Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33])([CH3:26])[CH3:25].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of 2-isopropylbenzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ 1.16 (t, 6 H), 2.21-2.35 (m, 3 H), 2.60 (m, 1 H), 3.21 (m, 1 H), 3.42 (q, 2 H), 5.88 (d, 1 H), 6.56 (t, 1 H), 6.94 (t, 1 H), 7.13 (m, 4 H), 7.25 (m, 2 H), 7.45 (m, 5 H).
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.CO.[C:15](=O)(O)[O-:16].[Na+]>O>[CH3:15][O:16][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: c1ccc[cH+]cc1
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C=CC=CC=C1

Procedure:
1-methoxy-1,3,5-cycloheptatriene can be produced from cycloheptatrienyl tetrafluoroborate (I) as described in Conrow K 1963 Organic Synthesis 43, 101. The reaction of (I) with methanol and sodium bicarbonate in water gives 7-methoxy-1,3,5-cycloheptatriene (II), (reference Conrow K1961, J. Am. Chem. Soc. 83,2342). The 1-methoxy-1,3,5-cycloheptriene can be made by the thermal isomerisation of (II) by heating at 150° for 2.5 hours in nitrogen atmosphere in the presence of antioxidants and absence of water, as described by T. NOZOE and K., Takahashi, Bull Chem. Soc. Japan, 38, 665, 1965. Pratt, J. T. Reaction of Cycloheptatriene, PHD Thesis, University of Washington, Seattle, Wash. 1964.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:13]=[N:12]1)[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)#[N:2].[O:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([CH2:3][CH:4]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:38][CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)=[O:28])=[CH:30][CH:31]=3)[N:17]=2)[CH:13]=[N:12]1)[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)#[N:2]
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)NC4CCOCC4)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[(4-{1-[2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]benzoic acid (20 mg, 0.00005 mol), tetrahydro-2H-pyran-4-amine (4.8 mg, 0.000048 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.000057 mol) in N,N-dimethylformamide (0.3 mL, 0.004 mol) was added N,N-diisopropylethylamine (20 μL, 0.00011 mol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to obtain the desired product as a racemic mixture (free base). LCMS (M+H) 502.4.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[F:5][C:6]([F:24])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO.CCOC(C)=O.[Pd]>[F:24][C:6]([F:5])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH:1]=[O:3])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=C[O-]
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=CNc1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Yield: 77.8 %

Procedure:
Ammonium formate (1.38 g, 22 mmol) and 10% Pd/C (230 mg, 0.2 mmol) are added to a solution of 1-(2,2,2-trifluoroethyl)-4-(4-nitrophenyl)piperidine (1.26 g, 4.4 mmol) in EtOH (10 mL) and EtOAc (10 mL). The suspension is heated at reflux for 24 hours, adding further portions of ammonium formate (2 g) after 4 h and 8 h. The mixture is filtered through celite and evaporated to afford an orange solid. This is partitioned between DCM (40 mL) and water (20 mL) and the layers separated. The aqueous phase is extracted with DCM (2×20 mL) and the combined organic layers are dried over MgSO4 and evaporated under reduced pressure to afford N-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}formamide as a pale orange solid (980 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:13]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][O:9][CH3:13])[CH:7]=1
Reactant: CI
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-2-fluorophenyl)methanol (5.00 g) in THF (100 ml) was added 60% sodium hydride (1.08 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.80 ml) was added, and the mixture was stirred for 1.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane→hexane:ethyl acetate=50:1) to give the title compound (4.86 g) as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.3 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64.2 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2CL2 1:9 to provide 2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (30 mg, 29%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5].[CH3:20][O:21]C1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O.COC1C=CC=CC=1C(O)=O.COC1C=C(OC)C=C(OC)C=1.COC1C(OC)=C(OC)C=CC=1C(C1C=CC=CC=1O)=O>>[CH3:20][O:21][C:17]1[C:2]([OH:1])=[C:3]([CH:14]=[CH:15][C:16]=1[O:18][CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2O)c(OC)c1
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(O)c1
Agent: COc1cc(OC)cc(OC)c1
Agent: COc1ccc(C(=O)c2ccccc2O)c(OC)c1OC
Agent: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)c1ccc(OC)c(OC)c1O

Procedure:
According to the method of production of 2-hydroxy-4-methoxy-2'-methoxybenzophenone (4a) and 2,4-dimethoxy-2'-hydroxybenzophenone (4b), 2.00 g (13.14 mmol) of 2-methoxybenzoic acid was reacted with 2.19 g (13.04 m mol) of 1,3,5-trimethoxy benzene to give 2.20 g (7.75 mmol) of 3,4-dimethoxy-2-hydroxy-2'-methoxybenzophenone and 2,3,4-trimethoxy-2'-hydroxybenzophenone. Then, described in example 3, 1.35 g (5.92 m mol) of 3,4-dihydroxybenzophenone as pale yellow powder was produced. The physical properties were measured and are listed below.
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:24])[C@@H:6]([NH:14][C:15]([C@@H:17]1[C@@H:19]([CH2:20][CH2:21][CH2:22][CH3:23])[O:18]1)=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N-:25]=[N+:26]=[N-:27].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>>[CH3:3][O:4][C:5](=[O:24])[C@@H:6]([NH:14][C:15](=[O:16])[C@@H:17]([OH:18])[C@@H:19]([N:25]=[N+:26]=[N-:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Yield: 69 %

Procedure:
A suspension of 30 ml of methanol containing 558 mg (1.84 mmol) of (2S-trans)-N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-butyloxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and then, the resulting mixture was washed successively with water, and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 442 mg (Yield: 69%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1.[C:32]([O-])(O)=O.[Na+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:32])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1
Reactant: O=C([O-])O
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated HCl (1 mL) was added to a solution of the product from step (i) (0.1 g) in MeOH (2 mL). The mixture was heated at 70° C. for 2 h, poured into saturated aqueous NaHCO3 solution (10 mL) and the aqueous was adjusted to pH ˜7 by adding NaHCO3. The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.018 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(O)cc1
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 49.6 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 3a) (503 mg, 1.9 mmol) was coupled with 4-hydroxy-benzohydrazide (285 mg, 1.9 mmol) similarly to the procedure described for the preparation of intermediate 1b. Trituration with hot methylene chloride provided the title compound as a white solid (380 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.68 (br s, 1H), 9.30 (br s, 1H), 7.85 (AA′XX′, J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz, 1H), 6.91 (AA′XX′, J=8.8 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.59 (d, J=7.1 Hz, 1H), 4.84 (br s, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 2.34 (s, 3H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:32]1.ClC1C=C2C(=CC=1)N(S(C1C=CC(OC)=CC=1OC(F)(F)F)(=O)=O)C(=O)C2(N1C[C@H](OCC(O)CO)C[C@H]1C(N(C)C)=O)C1C=C(C)C=CC=1OC>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:34]1[CH2:35][C@H:31]([OH:30])[CH2:32][C@H:33]1[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[C:13]1[CH:14]=[C:15]([CH:16]=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(C=O)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCC(O)CO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C=O)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 26.3 g of the compound obtained in Step 198-1 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (35.1 mmol) as starting materials, 12.5 g of a diastereoisomer mixture of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:26][C:27]1[C:28](=[O:40])[N:29]([CH2:37][CH:38]=O)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[C:27]([Br:26])[C:28]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)c(Br)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)c(Br)cc3ccccc32)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To 3 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.36 g of (3-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde, 30 μL of acetic acid and 0.43 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.54 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:23])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of p-acetoxyphenylacetic acid was dissolved in 5 ml of methylene chloride. To the solution were added, with ice cooling, a catalytic amount of N,N-dimethylformamide and 0.12 ml of oxalyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain p-acetoxyphenylacetyl chloride. This compound was dissolved in 5 ml of methylene chloride. To the solution was added 260 mg of a sulfur trioxide-dioxane complex with ice cooling. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure to obtain DL-2-(p-acetoxyphenyl)-2-sulfoacetyl chloride. This compound was dissolved in 5 ml of anhydrous tetrahydrofuran.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=O)C.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:19]>C(O)C>[ClH:19].[C:12]1([CH:11]=[C:8]2[C:7](=[O:10])[C:6](=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:5][NH:4][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 14 g. (0.1 mole) of N-acetyl-4-piperidinone and 32 g. (0.3 mole) of benzaldehyde in 150 ml. of ethanol containing 33 ml. of conc. HCl is refluxed for 6 hours and then kept overnight at room temperature. The light yellow solid is filtered, washed with ethanol, washed with ether, and air-dried to yield 26 g. of product; m.p. 273°-275° (dec.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26]3)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][CH:31]=[C:23]([C:21]([C:20]3[CH:33]=[CH:34][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:18][CH:19]=3)=[O:22])[CH:24]=2)[NH:28]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.608 mg, 3.53 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 5-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (0.685 g, 2.72 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (0.760 g, 1.96 mmol, 72%).
Reaction SMILES: C[O-].[Na+].Cl.[CH:5]1([C:8]2[N:12]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[CH:16][C:15]=3[F:24])[N:11]=[C:10]([C:25](=[NH:27])[NH2:26])[C:9]=2[CH3:28])[CH2:7][CH2:6]1.C(O[CH:32]=[C:33]([C:36]#[N:37])[C:34]#[N:35])C>>[NH2:37][C:36]1[C:33]([C:34]#[N:35])=[CH:32][N:26]=[C:25]([C:10]2[C:9]([CH3:28])=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:12]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[CH:16][C:15]=3[F:24])[N:11]=2)[N:27]=1
Reactant: CCOC=C(C#N)C#N
Reactant: CCOc1cc(F)c(Cn2nc(C(=N)N)c(C)c2C2CC2)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(C#N)c(N)n3)c(C)c2C2CC2)c(F)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
146 mg of sodium methanolate (2.70 mmol, 1.0 eq) were diluted in 20 ml of methanole at room temperature under a nitrogen atmosphere. Then 1.0 g of 5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazole-3-carboximidamide hydrochloride 1:1 1-3-6 (2.70 mmol, 1.0 eq) and 329 mg of (ethoxymethylene)malononitrile (2.70 mmol, 1.0 eq) were added and the mixture was stirred at 65° C. bath temperature for 18 hours. After cooling to rt the reaction mixture was concentrated in vacuo and purified via HPLC (ACN/H2O/0.2% NH3) to give 284 mg (0.65 mmol, 24%) of analytically pure target compound.
Reaction SMILES: [CH:1]1([C:7](=O)[C:8](=[N:16]O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH:1]1([C:7]2[NH:26][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)C1CCCCC1
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1C1CCCCC1
Yield: 27.1 %

Procedure:
tert-Butyl 3-cyclohexyl-2-hydroxyimino-3-oxopropionate (2.6 g) and benzylamine (2.1 g) were dissolved in benzene (50 ml), and the mixture was refluxed under heating for 16 hr. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:ethyl acetate=8:1) to give tert-butyl 5-cyclohexyl-2-phenylimidazole-4-carboxylate (0.90 g), melting point 222-223° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a mixture of benzaldehyde (0.061 mL, 0.6 mmol) and N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.278 g, 0.60 mmol) in CH2Cl2 (10 mL) was added NaB(OAc)3H (0.128 g, 0.60 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.5) to give 0.21 g of the title compound. MS (EI) calcd: (M+H)+=503.3; found: 503.4.