C-18 column) (eluent: gradient mixture of acetonitrile-water with 0.5% TFA) to give the title compound (414 mg). LC/MS: m/z 423(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.59 (s, 2H), 7.06 (d, 1H), 7.35-7.39 (m, 4H), 7.61-7.68 (m, 3H), 7.93 (d, 1H), 13.14 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]=[O:33])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.05 g (5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea is dissolved under argon in 46 ml of chloroform. Then 3.5 g of silica gel and, under vigorous agitation, dropwise 3.5 ml of water are added. During a time period of 30 minutes, a solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform is added drop by drop. After stirring for 3 hours at room temperature, 7.5 g of potassium carbonate is added and the mixture is vigorously stirred for 20 minutes. The precipitate is filtered off and washed with chloroform. The precipitate is moistened with ethanol and introduced into 300 ml of saturated sodium chloride solution which is then repeatedly extracted with chloroform. The chloroform extracts and the chloroform filtrate are jointly dried over magnesium sulfate and evaporated. The subsequent crystallization is performed from ethyl acetate, thus isolating 0.93 g of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (54% yield).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](=[NH:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:23]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
In a 50-mL round-bottom flask equipped with a water-jacketed condensor and magnetic stirring bar, a mixture of t-butyl chloroacetate (10 g, 66.4 mmole), benzophenone imine (8.02 g, 44.3 mmole), and anhydrous potassium carbonate (9.18 g, 66.4 mmole) was stirred overnight at 110° C. Using a course Buchner funnel, the solid inorganic salts were removed from the solution by filtration and the solids were washed with ethyl acetate (2×25 mL). The combined filtrates were diluted with ethyl acetate to a total volume of 100 mL. The organic mixture was washed with water (3×100 mL), dried (Na2SO4), filtered, and the solvent was removed in vacuo. The crude residue was recrystallized with hexanes to afford white crystals (5.24 g, 40%): m.p. 114–115° C. (Lit. m.p. 111–112° C.).3 1H-NMR (CDCl3) δ 1.46 (s, 9H), 4.12 (s, 2H), 7.18 (m, 2H), 7.34 (m, 3H), 7.45 (m, 3H), 7.66 (m, 2H). 13C-NMR (CDCl3) δ 28.13, 56.37, 80.99, 127.74, 128.01, 128.27, 128.61, 128.73, 128.76, 130.05, 130.34, 132.39, 136.25, 139.45, 169.82, 171.48
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[N:14]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound C8) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B8*HCl)
Reaction SMILES: C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Reactant: CCCCc1ncc(CN)n1Cc1ccc(C(=O)OC)c(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 μL, 1.0 mmol) and added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H+] calcd for C22H29F2N3O3S, 454.19. found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=O)[CH3:13]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[C:12]([CH3:13])[C:11]2([CH3:15])[CH3:10]
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(Br)cc1
Product: CC1=Nc2ccc(Br)cc2C1(C)C
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a 500 mL flask were added p-bromophenylhydrazine 1 (50.3 g, 0.27 mol) glacial acetic acid (300 mL) and 3-methylbutanone (40 mL, 0.37 mol). The mixture was heated at reflux for 4 h and then cooled to rt. The volatile components were removed in vacuo and the residue was partitioned between petroleum ether (350 mL) and water (100 mL). The aqueous phase was washed again with petroleum ether (2×100 mL). The combined organic solutions were dried (MgSO4) and filtered and the solvent was evaporated in vacuo to afford 5-bromo-2,3,3-trimethyl-3H-indole 2 (56.3 g, 87%).