Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:12]1[CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4][CH:3]1[N:2]([CH3:1])[C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: CNC1CCN2CCc3ccccc3C2C1
Reactant: O=C=Nc1ccccc1
Product: CN(C(=O)Nc1ccccc1)C1CCN2CCc3ccccc3C2C1

Procedure:
By a procedure analogous to that of Example 1, 2-methylamino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (J. Med. Chem., 1972, 15, 91) is reacted with phenyl isocyanate to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:21][O:20][CH2:19][C:18]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][C:9]=2[CH:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COCc1c(C(=O)O)ncc2[nH]c3c(c12)CCCC3
Yield: 96.3 %

Procedure:
1.15 g of 5,6,7,8-tetrahydro-4-methoxymethyl-betacarboline-3-carboxylic acid ethyl ester is refluxed in 45 ml of ethanol with 5 ml of 2N aqueous potassium hydroxide solution for 2 hours. After cooling, it is acidified with glacial acetic acid. The precipitated product is suctioned off; the mother liquor is concentrated to approximately 30 ml. The precipitated product is again suctioned off. 1 g of 5,6,7,8-tetrahydro-4-methoxymethyl-beta-carboline-3carboxylic acid with a melting point greater than 260° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[N:21][CH:22]=2)[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Reactant: O=C(O)c1ccc(CBr)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (1.0 mmol) was used in general procedure 2 with 6-(bromomethyl)nicotinic acid (21.1 mmol) to give N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)-nicotinamide. MS (Q1) 444.0 (M)+
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[C:21](O)=[O:22].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]([NH:14][CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:16])[CH3:15])[CH:8]=2)=[O:22])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 8; 5.80 g, 24.5 mmol) in dry dichloromethane (20 mL) was added to a cooled (0° C.) suspension of 3,5-dichloro-4-hydroxybenzoic acid (4.2 g, 20.4 mmol) and BOP reagent (9.80 g, 22.3 mmol) in dry dichloromethane (50 mL). Diisopropylethylamine (10.6 mL, 60.9 mmol) was added slowly, and the cooling bath was removed. The solution was stirred at room temperature for 5 h, then the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 1 M HCl (2×100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), and brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 87%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:17]([CH:18]=2)[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[C].[Pd].C1(C)C=C(C)C=C(C)C=1>[C:1]1([C:7]2[N:8]=[C:9]3[N:17]([CH:18]=2)[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cn3c4c(sc3n2)CNCC4)cc1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Product: c1ccc(-c2cn3c(n2)sc2cnccc23)cc1
Yield: 53.8 %

Procedure:
A mixture of 5.1 g of 2-phenyl-5,6,7,8-tetrahydroimidazo[2',1':2,3]thiazolo[5,4-c]pyridine, 10 g of 10% palladium carbon and 150 ml of mesitylene was refluxed with heating for 19 hours. After the catalyst was filtered off, the solvent was distilled off. To the residue was added n-hexane and crystals were filtered off. The crude crystals were recrystallized from ethyl acetate to give 2.7 g of 2-phenylimidazo[2',1':2,3]thiazolo[5,4-c]pyridine, melting at 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 23.3 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (22.0 mg, 0.055 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (17 mg, 0.066 mmol) and sodium carbonate (58 mg, 0.55 mmol), to obtain 6 mg of the title compound (23%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]([CH3:9])[C:7]([C:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:6]([O:24]CC2C=CC(OC)=CC=2)[C:5](=[O:34])[CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl.O>[OH:24][C:6]1[C:5](=[O:34])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH3:9])[C:7]=1[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: COc1ccc(COc2c(-c3c[nH]c4c(CC=C(C)C)cccc34)n(C)c(CO)cc2=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCc1cccc2c(-c3c(O)c(=O)cc(CO)n3C)c[nH]c12
Reaction time: 2 h

Procedure:
To a stirring solution of 213 (75 mg, 0.16 mmol) in dichloromethane (1.5 mL) and water (88 μL) was added DDQ (38 mg, 0.17 mmol) at 0° C. After the cold bath was removed, the mixture was stirred for 2 h. The DDQH2 was removed by filtration and washed with EtOAc. The solution was washed with water and brine. The organic layer was dried over Na2SO4 and the solvent removed under vacuum. After flash column chromatography, the desired product was obtained as a yellow solid (45 mg, 81%). Mp: 215° C. (dec). 1H NMR (CDCl3): δ 1.65 (3H, s), 1.74 (3H, s), 2.49 (3H, s), 3.71 (2H, d, J=6.6 Hz), 4.67 (2H, s), 5.29 (1H, m), 5.67 (1H, s), 7.3-7.4 (2H, m), 7.81 (1H, m), 8.31 (1H, m). 13C NMR (CDCl3): δ 28.4, 30.9, 33.3, 34.7, 61.7, 109.7, 119.2, 123.5, 123.7, 125.0, 126.4, 127.6, 129.2, 129.9, 130.6, 133.8, 134.5, 137.7, 149.6, 160.5, 176.2. IR (KBr): 3360, 3197, 2971, 2856, 1604, 1552, 1298, 984 cm−1. HRMS (EI): m/z Calcd. C20H22N2O3 for [M+]338.1630. found 338.1632.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21]C)=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:23])[C:18]([O:20][CH3:21])=[O:19])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) were dissolved in methylene chloride (26 ml), ethyl chlorooxoacetate (1.10 ml) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1). The thus-obtained pale yellow solids were dissolved in methanol (20 ml), and the solution was stirred at 50° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and crystals deposited were collected by filtration and dried to obtain the title compound (0.43 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:8]([O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:8]([O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCCCCn1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
1.1 equivalents of 5-bromovaleronitrile are added to 40 mmol of 3-indolecarboxylic acid benzyl ester dissolved in tetrahydrofuran. After cooling to 0° C., 1.8 g of sodium hydride are added portionwise. After one hour of reaction at 0° C. and 14 hours at room temperature, ethyl acetate and water are added. The organic phase is separated and washed several times in succession with an aqueous phase containing hydrochloric acid followed by a basic aqueous phase. After drying and evaporation, the residue is purified by chromatography on silica gel using an ethyl acetate/pentane (2:3) mixture as solvent, and the expected product is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:27][CH2:26][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:4]6[S:5][CH:6]=[CH:7][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:30][CH2:29]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cc1ccsc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5sccc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-methylthiophen-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B96) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (4 ml) in the presence of DIPEA (0.28 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography as a solid.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH2:19]>O1CCCC1.[Zn]>[Cl:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH2:19]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Acetic acid (13 mL) was added slowly to a mixture of zinc dust (12.4 g) and 2-chloro-4-nitro-6-trifluoromethyl-phenylamine (4 g) in tetrahydrofuran (40 mL). The reaction mixture was stirred for 1 hour, filtered through silica and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 2.9 g (83%) of the title compound as a black solid. 1H NMR (500 MHz, CDCl3): 3.44 (b, 2H), 4.16 (b, 2H), 6.77 (d, 1H), 6.86 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Commercially available 4-methoxybenzenesulfonylchloride (Aldrich; 25 g, 0.12 moles) is added portionwise to a solution of decylamine (Kodak; 19 g, 0.12 moles) in pyridine (75 mL). The heterogeneous reaction mixture is stirred overnight at room temperature and poured into dilute HCl/ice water (1.5 L). After stirring 30 minutes, the light orange solid is isolated by filtration, washed with water and air dried. Recrystallization from ethanol (Norite) affords 26.3 g (66% yield) of the desired product as golden platelets, mp 53°-54.5° C. NMR (CDCl3) d 0.8-0.95 (t, 3H's); 1.1-1.6 (m, 16H's); 2.8-3.0 (t, 2H's); 3.9 (s, 3H's); 6.95-7.0 (d, 2H's); 7.75-7.85 (d, 2H's).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22](=[O:23])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CC(C)N(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 29.3 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.154 g, 0.63 mmol), 1-(2,5-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-isopropyl-urea (1.0 mmol), glacial acetic acid (0.036 g, 0.63 mmol) and sodium cyanoborohydride (0.039 g, 0.63 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.131 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]2[CH2:14][CH2:13][CH2:12][C:5]=2[N:6]([CH2:8][C:9]([OH:11])=O)[N:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:63]3[CH2:62][CH2:61][CH2:60][NH:59][C:58]=3[CH:57]=[N:56]2)=[CH:51][CH:50]=1>CN(C=O)C.O>[F:48][C:49]1[CH:50]=[CH:51][C:52]([N:55]2[C:63]3[CH2:62][CH2:61][CH2:60][N:59]([C:9](=[O:11])[CH2:8][N:6]4[C:5]5[CH2:12][CH2:13][CH2:14][C:4]=5[C:3]([C:2]([F:1])([F:16])[F:15])=[N:7]4)[C:58]=3[CH:57]=[N:56]2)=[CH:53][CH:54]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCC2
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution 2-[3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-1-yl]acetic acid (83 mg, 0.35 mmol) in DMF (2 mL) was added Et3N (75 μL, 0.525 mmol), HATU (160 mg, 0.42 mmol), followed by 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (77 mg, 0.35 mmol) at room temperature. The resulting solution was then stirred at 50° C. for 30 min. The reaction mixture was then cooled to room temperature, H2O (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white powder (0.011 g, 0.025 mmol, 7%). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.6 (m, 2H), 7.35 (t, 2H, J=8.6, 17.6 Hz), 5.38 (s, 2H), 3.77 (m, 2H), 2.85 (t, 2H, J=6.3, 12.5 Hz), 2.66 (m, 4H), 2.53 (m, 2H), 1.97 (m, 2H); MS: (ES) m/z calculated for C21H19F4N5O [M+H]+ 434.2, found 434.1.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8].Br[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>O1CCCC1>[N+:7]([C:9]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8]
Reactant: [C-]#[N+]C(CC)C(=O)OC
Reactant: BrCc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+]C(CC)(Cc1cccs1)C(=O)OC
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A suspension of potassium tert.-butoxide (5.5 g) in tetrahydrofuran (50 ml) is cooled to -30° C., and a solution of methyl 2-isocyanobutyrate (5.5 g) in tetrahydrofuran (10 ml) is added dropwise to the suspension at -30° C. The mixture is stirred at the same temperature for 30 minutes and a solution of 2-bromomethylthiophene (6.9 g) in tetrahydrafuran (10 ml) is added dropwise to the mixture. The mixture is stirred at room temperature for 4 hours, adjusted to pH 7 with acetic acid and then concentrated under reduced pressure to remove solvent. The residue is dissolved in a mixture of ethyl acetate and water and the organic layer is collected therefrom. The organic layer is washed with an aqueous saturated sodium chloride solution, dried and concentrated to remove solvent. The residue is distilled under reduced pressure, whereby methyl 2-isocyano-2-(2-thienylmethyl)butyrate (7.7 g) is obtained as pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[NH:38]1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH:40]=[CH:39]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[C:3]5[C:2](=[CH:7][CH:6]=4)[NH:38][CH:39]=[CH:40]5)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc3[nH]ccc3c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (1H-indol-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=536, obsd.=536).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:22]([NH:24][NH2:25])=[O:23])[CH:3]=1.CN([CH:29]=[O:30])C>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:13]2)[CH:5]=[C:4]([CH:22]2[N:24]=[N:25][C:29](=[O:30])[O:23]2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(=O)NN)cc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N′-Carbonyldiimidazole (0.12 g, 0.82 mmol) was added to a solution of tert-butyl 1-[6-chloro-4-(hydrazinocarbonyl)pyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 49, 0.15 g, 0.41 mmol) in DMF (3 ml). The mixture was stirred at room temperature overnight and was purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to afford the title compound (0.125 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 0 °C
Yield: 40.9 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-chloropyridine (117 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-chloro-pyridin-2-yl)-propionamide (110 mg, 41%) as a yellow foam: EI-HRMS m/e calcd for C20H22Cl2N2O3S (M+) 440.0728, found 440.0728.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[CH3:26]O>>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:1]([O:3][CH3:26])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Product: COC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O

Procedure:
Hydrogen chloride gas was bubbled through a boiling mixture of 25.0 g. (0.075 mole) of 1-(3-carboxy-4-hydroxyphenyl) 2-phenyl-4,5,6,7-tetrahydroindole and 750 ml. of methanol for 2 hours. The mixture was heated under reflux for 18.5 hours, cooled and filtered to provide 19.6 g. (75%) of white solid. Recrystallization from methanol gave colorless crystals, m.p. 141°-142°.