Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C(Cl)CCl.[CH:29]1[CH:30]=[CH:31][C:32]2N(O)N=[N:35][C:33]=2C=1.[N:39]1C=CC=[CH:41][C:40]=1CCN>CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([NH:39][CH2:40][CH2:41][C:31]3[CH:30]=[CH:29][N:35]=[CH:33][CH:32]=3)=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: NCCc1ccccn1
Reactant: O=C(O)C1CCN(C(=O)c2cccn2Cc2ccc(Cl)cc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCc1ccncc1)C1CCN(C(=O)c2cccn2Cc2ccc(Cl)cc2)CC1
Reaction time: 18 h

Procedure:
The following was added sequentially to DCM: 1-(1-(4-chlorobenzyl)-1H-pyrrole-2-carbonyl)piperidine-4-carboxylic acid (600 mg, 1.73 mmol), TEA (0.725 mL, 5.19 mmol), EDC (365 mg, 1.903 mmol), and HOBt (291 mqg, 1.903 mmol). This was allowed to stir at rt for 30 min, at which time pyridylethylamine (0.227 mL, 1.903 mmol) was added. Stirring continued for 18 h. At this time, the DCM and TEA were stripped off, and the residue was taken up in EtOAc and washed with 10% aqueous sodium carbonate (3×). The organic phase was collected, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid/oil mixture was recrystallized from EtOAc to afford the title compound as small, white crystals. (Yield: 586 mg, 1.29 mmol, 75%) 1H NMR (400 MHz, CDCl3) 8.50, 7.21, 7.09, 7.02, 6.78, 6.30, 6.11, 5.55-5.42, 5.25, 4.32, 3.52, 2.87-2.71, 2.28-2.10, 1.72-1.65, 1.42-1.25
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: CC(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(O)CNC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 36 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 1-amino-2-propanol as for example 34. After workup, the residue was triturated with hexane then dried, affording 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (36%) as a white solid; m.p. (EtOAc/Hexane) 161-166° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 10.13 (br s, 1H), 8.31 (t, J=1.7 Hz, 1H), 7.73 (br s, 1H), 7.66-7.58 (m, 2H), 7.37-7.31 (m, 1H), 5.75 (dd, J=5.2, 0.9 Hz, 1H), 3.96-3.88 (m, 1H), 3.46-3.39 (m, 1H), 3.42 (s, 3H), 3.25-3.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0371. HPLC 96.8% (254 nm).
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]>CO>[CH3:1][O:2][C:9](=[O:4])[CH2:8][CH2:7][CH2:6][CH2:5][OH:10]
Reactant: O=C1CCCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of sodium methoxide (71.3 mg, 1.32 mmol) in anhydrous MeOH (4 ml), tetrahydro-pyran-2-one (1.32 g, 13.2 mmol) is added dropwise at room temperature under nitrogen. The mixture is stirred at 50° C. for 4 hours and filtered through a silica gel short column (eluent: diethyl ether). Collected filtrate is concentrated under reduced pressure to give 5-hydroxy-pentanoic acid methyl ester; 1H NMR (400 MHz, chloroform-d) ppm 1.57-1.76 (m, 4H), 2.35 (m, 2H), 3.65 (m, 5H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C:21]1[S:22]C=[C:24]([C:26](OC)=[O:27])[N:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:30][C:31]([CH3:33])=[O:32]>O1CCCC1>[CH3:30][C:31]1([CH3:1])[C:33]2[S:22][C:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:25][C:24]=2[C:26](=[O:27])[O:32]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)C(C)(C)OC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (23.5 mL, 165 mmol) in tetrahydrofuran (200 mL) was added butyllithium (103 mL, 1.6 M in hexanes, 165 mmol) dropwise at −78° C. The solution was stirred at −78° C. for 30 minutes then transferred via cannula into a solution of methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (Combi-Blocks, 14.2 g, 55 mmol) in tetrahydrofuran (300 mL) at −78° C. After stirring at −78° C. for 30 minutes, dry acetone (Acros, 16.2 mL, 220 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL) and the aqueous layer was extracted with ethyl acetate (4×200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound MS (ESI+) m/z 285 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]3)[C:12]2=O)=[CH:8][CH:7]=1.[CH3:23][C:24]([S:27]([NH2:29])=[O:28])([CH3:26])[CH3:25].O>CC1CCCO1.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9](=[CH:8][CH:7]=1)[CH2:10][C:11]1([CH2:16][CH2:17][CH:18]([O:21][CH3:22])[CH2:19][CH2:20]1)[C:12]2=[N:29][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=NS(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 65, 611 mg, 1.99 mmol) and 2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) were dissolved in 2-methyl-tetrahydrofuran (40 mL). Titanium(IV) ethoxide (0.84 mL, 3.99 mmol) was added and the resulting mixture was heated to 80° C. over a weekend. The reaction mixture was cooled to r.t. and diluted with EtOAc (85 mL). Water (3 mL) was added under vigorous stirring and then the mixture was allowed to stand for 1 h. The mixture was filtered, the solvent was evaporated, and the residue was purified by flash chromatography using a gradient of EtOAc (0-70%) in heptane to give 244 mg (30% yield) of the title compound: MS (ES+) m/z 410 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[CH:23]2)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:21]=2)[NH:25][C:24]=1[CH3:29])=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 41 h
Yield: 62.7 %

Procedure:
Aluminium chloride (0.86 g) is suspended in methylene chloride (30 ml), to which are added 2,4-dichlorobenzoyl chloride (0.67 g) and then 5-(methoxycarbonyl)-2-methylindole (0.50 g) and stirred at 50° C. for 3 hours and then at room temperature for 41 hours. The reaction mixture is poured into water with ice, and extracted twice with ethyl acetate. The organic layer is washed twice with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with t-butyl methyl ether, and dried to obtain a crystal of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylindole (61) (0.60 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.CN(C=O)C.[Cl:16]N1C(=O)CCC1=O>O>[Cl:16][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C(F)(F)F)c1Cl
Temperature: 70 °C

Procedure:
3-methyl-5-trifluoromethylpyrazole was taken into dry DMF (20 mL) and N-chloro succinimide (1.78 g) was added in portions. The mixture was then heated at 70° C. for 22 h, cooled to room temperature, and then water (100 mL) was added and the mixture extracted with ethyl acetate (4×25 mL). The organic layer was washed with water and brine and dried with Na2SO4. Evaporation of the solvent afforded the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[NH2:17]>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:17][C:11]2[C:10](=[CH:15][CH:14]=[C:13]([Cl:16])[CH:12]=2)[N:9]=1
Reactant: O=C(CBr)C(=O)CBr
Reactant: Nc1ccc(Cl)cc1N
Product: Clc1ccc2nc(CBr)c(CBr)nc2c1

Procedure:
Following the procedure of Example 1, condensation of 1,4-dibromo-2,3-butanedione with 1,2-diamino-4-chlorobenzene yielded 2,3-bis(bromomethyl)-6-chloroquinoxaline, m.p. 149°-150° C.; 1H NMR (CDCl3, 400 MHz): δ4.89 and 4.90 (singlets, 4H, CH2), 7.74 (dd, J1 =8.9 Hz, J2 =2.3 Hz, 1H, H-7), 8.01 (d, J=8.9 Hz, 1H, H-8), 8.07 (d, J=2.3 Hz, 1H, H-5).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1.[C:11]([O:15][C:16](N=[N+]=[N-])=[O:17])([CH3:14])([CH3:13])[CH3:12].O.O1CCOCC1>C(N(CC)CC)C>[C:11]([O:15][C:16]([NH:2][CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCCn1nnnc1S
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1nnnc1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 1-(2-aminoethyl)-1H-tetrazole-5-thiol hydrochloride (1.82 g.), t-butoxycarbonylazide (2.86 g.), water (20 ml.) and dioxane (20 ml.) was added triethylamine (6.0 g.), and the mixture was stirred at room temperature for one hour. After dioxane was removed therefrom under reduced pressure, the residue was adjusted to pH 7.5 to 8.0 with 5% aqueous solution of sodium bicarbonate and washed twice with ether. The resultant solution was adjusted to pH 1 with 5% hydrochloric acid and extracted three times with ethyl acetate (each 50 ml.). The extract was washed with an aqueous saturated solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to give 1-(2-t-butoxycarbonylaminoethyl)-1H-tetrazole-5-thiol (2.05 g.), m.p. 117° to 120° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)nc23)CC1
Yield: 60.3 %

Procedure:
Beginning with 0.15 gm (0.65 mmol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.092 mL (0.85 mMol) phenyl isocyanate, 0.137 gm (60%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1ccccc1
Yield: 41.3 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (0.510 g, 1.18 mmol) was dissolved in methylene chloride (12 ml) and after adding thereto in sequence copper acetate (0.215 g, 1.18 mmol), phenylboronic acid (0.289 g, 2.37 mmol), Molecular Sieves 4A (0.300 g), triethylamine (0.299 g, 2.96 mmol) and pyridine (0.234 g, 2.96 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (0.220 g, 0.487 mmol, 41%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH3:15]>C(OCC)(=O)C.C(O)C.Cl.[Pd]>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=[C:3]1[CH2:14][CH3:15]
Reactant: CCOC(=O)C=Cc1cnc(CC)n1C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cnc(CC)n1C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A mixture of ethyl β-(1-methyl-2-ethyl-imidazol-5-yl)acrylate (2.1 g, 10.1 mmol) and 1.1 g of 10% Pd/C in ethyl acetate/ethanol/HCl (1M in ethyl acetate; 50 ml/8 ml/8 ml) was hydrogenated under hydrogen (50 psi) for 2 h. The mixture was filtered through celite, the residue was washed with ethylene chloride/methanol (5:1, 2×), and the combined organic layer was concentrated in vacuo. The residue was basified with aqueous sodium bicarbonate solution, extracted with methylene chloride (4×), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo. Upon chromatographic purification of the residue on 20 cm silica column (methylene chloride/methanol 50/1 - 15/1), 1.9 g (90%) of ethyl 3-(1-methyl-2-ethyl-imidazol-5-yl)propionate was isolated as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([C:12](=[O:14])[CH3:13])=[CH:3]1.[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20]>C(O)C>[ClH:17].[CH3:18][N:19]([CH3:15])[CH2:20][CH2:13][C:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:14]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1cn(C)c2ccc(C)cc12
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)c(C(=O)CCN(C)C)cn2C
Yield: 38.1 %

Procedure:
A mixture of 1-(1,5-dimethyl-1H-indol-3-yl)-1-ethanone (1.4 g), paraformaldehyde (0.7 g) and dimethylamine hydrochloride (1.8 g) in ethanol (60 ml) was heated at reflux for 24 h, cooled, and the solvent was evaporated in vacuo. The residue was partitioned between sodium carbonate (2N; 75 ml) and ethyl acetate (2×75 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil, which was purified by FCC eluting with System A to give the free base of the title compound as an oil (0.8 g). A sample of the free base (0.1 g) was dissolved in hot ethanol (10 ml) acidified with ethanolic hydrogen chloride, and diluted with hot ethyl acetate (40 ml). On cooling, the salt crystallised out and was filtered off, and dried in vacuo to give the title compound (0.1 g), m.p. 225°-228°.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].C(O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30](=[S:32])=[S:31]>>[CH2:22]([S:32][C:30]([N:2]1[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: S=C=S
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (5.4 g), 2N NaOH (25 ml) and 50% ethanol (70 ml) is added dropwise carbon disulfide (1.5 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise benzyl bromide (3.5 ml), and the mixture is further stirred at the same temperature for 3 hours and then distilled to remover the solvent. To the residue is added water, and the mixture is extracted with ether. The aqueous layer is acidified with 10% HCl, extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol=20:1) to give the title compound (4.5 g) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[N:14]1([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[CH:25][CH:26]=3)[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: CN
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2)nc2cnc(Cl)cc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 4-(3-piperidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:28]=[CH:27][CH:26]=[C:4]([CH2:5][N:6]2[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:7]2)[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1n(Cc2cccc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 101A and 59 mg (0.23 mmol) of 2-chloro-phenylboronic acid were dissolved in 2 ml of dioxane. A stream of argon was passed through this solution for 10 min, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was then stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 51 mg (61% of theory) of the target compound.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=O)C.[ClH:40]>ClCCl.CO>[ClH:40].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)c2ccc3[nH]ccc3c2)cc2c3c(oc12)CCNC3

Procedure:
The product obtained in step D (10 mg, 0.02 mmol) was converted to hydrochloride salt by dissolving in dichloromethane and treating with 1.25 M HCl in methanol. The reaction mixture was concentrated in vacuo to give 8-((1H-indol-5-yl)sulfonyl)-6-methoxy-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (7 mg, 64%, AUC HPLC 97.6%) as a white solid: mp <<MP data>>; 1H NMR (DMSO-d6, 400 MHz) δ 11.64 (s, 1H), 9.20 (br s, 2H), 8.27 (d, J=2.0 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.8, 2.0 Hz, 1H), 7.59-7.51 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 6.67-6.61 (m, 1H), 4.35 (s, 2H), 4.00 (s, 3H), 3.49 (t, J=6.0 Hz, 2H), 3.11-3.02 (m, 2H); ESI MS m/z 383 [M+H]+.