Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[N:15](CC=C)[C:14]([Cl:22])=[N:13][C:12]=2[N:11]([CH2:23][CH2:24][CH2:25][CH3:26])[C:10]1=[O:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([N:11]1[C:12]2[N:13]=[C:14]([Cl:22])[NH:15][C:16]=2[C:17](=[O:18])[N:9]([CH2:8][CH2:7][CH2:6][N:44]2[CH2:45][CH2:46][N:41]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:42][CH2:43]2)[C:10]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCOS(C)(=O)=O)c(=O)n2CCCC
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c(=O)c2[nH]c(Cl)nc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A solution of 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (0.08 g, 0.19 mmol) in DMF (5 ml) was treated with potassium carbonate (0.08 g, 0.6 mmol) and 1-benzylpiperazine (0.04 g, 0.23 mmol) and then heated at 70° C. for 2 h. The mixture was cooled, evaporated to dryness and partitioned between 10 ml of DCM and 10 ml of water. The organic phase was evaporated to dryness and the residue dissolved in anhydrous THF (5 ml). The solution was cautiously degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) and morpholine (0.200 ml, 2.3 mmol) and the mixture stirred for 2 h in a nitrogen atmosphere. The mixture was evaporated and the residue taken up in 5 ml of methanol and added to a 2 g aminopropyl SPE cartridge which was then washed with methanol and the product eluted using a 3% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated to dryness. The product was then purified by flash chromatography using a gradient elution from DCM/2% Acetic acid to DCM/20% MeOH/2% Acetic acid and the final product freeze-dried from 1,4-dioxan to give the title compound as a white solid (0.021 g, 24%).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:27])[C:10](=[CH2:26])[CH2:11]2)=[CH:19][CH:18]=1
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (509 mg) is dissolved in dichloromethane (10 ml). Mixture is cooled to 0° C. and trifluoroacetic acid (0.5 ml) is added. The mixture is then stirred for 2 h then extracted with saturated sodium carbonate solution (20 ml). Phases are separated. The organic phase is dried (MgSO4) and concentrated to give (R)-5-biphenyl-4-ylmethyl-3-methylenepyrrolidin-2-one (4-a, R1=H). δH (400 MHz, DMSO) 2.47 (1H), 2.68 (1H), 2.74 (1H), 2.87 (1H), 3.87 (1H), 5.22 (1H), 5.64 (1H), 7.33 (3H), 7.45 (2H), 7.60 (2H), 7.65 (2H), 8.32 (1H); m/z (+) 264 ([MH]+, 100%); m/z (+ESI) 264 ([MH]+, 100%).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and pyrrolidine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][NH2:13].C1COCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:13][CH3:12])=[O:6]
Reactant: CN
Reactant: Cc1ccc(C(=O)Cl)cc1I
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(I)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cooled (0° C.) solution of 3-iodo-4-methylbenzoyl chloride (2.80 g; 10.0 mmol) in DCM (10 mL) was slowly added a 2 M solution of methylamine in THF (11 mL, 2.2 eq.). Upon completion of the addition, the ice bath was removed and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was treated with aq. NaHCO3 (25 mL) and subsequently extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and evaporated. The target compound 3-iodo-N,4-dimethylbenzamide (2.62 g, 95% yield) was used without further purification.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl>C(O)C>[OH:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CCC(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To rac-ethyl 7-(8-acetoxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (75 mg, 0.142 mmol) in ethanol (2 ml) was added 2M sodium hydroxide (0.283 ml, 0.566 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was acidified with 2M HCl (0.283 ml) and the solvent was removed in vacuo. To the residue was added DCM and water. The organic portion was separated, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH2:11][CH:10]([CH2:13][NH:14][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)CC(CN)CO2
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(CNC1CCCCC1)CO2
Yield: 104.3 %

Procedure:
To a solution of 8-t-butyl-3-aminomethyl-1-oxaspiro(4,5)-decane (1.2 g, 5.3 mmol), cyclohexanone (0.54 g, 5.5 mmol) and zinc chloride (0.4 g, 3 mmol) in methanol (15 ml) was added sodium cyanoborohydride (0.4 g, 6.4 mmol). The reacton mixture was stirred over night. The solvent was then evaporated in vacuo and the resulting residue was treated with a mixture of saturated aqueous sodium carbonate/toluene (50 ml each). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield 1.7 g of a pale yellow oil which was purified by flash chromatography (toluene/ethanol 4:1). Evaporaton of the fractions containing the product yielded a colourless oil (1.5 g).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
An alternative synthesis was provided to prepare the compound of D21: To a suspension of methyltriphenylphosphonium bromide (64.7 g, 181 mmol) in anhydrous tetrahydrofuran (THF) (20 mL) was added dropwise n-butyllithium (113 mL, 181 mmol) under −78° C. over 30 mins. The reaction mixture was stirred for 1 h, and then was added a solution of 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (36.3 g, 121 mmol) in anhydrous tetrahydrofuran (15 ml). The reaction mixture was warmed slowly to room temperature and stirred overnight at room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude sample was purified by silica gel column (220 g) using hexane/ethyl acetate (20:1) as eluent to afford the title compound (28 g, 94 mmol, 78% yield) LCMS: rt=4.29 min.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CN([CH:24]=[O:25])C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([N:3]1[C:7]([CH:24]=[O:25])=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cncn1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1ncnc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethyl-1H-1,2,4-triazole (9.9 g, 0.10 mol) and N,N,N′,N′-tetramethylethylenediamine (15 mL) in THF (60 mL) at −78° C. was added n-butyllithium (64 mL of a 1.6M solution in hexanes, 0.10 mol). After stirring for 2 hours, DMF (8.7 mL, 0.11 mol) was added, the reaction allowed to warm to room temperature and stirred for 14 hours before being poured into saturated aqueous sodium bicarbonate solution (300 mL). The mixture was extracted with dichloromethane (3×150 mL) and the combined organics dried over sodium sulfate, filtered and concentrated to give the title compound (>12 g) which also contained unreacted starting material 1H-NMR (CDCl3) δ 1.48 (3H, t, J=7 Hz), 4.63 (2H, q, 7 Hz), 8.03 (1H, s), 10.04 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[Br:27][C:28]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH:39]=O)=[N:35]2)=[CH:30][CH:29]=1>>[Br:27][C:28]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([C:39]3[N:6]4[CH:5]=[C:4]([C@@H:3]([N:12]5[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]5)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]4=[N:10][N:11]=3)=[N:35]2)=[CH:30][CH:29]=1
Reactant: Cc1c(Br)ccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Product: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Yield: 78.3 %

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.80 g, 2.13 mmol) and 7-bromo-8-methylquinoline-2-carbaldehyde (0.533 g, 2.13 mmol) in place of 8-methoxyquinoline-2-carbaldehyde to provide tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (1.01 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1-c1cccnc1
Product: OB(O)c1cccc(-c2cccnc2)c1F

Procedure:
3-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 11 to give 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]([CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12])(=O)[CH3:8].C(O)C>CN(C)C=O>[OH:13][CH2:14][CH2:15][C:10]1[C:11](=[O:12])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[NH:1][C:7]=1[CH3:8]
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1cc[nH]n1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1[nH]c2ccnn2c(=O)c1CCO
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 49.86 g (0.6 mole) of 3-aminopyrazole and 84.56 g (0.66 mole) of α-acetyl-γ-butyrolactone dissolved in 60 ml of N,N-dimethylformamide was heated under reflux for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, after which 100 ml of ethanol was added to it and the precipitated crystals were collected by filtration. They were then washed with ethanol to afford 104.9 g (yield 90%) of the title compound as prisms, melting at 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:27]=[N:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:9]=[C:8]([C:24]2[CH:25]=[N:26][CH:27]=[CH:20][C:21]=2[CH:22]=[O:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=Cc1ccncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnccc2C=O)cc1Cl
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.264 g, 1 mmol), 3-bromoisonicotinaldehyde (0.186 g, 1.000 mmol), sodium carbonate (1.000 ml, 2.000 mmol), bis(triphenylphosphine)palladium(II) chloride (0.018 g, 0.025 mmol) in DMF (6 mL, dry) was heated to 120° C. for 3 hrs. After concentration, the residue was dissolved into CH2Cl2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH—CH2Cl2, v/v, 0.5%-1%) yielded 2-chloro-4-(4-formylpyridin-3-yl)benzonitrile (20a) as colorless solid (170 mg) 1H NMR (400.3 MHz, CDCl3): δ 7.63 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 9.07 (s, 1H), 9.15 (s, 1H), 10.22 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[Li]CCCC.[C:17]([Si:21]([CH3:44])([CH3:43])[O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30](O)[O:31][C:32]3[C:37]([C:38]=2[CH3:39])=[CH:36][CH:35]=[C:34]([O:40][CH3:41])[CH:33]=3)=[CH:25][CH:24]=1)([CH3:20])([CH3:19])[CH3:18].Cl>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC>[C:17]([Si:21]([CH3:44])([CH3:43])[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][CH:7]=3)[O:31][C:32]3[C:37]([C:38]=2[CH3:39])=[CH:36][CH:35]=[C:34]([O:40][CH3:41])[CH:33]=3)=[CH:27][N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: ClCCOc1ccc(I)cc1
Reactant: COc1ccc2c(c1)OC(O)C(c1ccc(O[Si](C)(C)C(C)(C)C)nc1)=C2C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC(c1ccc(OCCCl)cc1)C(c1ccc(O[Si](C)(C)C(C)(C)C)nc1)=C2C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a single neck, 100 mL round bottom flask was dissolved and stirred 1-(2-chloro-ethoxy)-4-iodo-benzene (530 mg, 1.88 mmol, 5.0 eq), in tetrahydrofuran (5 mL) under nitrogen, and the mixture cooled to −78° C. After 5 minutes of stirring, a hexane solution of n-BuLi (0.75 mL of 2.5 M, 1.88 mmol, 5.0 eq) was added via syringe. The reaction mixture was then stirred for 30 min at about −78° C. A tetrahydrofuran solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H-chromen-2-ol (150 mg, 0.376 mmol, 1 eq, in 2 mL), prepared as in Example 24, was then added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. After about 18 hours, the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a sticky semisolid residue. To this solid was added 0.2 mL HCl in 10 mL toluene at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a brown oil. The title product was isolated as a white semisolid foam via chromatography on silica gel eluted with 1:1 hexanes:ethyl acetate as eluent.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N:26](OC(C)(C)C)=[O:27].Cl>C(O)(C)(C)C.C(OCC)C>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][C:11](=[N:26][OH:27])[C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1=NO
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A solution of 10.1 g of 4,4-diphenylcyclohex-2-enone in 60 cm3 of tert-butanol is added to a solution of 6.5 g of potassium tert-butoxide in 50 cm3 of tert-butanol at a temperature in the region of 30° C. After stirring for about 15 minutes at a temperature in the region of 30° C., this solution is added dropwise to 14 cm3 of tert-butyl nitrite. The reaction mixture is stirred at a temperature in the region of 20° C. for 2 hours. 100 cm3 of aqueous 3 M hydrochloric acid solution and 100 cm3 of diethyl ether are then added to the preceding mixture at a temperature in the region of 20° C. After separation of the phases by settling, the aqueous phase is extracted with 100 cm3 of diethyl ether. The combined organic phases are washed with three times 100 cm3 of saturated aqueous sodium bicarbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate, filtered and concentrated. After concentrating to dryness under reduced pressure (13 kPa), the residue is purified by flash chromatography on a column of silica (eluent: cyclohexane/ethyl acetate (80/20 by volume)]. 2.23 g of 5,5-diphenylcyclohex-3-ene-1,2-dione 1-oxime are thus obtained in the form of a yellow foam, which is used without further modification for subsequent syntheses and the characteristics of which are as follows:
Reaction SMILES: [ClH:1].Cl.CO[CH:5]1[N:10]([CH2:11][CH2:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH:8](C2C(OC(F)(F)F)=C(C3C=CC=CC=3)C=CC=2)[N:7]([CH3:37])[CH2:6]1.Cl.Cl.[CH3:40][O:41][C:42]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:58])([F:57])[F:56])[CH:49]=2)=[CH:46][C:45](C(C2(O)CCCCC2)CN2CCNCC2)=[CH:44][CH:43]=1>>[ClH:1].[ClH:1].[CH3:40][O:41][C:42]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]([F:56])([F:57])[F:58])[CH:49]=2)=[CH:46][C:45]([CH:12]([C:13]2([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:11][N:10]2[CH2:9][CH2:8][N:7]([CH3:37])[CH2:6][CH2:5]2)=[CH:44][CH:43]=1
Reactant: COc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1-c1cccc(OC(F)(F)F)c1
Reactant: COC1CN(C)C(c2cccc(-c3ccccc3)c2OC(F)(F)F)CN1CCC1(O)CCCCC1
Agent: Cl
Product: COc1ccc(C(CN2CCN(C)CC2)C2(O)CCCCC2)cc1-c1cccc(OC(F)(F)F)c1

Procedure:
In an analogous manner to Example 24, 1-[1-[6-methoxy-3′-(trifluoromethoxy-1,1′-biphenyl-3-yl]-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(3′-trifluoromethoxy-6-methoxy-1,1′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 251). MS m/z 493; HRMS: calcd for C27H35F3N2O3+H, 493.26780; found (ESI, [M+H]+), 493.2692.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:2].[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:31])[CH2:26][O:27][CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C@@H:8]([OH:9])[C@H:26]([O:27][CH:28]([CH3:30])[CH3:29])[C:25]([N:20]2[C@@H:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][O:22][C:21]2=[O:24])=[O:31])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: CCOc1ccc([C@@H](O)[C@H](OC(C)C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Yield: 105.4 %

Procedure:
Under the similar conditions to those described in Production example 332a), 2.4 g of 4-ethoxybenzaldehyde and 5.6 g of (4S)-4-benzyl-3-(2-isopropoxyacetyl)-1,3-oxazolidin-2-one were reacted, to give 7.2 g of (4S)-3-[(3R,2S)-3-(4-ethoxyphenyl)-3-hydroxy-2-isopropoxypropanoyl]-4-benzyl-1,3-oxazolan-2-one as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19]I)[O:6][C@H:7]2[N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[O:3]1.[H][H]>CO.C(N(CC)CC)C.[Pd]>[CH3:19][C@H:5]1[O:6][C@@H:7]([N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[C@@H:8]2[O:9][C:2]([CH3:1])([CH3:21])[O:3][C@@H:4]12
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(N)nc1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@@H]2OC(C)(C)O[C@H]21

Procedure:
A solution of 5'-deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorocytidine (48g, 116.5 mmol) in methanol (500 ml) and triethylamine (20ml) was treated with hydrogen at atmospheric pressure in the presence of palladium on carbon (5%, 25g) for 30 min. at room temperature. During this time the suspension was agitated using a "VIBROMIX" vibrator. The catalyst removed by filtration through celite, and the filtrate was evaporated to dryness and triturated with ethyl acetate (200 ml). After storage overnight the crystals were removed by filtration, and the filtrate was evaporated to approximately 100 ml and again stored overnight. A second batch of crystals was removed by filtration, and the filtrate was evaporated to dryness, pumped in vacuo, to give 5'-deoxy-2',3'-O-isopropylidene-5-fluorocytidine as a foam 31g (93%). This material was characterized by formation of a crystalline picrate salt, mp 168°-170°. uv (CH3OH) λ max 237-238 mμ(ε 20,700), λmax 282 mμ(ε 9,400), λ max 353-354mμ(ε 15,300). NMR ((CH3)2SO-d6) δ 8.58 (S, 2, picrate) δ 8.29 (d, 1, J = 7 Hz, CHCF) δ5.72 (d,J= 4 Hz, C'1) δ1.47, 1.28 (S, 3, (CH3)2C) δ 1.31 (d, 3, J = 6 Hz, CH3CH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10](O)=[O:11])=[C:4]([CH3:13])[C:3]=1[CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:13])[C:3]=1[CH3:14]
Reactant: Cc1cc(O)c(C)c(C)c1CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(O)c(C)c(C)c1CCO
Temperature: 40 °C
Yield: 99.1 %

Procedure:
To a solution of 4-hydroxy-2,3,6-trimethylphenyl-acetic acid (2.5 g) in anhydrous tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.5 g) at 0° C. and the mixture was heated at 40° C. for 3 hours. The mixture was cooled to 0° C. Diluted sulfuric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 2-(4-hydroxy-2,3,6-trimethylphenyl)ethanol (2.3 g) (Compound A-24). The physical properties and NMR spectrum data thereof are shown in Table 1.