Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15]NCC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:6]=1.CC[N:27]([CH2:30][CH3:31])CC.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:24])[CH2:15][CH:33]3[CH2:34][O:35][CH2:36][CH2:37][N:32]3[C:38]([NH:27][CH2:30][C:31]3[CH:9]=[CH:8][CH:7]=[CH:5][CH:4]=3)=[O:39])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1nc(-c2ccc(NC(=O)CC3COCCN3C(=O)NCc3ccccc3)cc2)cs1
Reaction time: 0.5 h
Yield: 136.6 %

Procedure:
To a cooled (0°) suspension of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)amino}acetamide (1.02 g, 3.00 mmol, described in example 2) in CH2Cl2 (30 mL) and Et3N (836 μL, 6.00 mmol), were added DMAP (36.6 mg, 0.30 mmol) and 4-morpholinecarbonyl chloride (350 μL, 3.00 mmol). The reaction mixture was stirred at 0° for 30 min, and then at room temperature for 18 h. The reaction mixture was then dissolved in EtOAc (300 mL). The resulting solution was washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), then dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc) to afford the title compound (925 mg, 68% yield) as a white solid: M.p. 105° (decomp.); 1H NMR (400 MHz, DMSO-d6) δ9.94 (s,1H), 7.71 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.25-7.39 (m, 5H), 6.99 (s, 2H), 6.88 (s, 1H), 4.47 (s, 2H), 3.84 (s, 2H), 3.59 (t, J=4.9 Hz, 4H), 3.19 (t, J=4.9 Hz, 4H); MS (FAB) m/z 452 (MH)+; Anal. Calcd for C23H25N5SO3: C, 61.18; H, 5.58; N, 15.51. Found: C, 60.61; H, 5.60; N, 15.35.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:13]1O[CH:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([OH:25])(C)C>O1CCCC1.CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)O
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCCc2ccccc2O)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
N-Acetyl-4-hydroxypiperidine (5.0 g.) in tetrahydrofuran (THF) (50 ml.) was added to a stirred suspension of sodium hydride (1.84 g., 50% dispersion in mineral oil) in tetrahydrofuran (THF) (25 ml.) under an atmosphere of nitrogen. When effervescence had ceased, styrene oxide (4.6 g.) in THF (25 ml.) was added, then the reaction mixture was diluted with dimethylformamide (DMF) (25 ml.) and stirred at 60° C. for 18 hours. After addition of isopropanol to the cooled solution, the solvent was removed in vacuo, the residue treated with water, adjusted to pH 4 with 2 N hydrochloric acid, and extracted with chloroform. The chloroform extract was dried (Na2SO4) and the solvent evaporated in vacuo to give N-acetyl-4(2-hydroxyphenethyloxy)piperidine. This product in ethanol (50 ml.) and 5 N sodium hydroxide solution (100 ml.) was heated under reflux for 3 hours. The solvent was then removed in vacuo, the residue taken up in water, extracted with chloroform, dried and the solvent evaporated in vacuo. The product in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and evaporation of the solvent.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:17]3[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[CH:26]=4)=[O:24])[CH:18]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Br
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 9 was prepared using using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-2-(1-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]#[N:11].C1C=[CH:14][C:15]2[C:21](C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)[C:16]=2C=1>[OH-].[Na+].C(O)C.O>[C:15]([C:4]1[CH:5]=[CH:6][C:1]([S:7][CH2:9][C:10]#[N:11])=[CH:2][CH:3]=1)([CH3:21])([CH3:16])[CH3:14]
Reactant: N#CCCl
Reactant: Sc1ccccc1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(SCC#N)cc1

Procedure:
The substituted phenylthioacetonitrile starting materials can be prepared by the reaction of the corresponding thiophenol with chloroacetonitrile in alcoholic sodium hydroxide. In a representative procedure, a solution of 100 grams of 4-tert-butylthiophenyl and 45.3 grams chloroacetonitrile in 225 milliliters of 95 percent ethanol is stirred at room temperature while a solution of 24 grams sodium hydroxide in 36 milliliters water is added dropwise until the mixture remains alkaline to phenolphthalein. Slight spontaneous warming occurs during the addition. The mixture is then diluted with an equal volume of water and extracted twice with ether. The ether extract is washed with water, dried over sodium sulfate, and distilled, yielding the 2-(4-tert-butylphenylthio)acetonitrile as a liquid boiling at 153°-6°C. under a pressure of 4 millimeters of mercury.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[N:6]1[C:5]2[CH:9]=[CH:10][C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:3][C:4]=2[NH:8][N:7]=1.[ClH:45].[N:6]1[C:5]2[CH:9]=[CH:10][C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:3][C:4]=2[NH:8][N:7]=1
Reactant: ClCCCl
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Nc1ccc2[nH]nnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3nn[nH]c3c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
268 mg 5-Aminobenzotriazole and 435 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 135 mg of the nonpolar diastereomer of N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.54 ml) in 2-butanone (5 ml) (98 mg; m.p. 168-173° C.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:8][CH2:7]2)=[O:10])=[CH:14][CH:15]=1
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-fluoro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.10 g, 0.38 mmol), 2-chloro-5-fluoro-pyrimidine (0.05 g, 0.38 mmol) and triethylamine (0.11 mL, 0.75 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S. (M+1): 363.31
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH2:3]1.C1N=CN([C:25]([N:27]2[CH:31]=N[CH:29]=[CH:28]2)=[O:26])C=1.Cl.[F:33][C:34]1([F:40])CCNC[CH2:35]1>N1C=CC=CC=1>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:25]([N:27]3[CH2:28][CH2:29][C:34]([F:40])([F:33])[CH2:35][CH2:31]3)=[O:26])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: FC1(F)CCNCC1
Reactant: c1cc2c(ncc3cnc([C@@H]4CCCNC4)n32)[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N1CCC(F)(F)CC1)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.24 g, 0.76 mmol) in pyridine (7.2 mL) was added CDI (0.14 g, 0.87 mmol) and the reaction mixture was stirred at about 50° C. for about 2 h. Additional CDI (0.02 g, 0.14 mmol) was added and the reaction mixture was stirred for about 1 h. To the reaction mixture was added 4,4-difluoropiperidine hydrochloride (0.12 g, 0.76 mmol). The reaction mixture was heated to about 55° C. for about 1 h, cooled to ambient temperature, and stirred for about 2 d. The solvent was removed under reduced pressure and the crude residue dissolved with DCM (5 mL) and washed with water (2 mL). The aqueous layer was back extracted with DCM (2 mL). The combined organic extracts were washed with brine (3 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidin-1-yl)(4,4-difluoropiperidin-1-yl)methanone (0.146 g, 49%) as an off white solid: LC/MS (Table 1, Method b) Rt=1.70 min; MS m/z: 389 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[CH3:14][C:15]([CH3:17])=[O:16].[OH2:18]>C(O)(=O)C.Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](/[CH:6]=[CH:9]/[C:10](=[O:18])/[CH:3]=[CH:4]/[C:5]2[CH:6]=[CH:17][C:15]([OH:16])=[C:14]([C:2]([F:1])([F:12])[F:13])[CH:8]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: O=Cc1ccc(O)c(C(F)(F)F)c1
Reactant: O
Reactant: CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(O)c(C(F)(F)F)c1)/C=C/c1ccc(O)c(C(F)(F)F)c1
Temperature: 27.5 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
A mixture of 3-(trifluoromethyl)-4-hydroxybenzaldehyde (2.19 g, 12 mmol) in acetone (423 μL, 5.8 mmol) was dissolved in glacial acetic acid (9 mL), saturated with anhydrous HCl and heated to 25-30° C. for 2 h. The red solution was stirred for 36 h and treated with cold water. The reaction mixture turned into a dark green suspension and the resulting precipitate was filtered, washed with water and dried in vacuo to afford NW310.1 as a dark green solid (740 mg, 32%). mp: 233-234° C. 1H NMR (250 MHz, CD3OD) δ (ppm): 7.86 (d, 4J=1.6 Hz, 2H, HAr), 7.80 (d, 3J=8.8 Hz, 4J=1.9 Hz, 2H, HAr), 7.75 (d, 3J=16.1 Hz, 2H, Hvin), 7.15 (d, 3, J=15.9 Hz, 2H, Hvin), 7.02 (d, 3J=8.6 Hz, 2H, HAr). 13C NMR (75 MHz, CD3OD) δ (ppm): 191.6 (C), 159.9 (C), 144.3 (CH), 134.8 (CH), 129.3 (CH), 127.8 (C), 127.3 (C), 125.3 (CH), 118.8 (CH). MS (FAB) m/z: 403.2 (M+). Anal. calcd for C19H12F6O3. 1H2O: C, 54.17; H, 3.59. Found: C, 54.39; H, 3.31%.
Reaction SMILES: C([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH2:6][C@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[C:31]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:39][C@@H:40]([CH3:44])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=1.[O:59]=[C:60]([CH3:66])[CH2:61][CH2:62][C:63]([OH:65])=[O:64].S(Cl)(Cl)=O.[Br:71][CH2:72][CH2:73][OH:74]>C1(C)C=CC=CC=1.CN(C)C=O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25]([O:74][CH2:73][CH2:72][Br:71])=[O:26])[CH2:6][C@@H:5]([CH3:29])[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1.[C:31]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:32]=[CH:33][C:34]([CH2:37][C@@H:38]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])[CH2:39][C@@H:40]([CH3:44])[C:41]([OH:43])=[O:42])=[CH:35][CH:36]=1.[Br:71][CH2:72][CH2:73][O:64][C:63](=[O:65])[CH2:62][CH2:61][C:60](=[O:59])[CH3:66]
Reactant: CC(=O)CCC(=O)O
Reactant: OCCBr
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)CCC(=O)OCCBr
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)OCCBr)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=Et) (5.5 g) is dissolved in toluene (33 ml) at room temperature. Dimethylformamide (0.1 ml) is added. Thionyl chloride (2.4 ml) is then added. The solution is cooled to 0° C. and 2-bromoethanol (0.94 ml) is added. The mixture is stirred at 0° C. for 2 h and then at room temperature for a further 1 h. A further portion of 2-bromoethanol (0.94 ml) is added and the mixture stirred for 0.5 h at room temperature. A further portion of 2-bromoethanol (0.94 ml) is then added and the resulting mixture stirred for 16 h at room temperature. The mixture is concentrated in vacuo to give the crude product. Purification by chromatography Heptane/EtOAc (2:1) gives (2R,4S)-5-Biphenyl-4-yl-4-[3-(2-bromoethoxycarbonyl)propionylamino]-2-methylpentanoic acid (3-a, R1=4-oxo-pentanoic acid 2-bromoethyl ester, R2=H, R3=Et). 1H NMR (DMSO): 1.07 (3H), 1.14 (3H), 1.41 (1H), 1.79 (1H), 2.37 (2H), 2.48 (1H), 2.50 (2H), 2.71 (2H), 3.66 (2H), 3.94 (1H), 3.99 (2H), 4.33 (2H), 7.25 (2H), 7.35 (1H), 7.46 (2H), 7.57 (2H), 7.64 (2H), 7.78 (1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(Cl)Cl.CCN(CC)CC>[CH2:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a stirred solution of 3-hydroxymethylpiperidine (1 g, 8.7 mmol) in CH2Cl2 (50 mL) and Et3N (1.12 mml) at 0° C. was added dropwise CbzCl (1.24 mL, 8.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography with hexane-EtOAc (2:1) to give a colorless oil (2 g, 94%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (m, 2H), 4.20-3.60 (m, 2H), 3.47 (m, 2H), 3.20-2.20 (m, 3H), 1.82-1.10 (m, 5H); 13C NMR (CDCl3) δ 155.55, 136.73, 128.38, 127.85, 127.69, 66.96, 64.31, 46.74, 44.71, 38.01, 26.77, 24.05.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:13].CN(CCN(C)C)C.[I:32]I>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:32])=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:6]2=[O:13]
Reactant: II
Reactant: COc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 84.6 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (300 mg, 0.904 mmol) was dissolved in THF (12 mL), and the solution was treated with TMEDA (0.30 mL, 2.0 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 2.0 mL, 2.0 mmol) and iodine (275 mg, 1.08 mmol), followed by purification by slurry using diisopropylether and hexane to obtain 4-chloro-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (350 mg, yield 85%).
Reaction SMILES: CC[O-].[Na+].[NH:5]([CH2:12][CH2:13][C:14]#[N:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH:29](O)CS(C)(=O)=O)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17].CS(C)=O>O>[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH2:29][C:13]([C:14]#[N:15])=[CH:12][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17]
Reactant: N#CCCNc1ccccc1
Reactant: CCOC(=O)Nc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC

Procedure:
A mixture of 4.42 g. of sodium ethylate, 5.1 g. of β-anilino-propionitrile and 10.0 g. of 4-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2,6-dimethoxy-carbanilic acid ethyl ester in 150 ml. of dimethylsulfoxide was stirred at 50° C. for 2 hours with the exclusion of moisture. The solution was poured into 1.5 liters of water and the resulting emulsion extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 500 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 800 g. of silica gel using methylene chloride/ethyl acetate (3:1) and there was obtained 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy-carbanilic acid ethyl ester having a melting point of 150°-151° C. (recrystallization from alcohol).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C@@H:15]1[CH2:19]OS(=O)(=O)[N:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:14][C@@H:15]([NH:16][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:19][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CN1CCc2c([nH]c3ccccc23)C1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of 1, 2, 3, 4-tetrahydro-9H-pyrido[3, 4-b]indole (1.7 g, 9.8 mmol) and (R)-4-methyl-3-(pyridin-2-yl)-[1, 2, 3]-oxathiazolidine-2, 2-dioxide (1.90 g, 8.9 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature for two hours. The dimethylformamide was removed under reduced pressure and the residue was dissolved in 15 ml of tetrahydrofuran plus 5 ml of water. Concentrated sulfuric acid (470 μl, 8.9 mmol) was added dropwise and the reaction stirred at room temperature for 30 minutes. Sodium bicarbonate (3.0 g, 35 mmol) is then added and the mixture stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The organic layer was separated. The aqueous layer was made basic with sodium bicarbonate and then extracted with ethyl acetate. The organic layers were combined, washed two times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.68 g (98%) of (R)-[1-methyl-2-(1, 3, 4, 9-tetrahydro-2H-pyrido [3, 4-b]indol-2-yl)-ethyl]-pyridin-2-yl-amine as a light yellow oil, MS [M+HI+ 307.
Reaction SMILES: BrC(=O)[CH:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:4][CH3:5].[NH2:18][C:19]([NH2:21])=[S:20].[CH2:22](O)C>>[NH2:18][C:19]1[S:20][C:4]([CH2:5][CH3:22])=[C:3]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[N:21]=1
Reactant: CCC(C(=O)Br)c1ccc2c(c1)CCC(=O)N2
Reactant: CCO
Reactant: NC(N)=S
Product: CCc1sc(N)nc1-c1ccc2c(c1)CCC(=O)N2
Reaction time: 0.5 h

Procedure:
A mixture of 6-(α-bromobutanoyl)-3,4-dihydrocarbostyril (7 g), thiourea (1.9 g) and absolute ethanol (250 ml) is stirred at reflux for 4 hours. The reaction mixture is cooled in an ice bath and the solid filtered, washed with ether, dried and suspended in aqueous sodium bicarbonate for 30 minutes. The neutralized solid is filtered, washed with water and isopropanol, and dried. The dried solid is suspended in boiling THF to which methane sulfonic acid is added. The resulting THF solution is concentrated and cooled in an ice bath resulting in the formation of a precipitate which is filtered, washed with ether, dried in vacuo and twice recrystallized from acetonitrile and isopropanol affording the desired product as the methane sulfonic salt, M.P. 221°-223° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21](C(Cl)=O)=[CH:20][CH:19]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[C:27]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]2[C:15]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:17])=[O:7])=[CH:31][CH:32]=1
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: COCCNC(=O)[C@@H]1CC(=CCl)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-methoxyethylamine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=399.6.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:19](=[O:26])[C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C(NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1ccncc1

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 was acylated with isonicotinoyl chloride following General Procedure K and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg) following General Procedure A to give 290. MS (Q1) 472 (M)+