Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: Nn1nc(C2CCCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CCCC2)c2ccccc2c1=O

Procedure:
The product of Example 71A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52-11.54 (bs, 1H), 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.97-8.02 (m, 1H), 7.87-7.91 (m, 1H), 7.35-7.47 (m, 4H), 3.62-3.77 (m, 3H), 1.96-2.10 (m, 2H), 1.59-1.87 (m, 6H); MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH2:30]>>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1c(F)cccc1F
Product: CN1c2c(cc(Nc3c(F)cccc3F)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (12 mg, 31%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,6-difluoroaniline (39 mg, 0.30 mmol). MS (APCI): 384 (base, M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 72.5 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (108 mg), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (52 mg) and DBU (0.036 mL) in DMA (0.5 mL) was heated in an oil bath (150° C.) for 1.5 h. After cooling, the reaction mixture was partitioned between EtOAc and diluted HCl solution; EtOAc phase was separated and washed with water, diluted NaCl solution respectively and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (60 mg). LC-MS ESI+: 510 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: CC1NCCc2ccc(Br)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(Br)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O1CCN(C2C=CC(O)=CC=2)CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Reactant: Oc1ccncc1
Agent: Oc1ccc(N2CCOCC2)cc1
Product: COc1cc(Cl)ccc1Cn1ccc(=O)cc1

Procedure:
The title compound was prepared by substituting (4-chloro-2-methoxy-phenyl)-methanol and pyridin-4-ol for Example 204A and 4-morpholinophenol, respectively, in Example 297A. MS (ESI) m/e 250 (M+H)+.
Reaction SMILES: C(OC(=O)[C@@H](NC(C1NC=CN=1)=O)C)(C)(C)C.[C:18]([O:22][C:23](=[O:43])[CH2:24][CH:25]([NH:30][C:31](=[O:42])[CH:32]([NH:34][C:35]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)=[O:36])[CH3:33])[CH:26]([OH:29])[CH2:27][F:28])([CH3:21])([CH3:20])[CH3:19].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:18]([O:22][C:23](=[O:43])[CH2:24][CH:25]([NH:30][C:31](=[O:42])[CH:32]([NH:34][C:35]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)=[O:36])[CH3:33])[C:26](=[O:29])[CH2:27][F:28])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(NC(=O)c1ncc[nH]1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(NC(=O)c1ncc[nH]1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
A solution of [3S/R, (2S)]-5-fluoro-4-hydroxy-3-{2-[(1H-imidazole-2-carbonyl)-amino]-propionylamino}-pentanoic acid tert-butyl ester (0.381 g) in dichloromethane was cooled to 0° C. before addition of 1,1,1 triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.476 g). The mixture was stirred at room temperature for 2 h before addition of an additional portion of 1,1,1 triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.05 g) and reaction mixture was then stirred for 90 min before being concentrated at reduced pressure. The residue was dissolved in ethyl acetate and washed with a 1:1 mixture of aqueous NaHSO4 and aqueous Na2S2O3. The organic layer was collected, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (5% methanol in dichloromethane) to give the sub-title compound as a colourless foam (319 mg, 84%): 1H NMR 400 MHz CDCl3 1.37+1.43 (9H, 2×s), 1.54 (3H, m), 2.85 (1H, m), 3.03 (1H, m), 4.85-5.30 (4H, m), 7.18 (2H, d, J 16), 7.90 (1H, m), 7.98 (1H, m), 11.37+11.45 (1H, 2×s); 19F NMR 376 MHz CDCl3 −231.85 (t, J 48), −232.12 (t, J 48).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH2:4][C:3]1=[O:17].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22](/[CH:24]=[C:4]1/[CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH2:6][CH2:7][C:2]([CH3:18])([CH3:1])[C:3]/1=[O:17])[CH3:23]
Reactant: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)C1
Reactant: COC(OC)N(C)C
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)/C1=C\N(C)C
Temperature: 25 °C
Yield: 27 %

Procedure:
4-(4,4-Dimethyl-3-oxo-cyclohexyl)-3-methyl-benzonitrile (0.6 g, 2.49 mmol) in N,N-dimethylformamide dimethylacetal (50 mL) is stirred at 90° C. for two days. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with ethyl acetate (50 mL) and water (50 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel flash chromatography, eluting with pet ether:EtOAc 1:1 to MeOH:DCM=1:30 to give 4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclohexyl]-3-methyl-benzonitrile (0.2 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)=[C:10]([C:15]#[N:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][NH2:18]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:17][N:18]=[C:15]([NH2:16])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)=C(C#N)C1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(N)c2C1
Temperature: 70 °C

Procedure:
To a solution of 141.5 g of 3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester in 1.2 L of ethanol were added under stirring 57.8 mL of aqueous 35% hydrazine. The mixture was heated at 70° C. for 4 h. The solution was evaporated at under vacuum, the residue was diluted with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was taken-up with 300 mL tert-butyl methyl ether and the crystallized compound was collected by filtration to give 115.6 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[N:8]=1.[CH2:36]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH2:23]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:27][CH2:28]3)[CH2:25]2)[N:8]=1
Reactant: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCNCC2)cc1Cl
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCN(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 65.4 %

Procedure:
In methanol (20 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-N-(2-(piperazin-1-yl)ethyl)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (250 mg, 0.5 mmol). Formalin (37%, 61 mg, 0.75 mmol) was added. The reaction was conducted at 0° C. for 1 h. Sodium borohydride (38 mg, 1.0 mmol) was added at 0° C. The reaction was continued for 2 h, then quenched with water. The reaction mixture was filtrated, dried and concentrated to give 4-((3-chloro-4-methoxybenzyl)amino)-N-(2-(4-methylpiperazin-1-yl)ethyl)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (168 mg, 65% yield). The product was dissolved in methanol (5 mL), and hydrochloric acid (0.1 mL) was added. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed by evaporation to give the hydrochloride salt of the compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]3)=[CH:16][C:15]([F:26])=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[NH:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][OH:25])[CH2:22][CH2:23]3)=[CH:16][C:15]([F:26])=[CH:14][N:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncc(F)cc2N2CCC(CO)CC2)C1
Agent: Cl
Solvent: CO
Product: OCC1CCN(c2cc(F)cnc2C2CNC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 3-(5′-fluoro-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl)-azetidine-1-carboxylic acid tert-butyl ester (76) (490 mg, 1.34 mmol) in 4 M HCl/MeOH solution (10 mL) was stirred at RT for 30 min. Then the solvent was evaporated at 40° C. to give (77) (392 mg, 1.3 mmol, 98% yield) as a yellow solid. ESI-MS (M+1): 266 calc. for C14H20FN3O 265.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Br
Yield: 61.3 %

Procedure:
1.79 g (0.0093 mol) of 1-benzyl-4-hydroxypiperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 70 ml of toluene and treated with 1.63 g (0.00745 mol) of 2-bromo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.71 g (61%) of 1-benzyl-piperidin-4-yl 2-bromo-benzoate were obtained as yellowish crystals; m.p. 69°-70°.
Reaction SMILES: [CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:17][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:24])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[O+][O-]
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.54 mmol) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (207 mg, 5.4 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (75 mg, 37%). 1H NMR (400 MHz, CDCl3): δ=2.12-2.30 (m, 2H), 2.47 (m, 2H), 3.19 (m, 1H), 3.40 (m, 1H), 3.53 (m, 1H), 3.76 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.22 (m, 1H), 7.25-7.40 (m, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:50])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH2:22][N:23]([C@@H:40]4[C:49]5[N:48]=[CH:47][CH:46]=[CH:45][C:44]=5[CH2:43][CH2:42][CH2:41]4)[CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[C:10]2=3)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[OH-].[Na+].O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:50])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[C@@H:40]4[C:49]5[N:48]=[CH:47][CH:46]=[CH:45][C:44]=5[CH2:43][CH2:42][CH2:41]4)[C:10]2=3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN(Cc2nccc3c4ccccc4n(CC(=O)N4CCOCC4)c23)[C@H]2CCCc3cccnc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Cn1c2ccccc2c2ccnc(CN(CCCN3CCNCC3)[C@H]3CCCc4cccnc43)c21)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 mmol of (S)-tert-butyl 4-(3-(((9-(2-morpholino-2-oxoethyl)-9H-pyrido[3,4-b]indol-1-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)propyl)piperazine-1-carboxylate was dissolved in 2 ml of dichloromethane and treated with 2 ml of trifluoroacetic acid. After the reaction was stirred at ambient temperature for 2 hours it was cooled to 0° C. with ice bath and then neutralized with 1M NaOH solution carefully. Let the mixture warmed up to room temperature. The organic layer was separated, dried over magnesium sulfate, filtered off, and evaporated. The desired product was purified with column chromatography using dichloromethane:methanol:NH4OH (9:1:0.1). ESI+ MS: m/z (rel intensity) 582.3 (100, [M+H]+). 1H-NMR (400 MHz, CDCl3): δ 8.31 (d, 1H, J=5.6 Hz), 8.28 (d, 1H, J=4.8 Hz), 8.11 (d, 1H, J=9.2 Hz), 7.89 (d, 1H, J=5.2 Hz), 7.57 (t, 1H, J=6.8 Hz), 7.32-7.25 (m, 5H), 6.94 (dt, 1H, J=2.8, 4.8 Hz), 5.67 (d, 1H, J=16.4 Hz), 4.37 (s, 2H), 4.14 (t, 1H, J=9.2 Hz), 4.05 (d, 1H, J=16.8 Hz), 3.93 (d, 1H, J=14.8 Hz), 3.83-3.76 (m, 1H), 3.72-3.47 (m, 4H), 3.45-3.30 (m, 1H), 3.29-3.26 (m, 1H), 2.88-2.51 (m, 6H), 2.41-2.32 (m, 2H), 2.11-2.02 (m, 2H), 1.90-1.59 (m, 8H), 1.02-0.96 (m, 1H), 0.95-0.80 (m, 1H). Elemental Analysis (C/H/N): C34H43N2O2×0.95 mol H2O; Calculated: 68.19/7.56/16.37. Found: 68.18/7.38/16.23.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the ethyl (2E)-3-[1-(2-tert-butoxy-2-oxoethyl)-1H-indol-2-yl] acrylate from Step 3 in EtOAc (0.08 M) was added 10% palladium on carbon (50 mg per g of substrate). The reaction mixture was flushed a few times with hydrogen and then stirred overnight at rt under a 1 atmosphere pressure of hydrogen. The reaction mixture was diluted with CH2Cl2 (2 mL/g) and was filtered through Celite. The filtrate was concentrated to dryness to afford the title compound crude (100%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].N[C:29]1C(C(OC)=O)=C2C(C3(C)CC3CO2)=CC=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3([CH3:29])[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21C
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 41, starting from methyl (1aRS,7bSR)-5-amino-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 50) and 2-bromo-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].Cl>CO>[OH:31][NH:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=3)=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH:22]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)cc2)c1
Reaction time: 48 h
Yield: 41.1 %

Procedure:
A mixture of 0.334 g (E)-3-[1-(3′-methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 11.0 ml methanol and 18.0 ml 1M aqueous HCl is stirred for 48 h. The suspension is evaporated and the solid is isolated and washed with water and diisopropylether. The crude product is purified by PLC plates chromatography. By this method 0.116 g of a red solid are obtained. Melting point: 137-148° C.
Reaction SMILES: CO.[NH2:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[C:7](=[O:23])[N:8]2[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C:19]#[C:20][CH3:21])[CH2:14]1.[BH4-].[Na+]>C(OCC)(=O)C>[NH2:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:25]=1)[C:7](=[O:23])[N:8]2[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C:19]#[C:20][CH3:21])[CH2:14]1
Reactant: CC#CC(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(C(=O)c4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC#CC(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(C(O)c4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A methanol (1 mL) solution of the compound (30 mg) prepared in Example 19(40) was cooled to 0° C.; sodium borohydride (2.4 mg) was added; and stirring was carried out for 30 minutes. The reaction mixture was diluted with ethyl acetate and was then washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate followed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=10:1) to obtain the title compound (28 mg) having the physical property values indicated below.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([CH3:23])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([O:21]C)=[O:20])=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1.CO.Cl>O>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([CH3:23])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(Cc2c(C)cc3c(c2C)C(C)(C)CCO3)o1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2c(c(C)c1Cc1ccc(C(=O)O)o1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
In a 100-mL round-bottom flask, methyl 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoate (532 mg, 1.62 mmol) and methanol (5 mL) were placed. The reaction was stirred at room temperature overnight, and then the mixture was poured in water, acidified with HCl (6N) and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over MgSO4, and concentrated to yield 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoic acid (208) (343.6 mg, 67.5% yield). 1HNMR (CDCl3) δ 1.31 (s, 6H), 1.82 (m, 2H), 2.13 (s, 3H), 2.21 (s, 3H), 2.62 (t, 2H), 4.01 (s, 2H), 5.82 (d, 1H), 6.55 (s, 1H), 7.16 (d, 1H). APCI-MS m/z 315 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][C:29]5([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: C[C@]1(C2CCN(CC3(C(F)(F)F)CC3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 4): tR=0.64 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH3:24][NH2:25]>>[CH3:24][NH:25][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Reactant: CN
Product: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid and methylamine (2M in THF)