Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=2)[C:23]([Cl:34])=[CH:22][N:21]=1>C(Cl)Cl>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([S:30]([NH:1][C:2]3([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)(=[O:32])=[O:31])[CH:28]=2)[C:23]([Cl:34])=[CH:22][N:21]=1
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCCC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
A mixture of methyl 1-aminocyclohexanecarboxylate (325 mg, 1.68 mmol), NEt3 (0.49 mL, 3.5 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (415 mg, 1.40 mmol) in CH2Cl2 (30 mL) was stirred at 23° C. for 16 h. The mixture was diluted with CH2Cl2, washed with dilute HCl (2 M), saturated aqueous NaHCO3, brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexane-EtOAc (80:20 to 70:30) as eluant, followed by trituration with i-Pr2O, to give to give methyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylate (132 mg, 0.32 mmol) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=O)(C)(C)C.[CH3:23][CH:24]([S:26]([C:29]1[CH:30]=[C:31]([C:35]2[N:43]3[C:38]([CH:39]=[N:40][C:41](O)=[N:42]3)=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25]>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([NH:21][C:41]2[N:40]=[CH:39][C:38]3=[CH:37][CH:36]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:30]=4)[N:43]3[N:42]=2)=[CH:20][C:15]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(N)ccc1Cl
Reactant: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@@H]5CCCN5)c4)nn23)c1

Procedure:
This example was prepared by using (S)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-[3-(Propane-2-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.35 (brs, 1H), 9.0 (s, 1H), 8.9 (brs, 1H), 8.5 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 7.8 (m, 2H), 7.5 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.8 Hz, 1H), 7 (d, J=4.8 Hz, 1H), 4.1 (m, 1H), 4.0 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.1 (d, J=6.5 Hz, 6H). LC/MS (ESI+): 526 (M+H).
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:28](=[O:29])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 14.85 g of 5-chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW=409.89; 1 eq.) in 145 mL toluene and 22 mL N-methylpyrrolidone were added 7.13 g (MW=162.15; 1.2 eq.) of 1,1′-carbonyldiimidazol. The reaction mixture was heated to 80° C. After stirring for 30 minutes the mixture was heated to 110° C. and stirred at this temperature for 2 hours. Then the mixture was cooled to 22° C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60 mL of toluene and 60 mL of water. The wet product was dried at 30° C. in vacuo to yield 15.99 g (MW=435.89; 1.013 eq.) of the title compound (90% of theory).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](/[C:38](=[CH:42]\[CH2:43][CH3:44])/[C:39]([OH:41])=O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:39](=[O:41])/[C:38](/[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:30])=[O:31])=[CH:37][CH:36]=1)=[CH:42]/[CH2:43][CH3:44]
Reactant: Nc1nccs1
Reactant: CC/C=C(/C(=O)O)c1ccc(S(C)(=O)=O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C(/C(=O)Nc1nccs1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.7 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (836 mg, 4.7 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid (703 mg, 2.76 mmol) in methylene chloride (5 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (829 mg, 8.28 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-(4-methanesulfonyl-phenyl)-pent-2-enoic acid thiazol-2-ylamide (150 mg, 16%) as crystalline solid: mp 155-158° C.; EI-HRMS m/e calcd for C15H16N2O3S2 (M+) 336.0602, found 336.0601.
Reaction SMILES: [NH2:1][CH:2]([CH:6]=[CH:7][CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl>C(O)CCCC>[CH2:3]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:2][CH2:6][CH2:7][CH3:8]
Reactant: NC(C=CCP(=O)(O)O)C(=O)O
Agent: Cl
Solvent: CCCCCO
Product: CCCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-pentanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 50°. After concentration, the residue is dissolved in 15 ml of n-pentanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160°-161°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([O:15][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
Under argon atmosphere, a solution of 955 mg of methyl (2S,3R)-3-(2,4-difluorophenyl)-2,3-dihydroxypropionate dissolved in 30 ml of dichloromethane was cooled to 0° C., and to the solution was added 940 mg of p-toluenesulfonyl chloride and 624 mg of triethylamine. After the mixture was stirred at 0° C. for 3 days, the reaction mixture was washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to obtain 1.15 g of methyl (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-(p-toluenesulfonyloxy)propionate.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([Br:28])[C:22]2[S:26][CH:25]=[N:24][C:23]=2[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:29]I>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([Br:28])[C:22]2[S:26][C:25]([CH3:29])=[N:24][C:23]=2[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cc(OCc2ccccc2)cc2ncsc12
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.0 M THF solution of LiHMDS (3.0 mL, 3.0 mmol) was diluted into THF (20 mL) under Ar, and the resulting solution was cooled to −78° C. 5-(benzyloxy)-7-bromobenzo[d]thiazole (4.03) (807 mg, 2.52 mmol) was added as a solution in THF (4 mL) over 2 min, washing with additional THF (3×2 mL). The resulting mixture was stirred 30 min, and MeI (0.47 mL, 7.6 mmol) was added in one portion. After stifling an additional 10 min, the mixture was removed from the cold bath and was allowed to warm to r.t. After 1.25 h at r.t., the reaction was diluted with saturated aqueous NH4Cl (50 mL), water (15 mL), and EtOAc (50 mL). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford 5-(benzyloxy)-7-bromo-2-methylbenzo[d]thiazole 4.03D. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13BrNOS: 334.0. found: 334.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cscc1CBr
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cscc1C#N
Yield: 82.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.097 g, 0.37 mmol), 4-Bromomethyl-thiophene-3-carbonitrile (0.168 g, 0.83 mmol) (Terpstra, J. W., et al., J. Org. Chem. (1986) 51:230-238), KI (21 mg, 0.13 mmol), and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was heated at 60° C. for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 118 mg (84%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-thiophene-3-carbonitrile as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[CH3:31][O:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(NC(=O)COC)cc3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 mL, 1.1 mmol) and methoxyacetylchloride (110 mg, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (250 mg, 74% in 2 steps) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][C:3]=1[NH2:17]
Reactant: Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)Cc2ccccc2)cc1N

Procedure:
1.8 G. 1-amino-2-nitro-4-benzylsulfinylbenzene is treated in 120 ml. methanol and 30 ml. water with 1.8 g. iron powder and 0.9 g. ferrous sulfate at reflux for four hours, filtered and the filtrate concentrated under vacuum. The residue is extracted into chloroform and isolated by evaporation. The residue is recrystallized from methylene chloride-benzene giving 1,2-diamino-4-benzylsulfinylbenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[CH:8]2)[CH3:2].[CH3:14][O:15]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[C:8]2[CH:14]=[O:15])[CH3:2]
Reactant: CCc1cccc2cccc(O)c12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cccc2c(C=O)ccc(O)c12
Reaction time: 0.17 h

Procedure:
24.0 g of 8-ethyl-1-naphthol was dissolved in 200 ml of dichloromethane, in which 30.6 ml of titanium tetrachloride was gradually dropped under ice-cooling conditions. Thereafter, 20.3 ml of dichloromethyl methyl ether was gradually dropped under ice-cooling condition. After agitation for 10 minutes, 50 ml of water was gradually dropped under ice-cooling conditions. The reaction solution was extracted with ethyl acetate and the organic phase was washed with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant crystals were washed with a mixed solvent of chloroform and isopropyl ether (1:1) to obtain 15.9 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:22]([C:18]2[C:19]3[CH2:20][CH2:21][N:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=[CH:2][CH:3]=4)[CH2:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[O:24])=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
2-(Quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (80 mg, 0.251 mmol) was suspended in N,N-dimethylformamide (1.2 mL) then added 4-chloroaniline (45 mg, 0.351 mmol), 1-hydroxy-7-azabenzotriazole (34 mg, 0.251 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.376 mmol) and N,N-diisopropylethylamine (89 mg, 0.878 mmol). The reaction mixture was stirred at room temperature for two days then concentrated under vacuum. The crude material was purified by silica gel chromatography (50% to 67% ethyl acetate/hexane) to afford N-(4-chlorophenyl)-2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (92 mg) as a white solid. MS (ESI, pos. ion) m/z: 428.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br.Br[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccnc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 10 minutes, a solution of 3-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) in DMF (0.3 mL) was added. The mixture was stirred for 45 minutes and then quenched by the addition of water, diluted to 5 mL with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (8 mg, 30%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of E3174 (234.58 g, 0.54 mol) in DCM (4500 mL) was added triethylamine (85 mL, 0.59 mol) followed by a solution of trityl chloride (159 g, 0.56 mol) in DCM (800 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography over silica eluting with 20-80% acetone/heptane afforded the title compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.78 g), Lawesson's reagent (2.26 g) and tetrahydrofuran (120 mL) was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.56 g, yield 84%) as pale-yellow crystals. MS:366 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Solvent: CO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Yield: 89.2 %

Procedure:
A mixture of 2.2 g of 10,11-dihydro-10-(4-nitrobenzoyl)dibenz[b,f][1,4]thiazepine in 150 ml of methanol is shaken in a Parr hydrogenator under 50 pounds per square inch of hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue is re-crystallized from chloroform-hexane to give 1.8 g of crystals, m.p. 52°-55° C.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-methoxyphenylboronic acid. The title compound was obtained in 38% yield as yellow foam. MS (m/e): 512.2 (MH+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18].[H-].[Na+].I[CH3:22].O>CN(C=O)C>[CH3:22][O:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]
Reactant: CI
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
A solution of 1.15 g (4.595 mmol) rac-3-Hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.10, step 1) in 11.5 ml DMF was cooled to 0° C. 220 mg (5.514 mmol) NaH (60% in oil) was added. The temperature rose to 3° C. The mixture was stirred at 0° C. for 15 minutes. 430 ul (6.893 mmol) iodomethane was added and the mixture was stirred at 0° C. for 30 minutes. 6.5 ml water was added and the solvent was removed in vacuo. The residue was taken in ethyl acetate. The solution was washed twice with water. The washings were reextracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 500 mg (42%) of the title compound as a light brown solid. MS (m/e): 265.1 (M+H).