Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:9]=[C:10]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:41][CH2:40][C:39]5[N:38]=[C:37]([CH3:42])[C:36]([C:43]([O:45]C)=[O:44])=[CH:35][C:34]=5[C:33]4=[O:47])[CH2:28][CH2:27]3)[C:11]([O:21][CH:22]([CH3:24])[CH3:23])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:41][CH2:40][C:39]5[N:38]=[C:37]([CH3:42])[C:36]([C:43]([OH:45])=[O:44])=[CH:35][C:34]=5[C:33]4=[O:47])[CH2:30][CH2:31]3)[C:11]([O:21][CH:22]([CH3:23])[CH3:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc2c(nc1C)CCN(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)nc3OC(C)C)CC1)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)nc3OC(C)C)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.1 %

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-((5-cyclopropyl-6-(4-fluorophenyl)-2-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (800 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 (727 mg).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[CH2:27][C:17]=2[C:18]([CH2:25]O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH:1]([O:14][C:15]1[C:16]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[CH2:27][C:17]=2[C:18]([CH2:25][Br:41])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2Cc3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3CO)C2=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3CBr)C2=O)cc1

Procedure:
For example, 9-benzhydryloxy-5-hydroxymethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A11.5 prepared by the method shown in Example 50, is reacted in dichloromethane with one molar equivalent of carbon tetrabromide and triphenylphosphine to produce 9-benzhydryloxy-5-bromomethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A11.6. The product is then heated at 120° C. with an excess of a trialkyl phosphite A11.3. The resulting phosphonate is then deprotected to afford the phenolic product A11.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:23])[C:10]3[C:15]([C:16]4([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[BH4-].[Na+]>C(O)C.O>[OH:23][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]1=2
Reactant: COc1cccc2c1C(=O)c1ccccc1C21CCN(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1C(O)c1ccccc1C21CCN(C)CC1
Reaction time: 8 h

Procedure:
4-Methoxy-1'-methyl-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine (1.8 g.), in ethanol (100 ml.) is treated with sodium borohydride (2 g.), allowed to stand at room temperature overnight, then the reaction mixture is diluted with water and extracted with ether. The ether is washed with water, dried (MgSO4) and evaporated to give an oil which is chromatographed on magnesium silicate. Elution with toluene-ethyl acetate gives 10-hydroxy-4-methoxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 149°-151°C. on recrystallisation from aqueous ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.[CH2:30]([N:37]1[CH2:41][CH2:40][CH:39](OS(C)(=O)=O)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH2:30]([N:37]1[CH2:41][CH2:40][C@H:39]([O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: Nc1nccc2cc(O)ccc12
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Product: Nc1nccc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc12
Temperature: 110 °C
Reaction time: 60 h
Yield: 40.1 %

Procedure:
1-Amino-6-hydroxyisoquinoline (50 mg, 0.312 mmol), prepared as described in WO 00/24718 (Akzo Nobel N.V.), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (284 mg, ˜2.2 mmol.g−1, ˜0.624 mmol) were stirred at ambient temperature in acetonitrile (4 ml) for 15 min. (R) Methanesulfonic acid 1-benzylpyrrolidin-3yl ester (0.312 mmol) was added and the mixture heated to 110° C. and stirred for 60 h. The mixture was filtered and the precipitate washed with acetonitrile. The filtrate was concentrated and then purified by prep-HPLC to give (S)-6-(1-Benzylpyrrolidin-3-yloxy)-isoquinolin-1-ylamine (40 mg),
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K].O>CN(C)C(=O)C>[CH3:19][C:3]1([CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 180 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (1.11 g, 2.99 mmol), 4-phenylpiperidine (723 mg, 4.48 mmol) and potassium carboante (826 mg, 5.98 mmol) in N,N-dimethylacetamide (6 ml) was stirred for 3 hours at 180° C. under nitrogen atmosphere. To the reaction mixture was added water, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, treated with an active charcoal, filtered and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 744 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:13]1([CH:19]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]([NH:22][C@H:23]2[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[CH2:25][CH2:24]2)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:2]([F:12])([F:11])[F:1])[CH:10]=1)[CH2:6][N:28]1[CH2:29][C@H:30]2[C@H:23]([NH:22][C:20](=[O:21])[CH:19]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:24][CH2:25][C@H:26]2[CH2:27]1
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 3,5-bis(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide from Example 74 for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.16 (d, J=7.1, 1H), 7.99 (s, 3H), 4.50-4.42 (m, 1H), 3.69 (d, J=13.9, 1H), 3.54 (d, J=13.9, 1H), 2.92 (dd, J=2.7, 9.0, 1H), 2.65-2.56 (m, J=10.2, 15.6, 2H), 2.55-2.50 (m, 1H), 2.31 (d, J=4.2, 2H), 2.10 (dq, J=5.9, 11.8, 1H), 2.03 (t, J=7.4, 1H), 1.99-1.83 (m, 5H), 1.80 (d, J=12.4, 2H), 1.75-1.64 (m, J=12.4, 18.4, 5H), 1.63-1.56 (m, J=8.7, 2H), 1.44 (td, J=7.6, 21.0, 3H), 1.31-1.16 (m, 4H), 1.16-1.04 (m, 4H); MS (ESI+) m/z 559 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)C1CN(C(=O)CCl)CCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
In a 100-mL round-bottom flask, the benzyl morpholine-2-carboxylate (50%, 1.00 g, 2.3 mmol) as the crude tfa salt was taken up in dichloromethane (8 mL), resulting in a white suspension. N-Ethyl-N-isopropylpropan-2-amine (1.4 ml, 7.9 mmol) was added, and the solid dissolved. The solution was cooled to 0 deg, and 2-chloroacetyl chloride (0.20 ml, 2.5 mmol) was added. The reaction mixture was allowed to warm naturally to ambient temperature where it was stirred for 14 h. The reaction mixture was diluted with DCM (75 mL), and the organic layer was extracted with dilute sodium bicarbonate (2×7 mL) then with half-saturated brine (7 mL), then was dried over sodium sulfate. The residue was purified through silica gel (100 mL) which had been deactivated with TEA (10 mL) using 90% EtOAc-hexane, affording the title compound (474 mg, 1.6 mmol). MS m/z 298 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:27][CH2:26][C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[N:17]=[CH:18][C:13]=2[CH2:12]1.C1COCC1>[Pd].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N:11]2[CH2:27][CH2:26][C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH2:12]2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of [6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-pyrimidin-5-yl-amine (100 mg, 0.275 mmol] in the mixed solvent of THF (3 ml) and methanol (3 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture is filtered and the filtrate was concentrated under vacuum to give [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-pyrimidin-5-yl-amine [16] (Yield: 84.2 mg 92.2%) as a off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[C:18]([CH3:24])([CH3:23])[CH2:17][N:16]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:30]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:25]1([N:16]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19](=[O:22])[N:20]([CH3:21])[C:14]3[CH:13]=[N:12][C:11]([NH:10][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[CH:3][CH:4]=4)[CH3:9])=[N:30][C:15]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccc(N2CCN(C)CC2)cc1
Temperature: 100 °C
Yield: 9.5 %

Procedure:
(S)-2-(1-(4-Bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.2117 mmol), 1-methylpiperazine (84.82 mg, 93.93 μL, 0.8468 mmol), di-tert-butyl-(2-phenylphenyl)phosphane (6.317 mg, 0.02117 mmol) and K3PO4 (89.87 mg, 0.4234 mmol) were taken in up DME (2 mL) and degassed using cycles of vacuum and nitrogen. Pd2 DBA3 (19.39 mg, 0.02117 mmol) was added and the reaction mixture was further degassed and then heated at 100° C. in a sealed tube for 4 hours and then allowed to cool to the ambient temperature. The reaction mixture was then diluted with ethyl acetate (5 mL) and filtered. The filtrate was concentrated in vacuo and the residue purified by mass directed HPLC and the combined product fractions passed through a bicarbonate cartridge and lypholized to give the title compound as a white solid (9.9 mg, 10% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH:18]=[O:19].C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][OH:19]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To an ice cooled solution of ethyl 5-bromo-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (3.82 g, 11.86 mmol, 1 eq) in a 1:1 mixture of THF: EtOH is added sodium borohydride (0.5 g, 13.04 mmol, 1.1 eq) portion wise. The reaction mixture is stirred at RT for 2 h. The reaction mixture is quenched with sat. NH4Cl solution and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The crude is purified by column chromatography to afford 2.91 g (75%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.60-7.56 (m, 5H), 4.95 (t, J=5.4 Hz, 1H), 4.60-4.58 (d, J=5.4 Hz, 2H), 4.32 (q, J=7.01 Hz, 2H), 1.30 (t, J=7.7 Hz, 3H). HPLC (max plot) 96.75%; Rt 3.69 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23]B1OB(C)OB(C)O1>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 15 h
Yield: 69 %

Procedure:
To a suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A11) (5.00 g, 14.7 mmol) and tetrakis(triphenylphosphine)-palladium in dioxane/water (9:1; 50 ml) was added at RT trimethylboroxine (2.04 ml, 14.7 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (3.25 g, 69%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(N[Si](C)(C)C)=O.[NH2:46][C:47]1[S:48][CH:49]=[C:50](/[C:52](=[N:56]/[O:57][C:58](=[O:60])[CH3:59])/[C:53](Cl)=[O:54])[N:51]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(#N)C.C(OCC)(=O)C>[NH2:46][C:47]1[S:48][CH:49]=[C:50](/[C:52](=[N:56]/[O:57][C:58](=[O:60])[CH3:59])/[C:53]([NH:1][C@@H:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])=[C:6]([S:9][CH2:10][C:11]4[CH:15]=[N:14][NH:13][CH:12]=4)[CH2:7][S:8][C@H:3]23)=[O:54])[N:51]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1csc(N)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12)c1csc(N)n1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a suspension of diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (30.2 g) in THF (800 ml) was added herein 1,3-bis(trimethylsilyl)urea (25.8 g) was added at the room temperature. The reaction mixture was warmed at 35° C. and dissolved, and then it was cooled below 0° C. A suspension of 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetylchloride monohydrochiloride salt (17.93 g) in acetonitrile (200 ml) was dropped into the above reaction mixture below 0° C. After stirring at the same temperature for 10 minutes, it was poured into a mixture of ethyl acetate (1.2 l) and ice-water (1.5 l). The aqueous layer was adjusted at pH 6.5 with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine (1.0 l), and dried over magnesium sulfate, and then evaporated until the volume amounted to 500 ml. The solution was poured into IPE (1.5 l). The resulting precipitate was filtered, dried under reduced pressure to give diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (41.3 g) as powder.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+]>O>[CH3:6][CH:5]([O:4][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:3])[CH3:7]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)OC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Isopropyl chloroformate (1.0M in toluene, 55 mL, 55 mmol) was added dropwise to a mixture of 4-piperidinecarboxylic acid (6.5 g, 50 mmol) and sodium hydroxide (4.4 g, 110 mmol) in water (25 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The aqueous phase was separated and adjusted to pH=1 with concentrated HCl. The aqueous phase was extracted with EtOAc, and the organics were dried over MgSO4, filtered, and the filtrate was concentrated to give 10.2 g (95%) of 1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.89 (septet, 1H, J=6.2 Hz), 4.04 (d, 2H, J=3.9 Hz), 2.97-2.79 (m, 2H), 2.58-2.38 (m, 1H), 2.00-1.80 (m, 2H), 1.72-1.53 (m, 2H), 1.21 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 214 (M−H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.Cl>C1C=CC=CC=1>[C:5]1([CH:8]2[CH2:9][CH2:10][CH:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)C1=CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)C1CCC(c2ccccc2)CC1
Temperature: 45 °C
Yield: 76.5 %

Procedure:
To a mixture of AlCl3 (13 g, 97.5 mmol, 1.0 equiv) in benzene (100 mL) kept at 35° C., was added 1-cyclohexenecarboxylic acid (5 g, 39.7 mmol, 0.41 equiv) dropwise. After addition was complete, the reaction solution was heated to 70° C. for 1 h and 45° C. overnight. The reaction was cooled, and 200 mL of 1 N HCl was slowly added. The product was extracted with EtOAc. The organic layer was extracted with 1 N NaOH and the aqueous layer was acidified with concentrated HCl to produce a white precipitate that was collected by filtration, washed with water and dried to give the titled compound as a white solid (3.1 g, 38%) which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34]>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1ccc(F)c(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4(4-hydroxyphenyl)piperidine-1-carboxylate and 0.812 g of 2-(3-bromopropoxy)-1,4-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.35 (1:1 EtOAc-heptane); Rt=5.14.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:34]2([CH3:35])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:29])[C@H:18]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:37][C:38](=[O:40])[CH3:39])[CH2:6]1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@:34]2([CH3:35])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:29])[C@H:18]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][CH2:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:37][C:38](=[O:40])[CH3:39])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@@H](CCC(C)(C)O)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)[C@@H](CCC(C)(C)O)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
18.4 mg of (22R)-1α,3β,22-triacetoxycholest-5-en-25-ol (IVa1) was dissolved in 2 ml of carbon tetrachloride; the solution was refluxed under heating under argon gas atmosphere, and then 8.2 mg of N-bromosuccinimide was added to the mixture. After refluxing for 25 minutes, the mixture was cooled with ice-water, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1.5 ml of xylene, and the solution was added dropwise to a refluxed solution of 1 ml of xylene and 1.5 ml of 2,4,6-collidine under argon gas stream atmosphere. After the dropping was completed, the mixture was refluxed for 10 minutes. The mixture was diluted with ethyl acetate, and the mixture was washed with 2N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, successively, and dried over magnesium sulfate. The residue was dissolved in 10 ml of acetone, and after adding thereto 5 mg of p-toluenesulfonic acid, the mixture was stirred overnight under argon gas stream atmosphere under dark condition at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was removed by distillation, and the residue was subjected to preparative thin layer chromatography (solvent: n-hexane-ethyl acetate=2:1; developing: 5 times) for purification to give 1.75 mg of (22R)-1α,3β,22-triacetoxycholest-5,7-dien-25-ol (Va1).