Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC(N[C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.[C:30]1(CC(N[C@@H]2C(=O)N3C(C(O)=O)=C(C=CC)CS[C@H]23)=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH:16]([NH:13][C:28](=[O:29])[CH3:11])[S:17][C@H:12]23)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CC=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Product: CC=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](c3ccccc3)[C@H]2SC1NC(C)=O

Procedure:
To a stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate in dichloromethane (30 ml.g-1) was added Lewis acid (3-5 equiv., see table for conditions). The formation of (6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylic acid was monitored either by HPLC or TLC. The results are summarized in the table.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Yield: 83.5 %

Procedure:
A mixture of 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.078 g, 0.18 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2,3-dihydro-isoindol-1-one (0.065 g, 83%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.31-2.72 (m, 15H), 4.18 (s, 2H), 4.74 (s, 2H), 7.08 (s, 1H), 7.28 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([OH:20])[CH2:2][NH:1][CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:37]=[CH:36][C:35]([S:32]([NH:31][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=4)(=[O:33])=[O:34])=[CH:40][CH:39]=3)[CH2:46][CH2:45]2)=[CH:7][CH:8]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCC(O)COc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(OCc5ccccc5)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 113-121° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.35 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.90 (m, 5H), 2.89 (s, 3H), 3.61 (s, 3H), 3.64 (s, 3H), 3.64-3.80 (m, 5H), 5.02 (s, 2H), 6.70-7.00 (m, 9H), 7.30-7.70 (m, 7H); MS (ES) m/z: 648.1 (MH+); HRMS Calcd. for C35H42N3O7S (MH+): 648.2743. Found: 648.2710.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4C)cc(F)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3C)cc(F)c2O1

Procedure:
The title compound was prepared (0.075 g, 75%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.141 g, 0.32 mmol) and methylamine (0.20 g, 6.4 mmol). mp 212-217° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:7][CH:8]=2)[CH2:3]1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1ccc(C2CN(C)Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C2CN(C)Cc3cc(-c4ccc(C)nn4)ccc32)cc1
Yield: 21.4 %

Procedure:
A mixture of the crude product from Step D (490 mg, 1.35 mmol), 3-chloro-6-methyl-pyridazine (217 mg, 1.69 mmol), and cesium carbonate (1.32 g, 4.05 mmol) in DMF (15 mL) and water (3 mL) was degassed with argon. To this mixture was added PdCl2(dppf) (66 mg, 0.08 mmol). The resulting mixture was degassed with argon and then heated to reflux for 5 hours. After completion by thin-layer chromatography analysis the cooled material was filtered through a bed of diatomaceous earth and washed with water (3×). The organic layers were separated, dried over sodium sulfate, filtered, and concentrated in vacuo. After purification by semi-preparative HPLC (95:5 acetonitrile/water gradient over 40 minutes), the material was free-based with sodium bicarbonate to afford 2-methyl-7-(6-methylpyridazin-3-yl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline (95 mg, 21%) as a light-yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.71-7.68, (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.13-7.09 (m, 4H), 7.01 (d, J=8.1 Hz, 1H), 4.30 (t, J=7.6 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H), 3.70 (d, J=14.9 Hz, 1H), 3.08-3.05 (m, 1H), 2.74 (s, 3H), 2.59 (t, J=9.4 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[CH:14]=[O:15]>ClC1C=CC=CC=1Cl>[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[C:14]([Cl:4])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nn(C)c(Cl)c1C=O
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Reaction time: 2 h
Yield: 72 %

Procedure:
Simultaneously, 68 g of sulphuryl chloride and 70.5 g of a 2.5% solution of 2,2-azoisobutyronitrile (AIBN) are added dropwise at 80° C. to 300 g of a 22.7% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene within 4 hours. After the metered addition has ended, the reaction solution is stirred for a further 2 hours. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 72%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:12][N:11]([CH3:13])[S:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[C:6]#[N:7])(=[O:15])=[O:14]
Reactant: CN1CCNCC1
Reactant: CN(C)S(=O)(=O)c1cc(C#N)ccc1Cl
Product: CN1CCN(c2ccc(C#N)cc2S(=O)(=O)N(C)C)CC1

Procedure:
In a manner analogous to that of Example 22, 49 g of 4-chloro-3-dimethylsulfamoylbenzonitrile (0.2 mole) were reacted with N-methylpiperazine, and the final product was recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][CH:13]([Cl:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCC(Cl)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(Cl)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1C(F)(F)F

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-3-trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=530.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:20][O:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCC3CO3)c2c1C
Reactant: NCc1cccnc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCC(O)CNCc3cccnc3)c2c1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
3-Methyl-4-oxiranylmethoxy-benzofuran-2-carboxylic acid ethyl ester (500 mg) (Naresh K. Sangwan et al., Eur. J. Med. Chem. (1987), 22(2), 153-6) and 3-picolylamine (1 ml) were dissolved in ethanol (5 ml) and stirred at 70° C. for two hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 4-[2-hydroxy-3-[(pyridin-3-ylmethyl)-amino]-propoxy]-3-methyl-benzofuran-2-carboxylicacid ethyl ester (330 mg) as a white powder. FAB-MS: m/z 385 (MH+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7 Hz), 2.70 (3H, s),2.86 (1H, dd, J1=12 Hz, J2=7 Hz),2.97 (1H, dd, J1=12 Hz, J2=3.5 Hz), 3.85 (1H, d, J=14 Hz), 3.91 (1H, d, J=14 Hz), 4.13 (3H, m), 4.44 (2H, q, J=7 Hz), 6.63 (1H, d, J=8 Hz), 7.14 (1H, d, J=8 Hz), 7.26 (1H, m), 7.28 (1H, t, J=8 Hz), 7.68 (1H, br d, J=8 Hz),8.52 (1H, dd, J1=5 Hz, J2=2 Hz), 8.58 (1H, d, J=2 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([SH:29])=[N:27][N:28]=2)[CH:25]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([S:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=4)[N:7]=3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Sc1nnc2ccc(Cl)cn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccc(Cl)cn34)ccc2n1
Temperature: 120 °C
Yield: 102.6 %

Procedure:
Combined compound 7B (50 mg, 0.14 mmol), 6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (28 mg, 0.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.01 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (14 mg, 0.025 mmol), DIEA (48 uL, 0.28 mmol) and DME (1.4 mL) and heated in a microwave unit at high absorbance, 120° C. for 30 min. The resulting crude material was purified by silica gel using 5% MeOH in DCM. The cleanest fractions were concentrated to give compound 7 (0.06 g; quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (br. s., 1 H), 8.86-8.82 (m, 1 H), 8.11-8.05 (m, 1 H), 7.89 (d, J=9.3 Hz, 1 H), 7.73 (s, 1 H), 7.66 (dd, J=1.9, 9.7 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 1.48-1.41 (m, 9 H), ESI-MS:m/z 418.2.0 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH:18]2[CH:7]([CH2:8][C:9]3[C:17]4[C:16]2=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=3)[N:6]([CH3:28])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].O.ClCCl>C(O)C>[C:22]1([S:19]([N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[CH:18]5[CH:7]([CH2:8][C:9]([C:17]=34)=[CH:10]2)[N:6]([CH3:28])[CH2:5][CH:4]5[CH:1]([OH:3])[CH3:2])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12

Procedure:
To a stirred solution of the 9-acetyl compound (Example 4) (0.10 g) in ethanol (2 cm3) was added sodium borohydride (0.0075 g) with visible reaction. After 2 hours reaction was indicated to be complete. Water (20 cm3) and dichloromethane (20 cm3) were added and the mixture partitioned, the separated aqueous layer was re-extracted with dichloromethane (20 cm3) to give, after evaporating under vacuum, a yellow-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O-:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[NH:23][C:19]=2[CH:18]=1>>[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]4[NH:21][C:20]5[CH:44]=[CH:45][C:17]([NH:16][C:11](=[O:13])[C:10]6[CH:9]=[CH:8][C:7]([N:4]7[CH2:3][CH2:2][O:1][CH2:6][CH2:5]7)=[CH:15][CH:14]=6)=[CH:18][C:19]=5[N:23]=4)=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)[CH2:39][CH2:40]1
Reactant: Nc1ccc2nc(-c3ccc(N4CCC(CCN5CCOCC5)CC4)cc3)[nH]c2c1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC(CCN5CCOCC5)CC4)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 446 was prepared from 4-morpholinobenzoate and 5-amino-2-(4-(4-(2-morpholinoethyl)piperidino)phenyl)benzimidazole by standard conditions. [M+H]+ calcd for: C35H42N6O3; 595.33 found: 595.12.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(C)=O>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:2]=1[O:1][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 20 h

Procedure:
A mixture of 5 g of 2-hydroxy-4-tert-butyl-benzoic acid, 9.1 ml of benzyl bromide, 17 g of caesium carbonate, 0.3 g of sodium iodide and 500 ml of acetone is stirred for 20 hours under reflux and then filtered and the filtrate is concentrated by evaporation. The residue is partitioned between diethyl ether and water, the organic phases are concentrated by evaporation and the residue is purified by means of FC (1000 g of silica gel, dichloromethane/hexane=1:1). Title compound: Rf (dichloromethane/hexane=1:1)=0.47.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCN3CCOCC3)ccc21
Yield: 107.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (37.6 mg, 0.0915 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-(2-aminoethyl)morpholine (0.048 mL, 0.37 mmol), acetic acid (0.105 mL, 1.83 mmol) and sodium triacetoxyborohydride (97 mg, 0.46 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-morpholinoethyl)aminomethyl]indol-2-yl)isoindolinone (51.7 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23](O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Br:1][C:2]1[C:11]([CH2:12][O:13][C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[CH3:26])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Reactant: Cc1ccc(F)cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of 7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), and tri-n-butylphosphine (874 μL, 3.50 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), 1,1′-(azodicarbonyl)dipiperidine (883 mg, 3.50 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. 5-Fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol), and 1,1′-(azodicarbonyl)dipiperidine (890 mg, 3.53 mmol) were added thereto and it was furthermore stirred for 20 minutes. After hexane (15 mL) was added to the reaction mixture and the precipitated solids were filtered out, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (900 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=O)=[C:5]([C:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=3)[CH:27]=2)[CH:4]=1.COC1C=CC(CC2C=CC(OCCN3CCCCC3)=CC=2)=C(C2CCC3C(=CC=C(OC)C=3)C=2)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[C:5]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=3)[CH2:27]2)[CH:4]=1
Reactant: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)=C2
Agent: COc1ccc2c(c1)CCC(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)cc1)=C2
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)cc1)C2

Procedure:
Synthesized from [4-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenyl][4-(2-piperidin-1-ylethoxy)phenyl]methanone according to an analogous synthetic method to Example 337 described below, 1-{2-{4-[4-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (228 mg) was used according to an analogous synthetic method to Example 30 described below to provide 1-{2-{4-[4-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (190 mg). This compound (188 mg) was used according to an analogous synthetic method to Example 364 described below to provide the title compound (104 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[C:29]([N+:30]([O-:32])=O)=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:29]3[N:30]([OH:32])[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1C(=C(OS(=O)(=O)C(F)(F)F)c1ccncc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of trifluoromethanesulfonic acid 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(pyridin-4-yl)vinyl ester (1.5 g, 3.20 mmol) in ethyl acetate (50 ml) was added stannous chloride dihydrate (2.89 g, 12.8 mmol) and the reaction mixture was warmed to 50° C. After 1 h, the warm solution was treated with saturated sodium bicarbonate solution (10 ml) and filtered through Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuO. Purification by flash column chromatography (CH2Cl2−95% CH2Cl2/MeOH gradient) gave 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a tan solid (700 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOP(=O)(OCC)C(NCCCCCCSc1ccccc1)P(=O)(OCC)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(NCCCCCCS(=O)c1ccccc1)P(=O)(OCC)OCC
Yield: 82.6 %

Procedure:
m-Chloroperbenzoic acid (2.62 g) in limited amounts was added to a solution of tetraethyl 6-(phenylthio)hexylaminomethylenebisphosphonate (6.85 g) in dichloromethane (100 ml) under ice-cooling over 30 minutes. The reaction mixture was stirred under ice-cooling for 3 hours, and then washed with a saturated aqueous solution of sodium bicarbonate and water and dried (MgSO4). The solvent was distilled off under reduced pressure. The residual oil was subjected to column chromatography on silica gel. Tetraethyl 6-(phenylsulfinyl)hexylaminomethylenebisphosphonate (5.84 g, 82.6%) was obtained as an oil from the fractions obtained by elution with ethyl acetate-chloroform-methanol (10:10:1, v/v).