Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][C:29]2[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]1)=[O:6]
Reactant: CCN(CC)Cc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CC(C)N1CCC(Oc2ccc(C(=O)N3Cc4ccccc4C3)c(Cl)c2)CC1
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D33) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E62) as a white solid (0.09 g). MS electrospray (+ion) 399/401 (MH+). 1H NMR δ (DMSO-d6): 10.90 (1H, s), 7.33-7.10 (6H, m), 6.96 (1H, m), 4.82-4.51 (3H, m), 4.39 (3H, m), 3.35 (2H, m), 3.00 (2H, m), 2.11-1.80 (4H, m), 1.17 (6H, m).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]1[N:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:14][N:13]2[CH2:29][CH2:30][CH2:31][C@H:12]12.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl.CN(C)C=O>[CH2:11]1[N:16]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@@H:2]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][OH:4])(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:14][N:13]2[CH2:29][CH2:30][CH2:31][C@H:12]12
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(c1ccc(S(=O)(=O)Cl)cc1)N1CCN2CCC[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)N[C@H](CO)c2ccccc2)cc1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Then (S)-2-amino-2-phenylethanol (0.494 g, 3.6 mmol) in dichloromethane/N,N-dimethylformamide (5:1, 40 mL) was added to the crude 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonyl chloride. The mixture was stirred at room temperature for 3 days, then sodium carbonate (0.21 g, 2 mmol) and methanol (10 mL) were added. The mixture was stirred for an additional 30 minutes, then the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1H), 1.60-2.10 (m, 6H), 2.90-3.20 (m, 4H), 3.30-3.50 (m, 3H), 4.30 (m, 1H), 4.50 (m, 1H), 4.85 (m, 1H), 7.10 (m, 5H), 7.30 (m, 2H), 7.61 (m, 2H), 8.30 (br s, 1H); MS (EST) m/z 430 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>C(O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccco1
Reactant: NCCc1cccc(OCc2cccc(F)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1.44 g (15 mmol) of furan-2-carboxaldehyde and 7.5 g of molecular sieves 3 Å were added to a solution of 2.45 g (10 mmol) of 2-[3-(3-fluoro-benzyloxy)-phenyl]-ethylamine in 50 ml of dry ethanol. The reaction mixture was refluxed for 3 hours. The molecular sieves were filtered off and the solution was cooled to 5° C. 0.57 g (15 mmol) of NaBH4 was added under N2 and the reaction was stirred at room temperature overnight. Solvent was removed, a 5% NaHCO3 aqueous solution was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:0:0→100:2:0.2, v:v:v). 2.2 g (68% yield) of an oil were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[S:15][CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]2[CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:6]([CH2:25][CH3:26])[CH:5]=1)(O)=[O:2].C[Li].[CH3:29][Si](Cl)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[S:15][CH2:14][C:13]3([CH2:16][CH2:17][CH2:18][CH2:19]3)[N:12]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[C:6]([CH2:25][CH3:26])[CH:5]=1)(=[O:2])[CH3:29]
Reactant: C[Si](C)(C)Cl
Reactant: CCc1cc(C(=O)O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]C
Solvent: C1CCOC1
Product: CCc1cc(C(C)=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of the 2-(4-carboxy-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D9a; 0.046 g, 0.128 mmol) in THF (10 mL) at −78° C. was added methyllithium (1.4 M in Et2O, 0.91 mL, 1.28 mmol). The reaction mixture was while allowed to gradually warm to room temp., then was stirred overnight. Trimethylsilyl chloride (0.5 mL) was added and the mixture was stirred at room temp. for 2 h, then a 1N HCl solution (2 mL) was added. The mixture was stirred for 0.5 h, then was treated with a saturated NaHCO3 solution (10 mL). The resulting mixture was extracted with EtOAc (4×20 mL), and the combined organic layers were washed with a saturated NaCl solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc/hex) to give 2-(4-acetyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a white solid (0.032 g, 73%): mp 114-115° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 74.6 %

Procedure:
Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) was obtained as a yellow crystalline solid; mp 208-209° C., lit. [22] 206° C.; δH (500 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.79 (d, J=15.5 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=7.9 Hz, 1H, H4), 7.25 (d, J5′,6′=8.5 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.56 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=7.9 Hz, 1H, H5), 8.00 (d, J3,4=7.9 Hz, 1H, H3), 8.62 (d, J5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[C:20]([C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:25])[S:22][C:23]=3[CH3:24])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1.O>CO>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[C:20]([CH:26]([OH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:25])[S:22][C:23]=3[CH3:24])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reaction time: 1 h

Procedure:
At 0° C., sodium tetraborohydride (10 mg, 0.26 mmol) was added to a solution of ethyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethyl thiophen-3-yl]-2-oxoacetate (17d) (90 mg, 0.26 mmol) in methanol (5 mL). After 1 hour, water (5 mL) was added, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired alcohol (17e) as a white solid without further purification (88 mg, 0.25 mmol, 98%).
Reaction SMILES: [F:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1([CH2:15][OH:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) in tetrahydrofuran (5 mL) was treated with 1.0 N LiAlH4 (2.54 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Water (0.6 mL) was added to the reaction mixture drop-wise, followed by 2 N aqueous NaOH (0.2 mL). The reaction was stirred for another 1 hour. The solid was removed by filtration via a pack of Celite and washed with ethyl acetate. The filtrate was washed with brine, dried over MgSO4, filtered, and concentrated to give the product.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].C(Cl)(=O)N.C(NC(Cl)=O)C.CN(C)C(Cl)=O.C([S:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[C:35]([Cl:45])[CH:34]=1)[C:30]([OH:32])=[O:31])(=O)N.C(NC(SC(C1C=CC(C2CCCCC2)=C(Cl)C=1)C(O)=O)=O)C.CN(C)C(SC(C1C=CC(C2CCCCC2)=C(Cl)C=1)C(O)=O)=O>>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([S:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[C:35]([Cl:45])[CH:34]=1)[C:30]([OH:32])=[O:31])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: NC(=O)SC(C(=O)O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: CCNC(=O)Cl
Agent: CCNC(=O)SC(C(=O)O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: CN(C)C(=O)Cl
Product: CCN(CC)C(=O)SC(C(=O)O)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
When diethylcarbamylchloride is replaced in the above procedure by carbamyl chloride (prepared in situ from potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride or dimethylcarbamyl chloride, then the products prepared are α-carbamylthio-3-chloro-4-cyclohexylphenylacetic acid, α-ethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acid or α-dimethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:36])[CH2:13][CH2:12][CH:11]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20](=[O:35])[CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)=[O:38].N#N.ClCCl>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:36])[CH2:13][CH2:12][CH:11]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20](=[O:35])[CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:38]
Reactant: O=Cc1ccccc1B(O)O
Reactant: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(Br)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccccc1-c1ccc(C2(O)CCC(N[C@H]3CCN(C(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1
Temperature: 130 °C
Yield: 74.4 %

Procedure:
A solution of N-[2-((3S)-3-[4-(5-bromopyridin-2-yl)-4-hydroxycyclohexyl]aminopyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl)benzamide (30.0 mg, 0.0527 mmol) and (2-formylphenyl)boronic acid (8.6 mg, 0.052 mmol) in DMF (0.60 mL) and aqueous sodium carbonate (2M, 0.198 mL) was degassed with N2 for 5 minutes. Then [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (2.2 mg, 0.0026 mmol) was added in under N2 flush. The reaction mixture was degassed with N2 for another 5 minutes and then the tube was sealed. The reaction mixture was heated under microwave at 130° C. for 5 minutes. After cooling down, the reaction mixture was filtered through a short pad of silica gel and washed with CH3CN. The resulting solution was acidified with TFA to pH 1˜2, then was subjected to purification on Prep-HPLC. The appropriate fractions were lypholized to give the product (23 mg, 53%) as a white powder. MS: (M+H)+ 595.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)cc3OCC)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (670 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. Then, the deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (442 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][NH2:13])=[CH:4][CH:3]=1.[C:14]([C:19]1[C:20](=[O:32])[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][C:24]=1[OH:25])(=O)[CH2:15][CH2:16][CH3:17]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1
Reactant: CCCC(=O)C1=C(O)CC(C2CCOCC2)CC1=O
Reactant: NOCCC#Cc1ccc(F)cc1
Solvent: CO
Product: CCCC(=NOCCC#Cc1ccc(F)cc1)C1=C(O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.7 g (15 mmol) of 4-(4-fluorophenyl)-but-3-ynoxyamine were added to a solution of 4 g (15 mmol) of 2-butyryl-3-hydroxy-5-tetrahydropyran-4-ylcyclohex-2-enone in 60 ml of dry methanol. After the mixture had been stirred for 16 hours at room temperature, the methanol was removed under reduced pressure from a water pump. The crude product was purified by chromatography over silica gel (eluent: methylene chloride). Yield: 5.2 g (81.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[CH:20][C:19](=[O:21])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=Cc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CC(=O)C=CC=Cc1ccc(OCc2ccccc2)cc1
Yield: 79.5 %

Procedure:
A solution of 19.7 g of p-benzyloxycinnamaldehyde and 27.6 g of acetylmethylenetriphenylphosphorane in 190 ml of xylene was heated under reflux for 2 hours, the solvent was then evaporated and the residual crystals were recrystallized from benzene to give 18.3 g of the desired compound melting at 132°-133° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].CCN(CC)CC.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:8][C:7]1[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cccc(N)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
Yield: 40 %

Procedure:
The procedure described in Example 3: step b was followed using 2-bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a), PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 mL), and Et3N (729 μL, 6 mmol), 4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolane (453 μL, 3 mmol). Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue yielded the title compound (94 mg, 40%) as a yellow solid. ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H) found: 234.1.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13](O)=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[Cl:16]C1C=CC(OS([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=CC=1.CN(C)C=O>N1C=CC=CC=1>[ClH:16].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: O=S(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(Cl)cc2)CC1
Yield: 79.4 %

Procedure:
A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 7.7 g of bis-(p-chlorophenyl)sulfite was stirred at room temperature for 30 minutes in a solution of 12 ml of dry dimethylformamide and 6 ml of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals. The crystals were washed with ether twice and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.75 g (yield: 79.5%) of p-chlorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 173° to 176° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[N+:19]([O-])=O)=[CH:6][CH:5]=1.O.NN>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[NH2:19])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CNc2ccc(C)cc2N)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A stirred solution 4-[(4-methyl-2-nitrophenylamino)methyl]benzoic acid methyl ester (7.0 g, 23 mmol,) in CH3OH was treated with 5% Pd/C (50% wet, 30% w/w) and hydrazine hydrate (5.8 g, 116 mmol). The reaction mixture was heated to reflux temperature for 2 h, cooled to room temperature and filtered through celite. The filtrate was evaporated to give a residue. The residue was dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and evaporated to afford 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester, which was used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CDCl3) 8.0 (d, J=8 Hz, 2H); 7.70 (d, J=8 Hz, 2H); 6.60 (m, 2H); 6.49 (d, 1H); 4.3 (s, 2H); 3.90 (d, 3H); 2.21 (s, 3H). LCMS (ESI+) 271 (MH+). A stirred solution of crude 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester (6 g, 22 mmol) in trimethylorthoformate was treated with formic acid (1.0 g), refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The resultant residue was purified by column chromatography using 1% MeOH/CHCl3 to afford 4-[(5-methylbenzimidazol-1-yl)methyl]benzoic acid methyl ester Yield: 61%. 1H NMR (400 MHz, CDCl3): 8.0 (d, J=8 Hz, 1H); 7.93 (s, 1H); 7.62 (s, 1H); 7.26 (s, 1H); 7.21 (d, J=8 Hz, 2H); 7.08 (m, 2H); 5.39 (s, 2H); 3.90 (s, 3H); 2.47 (s, 3H). LCMS (ESI+) 281 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: OC[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (S)-(−)-glycidol (0.10 mL, 1.51 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.36 g).