Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>ClCCl>[N:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Cn1ccnc1)OCc1ccccc1
Yield: 89.6 %

Procedure:
A solution of 1.4 g (21 mmol) of imidazole and 1.0 ml (6.3 mmol) of benzyl 2-bromoacetate in 40 ml of dichloromethane was stirred at ambient temperature for 16 h. The resulting solution was washed with water, dried over Na2SO4, and concentrated in vacuo. Silica gel chromotography of the residue using 5% methanol in chloroform provided 1.22 g (89%) of the desired compound as an oil. 1H NMR (CDCl3) δ 4.73 (s, 2H), 5.21 (s, 2 H), 6.96 (t, J=1 Hz, 1H), 7.11 (t, J=1 Hz, 1H), 7.36 (m, 5H), 7.51 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.O.[C:23](OCC(Cl)(Cl)Cl)(=[O:26])[CH2:24][CH3:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:23](=[O:26])[CH2:24][CH3:25])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCC(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
2-Amino-6-methoxy-9-(β-D-arabinofuranosyl)-9H-purine (1.0 g, 3.3 mmol) (prepared as described in European Patent Application No. 294 114) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2 ml of trichloroethyl propionate (Trichloroethyl propionate was synthesized by addition of 19 ml of propionyl chloride (Aldrich) over 30 minutes to 19.1 ml of trichlorethanol (Aldrich) in 40 ml of pyridine at 0° C.). The product was purified by successive washing with 2×100 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H-NMR (200 MHz, CDCl3, 4.74 (s, 2H, Cl3CH2-), 2.49 (q, 2H, J=7.6 Hz, CH3CH2CO2-), 1.21 (t, 3H, J=7.6 Hz, CH3CH2 CO2-). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot No. 38F-0356), which had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 23 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (9:1) as eluant. Product fractions were pooled and lyophilized from water to yield 0.76 g of the desired product as a white powder: m.p. 124° C.; TLC Rf =0.43 (silica gel; CH2Cl2 :CH3OH (9:1); UVλmax (ε, mM-1 cm-1) at pH 7.0, 278 nm (9.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[O:20]=[C:21]1[CH:25]([C:26](O)=[O:27])[CH2:24][CH2:23][NH:22]1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:25]2[CH2:24][CH2:23][NH:22][C:21]2=[O:20])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(O)C1CCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1NCCC1C(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 150.0 mg, 0.388 mmol), 2-oxopyrrolidine-3-carboxylic acid (100.3 mg, 0.777 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (223.4 mg, 1.17 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (157.5 mg, 1.17 mmol), N-ethyl-N-isopropylpropan-2-amine (0.347 ml, 1.94 mmol) and THF (100 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/Hexane from 1/4 to 4/1, v/v) to afford product (85.0 mg, 44%). LRMS (APCI pos): >97% purity, 254 nm, m/e 498 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15]([OH:17])=[O:16].[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([O:16][C:15]([C:3]2[C:2]([CH3:18])([CH3:1])[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[CH:7]=[CH:6][C:5]=3[N:4]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)C(C(=O)O)=Nc2ccc3ccccc3c21
Reactant: Oc1ccccc1
Solvent: ClCCl
Product: CC1(C)C(C(=O)Oc2ccccc2)=Nc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.8 %

Procedure:
200 mg of 1,1-dimethyl-1H-benzo[e]indole-2-carboxylic acid 3 (0.84 mmol) and 395 mg (4.2 mmol) phenol were dissolved in 50 mL methylene chloride. Then 188 μL (1.12 mmol) trifluorosulfonic acid anhydride were added and the reaction mixture was stirred at room temperature for 5 hours. After evaporation of the solvent under reduced pressure, the residue was taken up in methylene chloride and washed with 0.1 N NaOH and water. The organic phase was separated, dried over sodium sulfate and filtered. The solvent was removed under vacuum and the crude product was purified by preparative HPLC column chromatography (eluent: water-acetonitrile). The appropriate fractions were combined and dried by lyophilization to yield 7.5 mg of product 4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.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:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-aniline (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 48 mg.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.ClS(O)(=O)=O.Cl>O>[CH:11]1[C:12]([S:15]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:17])=[O:16])=[CH:13][CH:14]=[C:9]([I:8])[CH:10]=1
Reactant: Ic1ccccc1
Reactant: O=S(=O)(O)c1ccc(I)cc1
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(c1ccc(I)cc1)c1ccc(I)cc1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To 204 g (1 mole) of iodobenzene was added 312 g (1.1 moles) of 4-iodobenzenesulfonic acid and the mixture was cooled with water while 123 g of (1.1 moles) of chlorosulfonic acid was added thereto at about 10° to about 20° C. over a period of 1 hour. After the addition, the reaction system was stirred for 3 hours while being maintained at 20° to 30° C. The hydrochloric acid gas evolved during the reaction was continuously removed from the reaction system. After the completion of the reaction, about 400 ml of water was added to the reaction mixture and 20 g of (0.1 mole) of the unreacted iodobenzene was was recovered by distillation. Separation of the precipitate by filtration gave 123 g of 4,4'-diiododiphenylsulfone in 58% yield. M.P. 201° to 202° C. Purity of 99.6%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[H-].[Na+].[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36])[CH3:24])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(COC)OC>[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:36])=[O:37])[CH3:24])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)OCc1ccccc1)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Reaction time: 0.17 h
Yield: 61 %

Procedure:
2-Amino-5-bromo-3-methoxypyrazine (0.3 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.15 g) in dimethoxyethane (5 ml). After 10 minutes, 5-(N-benzyloxycarbonyl-N-methylamino)-1-naphthalenesulphonyl chloride (0.6 g) in dimethoxyethane (2 ml) was added and stirring was continued for 2 hours. The mixture was poured into water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (25 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-(N-benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.50 g) as a white foam; 1H NMR (d6 -DHSO): 3.34 (s,3H), 3.90 (s,3H), 5.08 (br,2H), 6.95 (br,1H), 7.19 (br,2H), 7.22-7.56 (m,2H), 7.6-7.77 (m,3H), 7.79 (s,1H), 8.07 (d,1H), 8.37 (dd,1H), 8.80 (d,1H), 11.58 (br,1H); mass spectrum (+ve FAB, DMSO/NBA): 557(M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[NH:33][C:32]4=[O:37])=[CH:38][CH:39]=3)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 51 %

Procedure:
Following a procedure similar to that described in Example 40(f), 170 mg of 4'-(phenylsulfonylamino)-acetophenone were reacted with 197 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 170 mg of the title compound, melting at 213-215° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[CH:11][C:10]=1[CH3:20])[C:6]([OH:8])=O.[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[NH:22][NH2:23].C(N(CC)C(C)C)(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[CH:11][C:10]=1[CH3:20])[C:6]([NH:23][NH:22][C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:8]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(C)c(C(CCCCl)C(=O)O)cc1C(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1C(C)C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
5-Chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid (6.2 g), tert-butyl carbazate (4.1 g) and N,N-diisopropylethylamine (10.8 mL) were dissolved in dichloromethane (120 mL). Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (7.9 g) was added under ice-cooling. After addition of the reagent, the mixture was brought back to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate solution and tert-butyl methyl ether were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.1 g). The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=3)=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:37][CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:40]([O:39][CH2:38][CH2:37][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:17]1[C:16]1[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)[nH]c2c1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)n(CCOCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
To a suspension of NaH (14 mg of 60% dispersion in mineral oil, 0.354 mmol) in DMF (2 mL), methyl 2-(2-(benzyloxy)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (130 mg, 0.295 mmol) was added and the reaction mixture was stirred at rt for 15 min. Benzyl 2-bromoethyl ether (0.052 mL, 0.325 mmol) was then added, and the reaction mixture was stirred at rt overnight before being quenched by the addition of water. The resultant mixture was extracted with ethyl acetate (2×20 mL) and the organic layers were combined, washed with 1N HCl solution, and then dried (MgSO4), filtered and concentrated under vacuum. The residue was then purified by Prep. reverse phase HPLC to give the title compound as light yellow solid (83.5 mg, 49% yield). MS m/z 575(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 1.21-1.31 (m, 3 H) 1.69-1.90 (m, 7 H) 2.53 (m, 1 H) 3.65 (m, 1 H) 3.72 (m, 1 H) 3.92 (s, 3 H) 4.17 (m, 1 H) 4.27 (m, 1 H) 4.32 (s, 2 H) 5.21 (s, 2 H) 6.18 (t, J=6.87 Hz, 1 H) 7.07-7.12 (m, 2 H) 7.21-7.36 (m, 9 H) 7.41 (dd, J=6.71, 2.14 Hz, 1 H) 7.74 (dd, J=8.54, 1.22 Hz 1 H) 7.78 (m, J=8.55 Hz, 1 H) 8.12 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH3:11])=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.N.[H][H]>CO.[Pt]>[N:12]1([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: [H][H]
Reactant: CC(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Agent: [Pt]
Agent: N
Solvent: CO
Solvent: c1ccsc1
Product: CC(c1ccc(N)cc1)n1ccnc1
Yield: 91.3 %

Procedure:
(a-3) A mixture of 34.4 parts of 1-[1-(4-nitrophenyl)ethyl]-1H-imidazole, 2 parts of a solution of thiophene in methanol 4%, 200 parts of methanol and 200 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 4 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane (2:1 by volume). The product was filtered off and dried, yielding 27 parts (91.3%) of 4-[1-(1H-imidazol-1-yl)ethyl]benzenamine; mp. 130° C. (int. 114).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])(OCC)(SCC)=[S:11]>Cl.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH2:9])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: CCOP([O-])(=S)SCC
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)Cc1ccccc1
Yield: 55 %

Procedure:
A solution of phenylacetonitrile (10.0 g, 85.4 mmol) and diethyl dithiophosphate (17.5 g, 93.9 mmol) in 4N-HCl/ethyl acetate (400 mL) was stirred at room temperature for 16 hours. This reaction mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 7.1 g of the title compound. Yield 55%.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.N=C=N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)CCN6CCCCC6)CC5)cc34)ccc21
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (155.3 mg, 0.3381 mmol, 1 eq), 1-piperidinepropanoic acid (150.1 mg, 0.9548 mmol, 2.8 eq), 1-hydroxybenzotriazole (HOBt) (46.7 mg, 0.346 mmol, 1 eq), and PS-carbodiimide (1.37 mmol/g loading; 1008.7 mg, 1.38 mmol, 4 eq) in anhydrous DMF (10 mL), DiPEA (290 μL, 1.7 mmol, 5 eq) was added and was shaken at rt for 13 h. The resin was filtered off and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 42° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 5%→10% →7N NH3(MeOH):DCM 3%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.30-1.40 (mc, 2H), 1.45-1.53 (mc, 4H), 2.30-2.41 (s, br, 4H), 2.41-2.63 (m, 6H), 3.69 (t, J=5.6 Hz, 2H), 4.03 (s, 3H), 4.23 & 4.13 (s, br, rotamers, 2H), 6.41 (s, br, 1H), 6.75 & 6.77 (s, br, rotamers, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.38 & 8.39 (s, br, rotamers, 1H), 9.34 (s, —NH), 11.90 & 11.93 (s, rotamers, 1H). MS (ES+): m/z 485.11 (45) [MH+]. HPLC: tR=1.72 min (ZQ2000, polar—5 min).
Reaction SMILES: C[O:2][C:3]1[C:8]([C@@:9]2([CH3:15])[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:7][CH:6]=[C:5]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH:20]=[CH:19]3)[N:4]=1.C([S-])CC.[Na+].CN(C=O)C>CCO>[CH3:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:5]3[NH:4][C:3](=[O:2])[C:8]([C@@:9]4([CH3:15])[CH2:13][CH2:12][NH:11][C:10]4=[O:14])=[CH:7][CH:6]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: COc1nc(-c2ccc3c(ccn3C)c2)ccc1[C@@]1(C)CCNC1=O
Agent: CCC[S-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-c3ccc([C@@]4(C)CCNC4=O)c(=O)[nH]3)ccc21
Temperature: 110 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
To a flask was added (R)-3-(2-methoxy-6-(1-methyl-1H-indol-5-yl)pyridin-3-yl)-3-methylpyrrolidin-2-one (534 mg, 1.59 mmol), sodium n-propanethiolate (1287 mg, 13.11 mmol), and DMF (9.5 mL). The mixture was stirred for 17 h at 110° C. Due to incomplete reaction, additional sodium n-propanethiolate (667 mg) was added. The reaction was stirred for 30 h at 110° C. The mixture was diluted with EtOH, concentrated and partitioned between 15% EtOH/DCM and pH 7 phosphate buffer. The aqueous phase was extracted 2× and the combined organic layers were dried over Na2SO4 to provide a crude product. Purification by slurrying at r.t. overnight (3.3 mL EtOAc/0.33 mL EtOH) followed by filtration, wash with EtOAc several times and dried under reduced pressure for 3 days at 60-80° C. provided (R)-6-(1-methyl-1H-indol-5-yl)-3-(3-methyl-2-oxopyrrolidin-3-yl)pyridin-2(1H)-one (495 mg, 97%) as a yellow solid. 1H NMR (600 MHz, methanol-d4) δ: 1.54 (s, 3H), 1.91-1.98 (m, 1H), 2.68-2.79 (m, 1H), 3.48 (dd, 2H), 3.85 (s, 3H), 6.55 (d, 1H), 6.62 (d, 1H), 7.26 (d, 1H), 7.47 (dd, 1H), 7.49-7.51 (m, 1H), 7.63 (d, 1H), 7.89 (d, 1H); MS (ES+)(M+H) 322.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)[S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Product: CN([C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1)S(C)(=O)=O

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 28 in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([C:15]2[O:16][C:17](=O)[CH2:18][N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:15]([NH:19][CH2:18][C:17]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)(=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CN=C(c2ccccc2)O1
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCc1nc2ccccc2s1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
2-Aminothiophenol (1.2 ml) is added to a solution of 2-phenyl-4,5-dihydro-1,3-oxazol-5-one (1.8 g) in acetic acid (14 ml), and the mixture is stirred for one hour while heating it at 40° C. Water is added to the reaction mixture, and the resulting precipitate is filtered off to give 2-(benzoylaminomethyl)benzothiazole (0.75 g) as crystals.