Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Br:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([Br:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1S(N)(=O)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cc(C(F)(F)F)c(Br)cc2S(N)(=O)=O)cc1

Procedure:
2-Amino-4-trifluoromethyl-5-bromo-benzenesulfonamide (formula (V): R2 = Br) is first prepared according to the above-described technique. M.p.= 202° C. The 2-amino-4-trifluoromethyl-5-bromobenzenesulfonamide (9.60 g) is then reacted, as in Example 2A, with p-anisic acid chloride (6.8 g), to give 12.2 g 2-p-anisoylamino-4-trifluoromethyl-5-bromo-benzenesulfonamide, M.p.= 321° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=1.[H][H]>CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CCCC#Cc1cccc(OCc2ccc3ccccc3c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCCCc1cccc(OCc2ccc3ccccc3c2)c1
Reaction time: 8 h

Procedure:
To a solution of 6-[3-(naphthalen-2-ylmethoxy)-phenyl]-hex-5-ynoic acid (0.54 g, 1.4 mmol) in methanol (15 mL) is added 10% Pd/C (0.10 g) and this mixture is placed on a Parr apparatus and pressurized to 43 psi with hydrogen. This reaction is allowed to shake overnight. The reaction is filtered and the solvent removed in vacuo. The residue is purified by flash chromatography (silica, 5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.83-7.89 (m, 4H), 7.46-7.56 (m, 3H), 7.17-7.22 (m, 1H), 6.77-6.85 (m, 3H), 5.21 (s, 2H), 2.59 (t, 2H), 2.31 (t, 2H), 1.58-1.70 (m, 6H); MS (EI) 348 (M)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([Cl:11])=[CH:9][N:8]([CH:12]([F:14])[F:13])[N:7]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:11][C:10]1[C:6]([CH:4]=[O:5])=[N:7][N:8]([CH:12]([F:13])[F:14])[CH:9]=1
Reactant: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C(F)F)cc1Cl
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (164 mg, 0.68 mmol) in tetrahydrofuran (5 ml) was added at 0° C. a solution of lithium aluminiumhydride (1M in tetrahydrofuran, 0.35 ml) and stirring was continued for 30 minutes. The mixture was quenched at −15° C. with a saturated aqueous solution of potassium hydrogensulphate and extracted with diethyl ether. The organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/ethyl acetate (4:1) as the eluent to give the title compound (71 mg) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[O:8]=[C:7]1[N:1]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[NH:4][CH2:5][CH2:6]1
Reactant: O=C1CCNc2ccccc2N1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCNc2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one (5.0 g, 30.8 mmol) in DMF (30 ml), at −10° C., was added sodium hydride (1.35 g, 60% dispersion, 33.9 mmol). The mixture was stirred at −10° C. for 15 min, then methyl bromoacetate (2.92 ml, 30.8 mmol) was added. The mixture was stirred at −10° C. for a further 1 h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 7.08 g (98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:38]([CH3:39])[CH3:37])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.03 g, 26%). LCMS: 518.25 (M+1)+; HPLC: 89.16% (@254 nm) (Rt; 3.982; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.81 (s, 1H), 8.18 (t, 1H), 8.08 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=8 Hz), 7.43 (s, 1H), 7.26 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.83-3.86 (m, 4H), 3.32 (2H merged in solvent peak), 3.03 (m, 1H), 2.64 (s, 3H), 2.50 (3H merged in solvent peak), 2.40 (bs, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.60 (bs, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[NH2:11][C@H:12]1[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][C@@H:16]([CH3:18])[CH2:17][C@H:12]([NH:11][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=2)[CH2:13]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H]1C[C@H](N)CN(C(=O)OCc2ccccc2)C1
Reactant: CSc1ncc(Br)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1

Procedure:
A solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (1.0 g, 4.2 mmol), (3S,5S)-benzyl 3-amino-5-methylpiperidine-1-carboxylate (2.7 g, 8.35 mmol) and triethylamine 1.3 g, 12.5 mmol) in dioxane (50 ml) were stirred for 16 hours. The reaction was concentrated and the residue dissolved in methylene chloride (50 ml) and washed with water. The organic layer was dried and concentrated and purified on a silica gel column with 10-20% ethyl acetate/dichloromethane as solvent to give (3S,5S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-5-methyl-piperidine-1-carboxylic acid benzyl ester as a viscous oil. MS (ES+): 452.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(F)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(5-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 76) (51 mg, 0.098 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 ml, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.11 mmol, 0.11 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (52 mg, 0.102 mmol, 104%) as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17].[CH2:18]=O.O>ClCCCl>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COCCCN
Reactant: C=O
Solvent: ClCCCl
Solvent: O
Product: COCCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 1,2-dichloroethane (50 ml) were dissolved p-nitrobenzaldehyde (5 g) and 3-methoxypropylamine (3.1 g), and to the mixture was added, under ice-cooling, triacetoxy sodium boron hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and to the mixture were added, under ice-cooling, 37% formalin (3 ml) and triacetoxy sodium boron hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and to the mixture was added water. The mixture was concentrated, neutralized with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and subjected to back extraction with 1N hydrochloric acid. The aqueous layer was washed with ethyl acetate, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N-(3-methoxypropyl)-N-methyl-4-nitrobenzylamine (5.6 g) as yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:16]3[CH:15]=[CH:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:9]=4[N:17]=3)[CH:19]=2)(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (0.043 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.034 g, 43%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.24 (1H, d, J=8.4 Hz), 7.86-7.90 (1H, m), 8.24 (1H, d, J=8.8 Hz), 8.39 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=7.6 Hz), 8.85 (1H, s), 9.19 (1H, s). m/z=516.1 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[CH:4]=1.[CH2:22]([N:29]=[C:30]=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:22]([NH:29][C:30](=[O:31])[N:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)[CH:4]=1)[CH3:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)CCc1ccc(-c2cc(NC)ccn2)cc1
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)N(C)c1ccnc(-c2ccc(CCC(=O)OCC)cc2)c1
Yield: 97 %

Procedure:
270 mg (0.63 mmol, 1 eq) of ethyl 3-[4-(4-methylaminopyrid-2-yl)phenyl]propanoate are mixed with 0.6 mL (3.7 mmol, 6 eq) of heptyl isocyanate and then irradiated in a microwave machine for 2 times 30 minutes, while keeping the temperature constant at 100° C. The reaction mixture is chromatographed on silica gel (90/10 heptane/ethyl acetate). 260 mg of ethyl 3-{4-[4-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate are obtained. Yield=64%.
Reaction SMILES: [Cl:1][C:2]1([C:10]2([Cl:21])[C:14](Cl)=[C:13]([Cl:16])[C:12](Cl)([Cl:17])[C:11]2([Cl:20])[Cl:19])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]1[Cl:9].S(=O)(=O)(O)[OH:23].Cl>>[Cl:1][C:2]1([C:10]2([Cl:21])[C:14](=[O:23])[C:13]([Cl:16])=[C:12]([Cl:17])[C:11]2([Cl:20])[Cl:19])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]1[Cl:9]
Reactant: O=S(=O)(O)O
Reactant: ClC1=CC(Cl)C(Cl)(C2(Cl)C(Cl)=C(Cl)C(Cl)(Cl)C2(Cl)Cl)C=C1
Agent: Cl
Product: O=C1C(Cl)=C(Cl)C(Cl)(Cl)C1(Cl)C1(Cl)C=CC(Cl)=CC1Cl

Procedure:
A mixture of 337 grams of 1,2,4-trichlorophenylheptachlorocyclopentene and 301 grams of concentrated sulfuric acid was stirred and heated at 105° to 124° centigrade for 10 hours. A total of 47 grams of hydrogen chloride was evolved and collected. The reaction mixture was mixed with water, the organic layer was separated and washed with water until neutral, after which it was dried and distilled. The product was collected as a red-orange viscous oil which crystallized on standing. Boiling point was 174°-178° centigrade at 0.4 millimeter of mercury pressure. Yield was 262 grams.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.I[CH:14]([CH2:19][C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][OH:18].P(O)(O)O.C(N(CC)CC)C>O1CCOCC1>[F:31][C:20]([F:32])([C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[CH2:19][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: OCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: OP(O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: OCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A solution of AIBN (4.9 g, 30 mmol) in dioxane (150 cm3) was added dropwise into a solution of 4iodo-6,6,7,7,8,8,9,9,9-nonafluorononan-1-ol (Preparation 1B, 25 g, 58 mmol), phosphorous acid (19.1 g, 0.29 mol) and triethylamine (32.3 g, 0.32 mol) in dioxane (150 cm3) under an atmosphere of nitrogen during reflux. After addition, the reaction mixture was refluxed for a period of time until the GLC analysis revealed a complete reaction (usually an hour). The crude product was extracted into diethyl ether (3×50 cm3) and dried (MgSO4). The solvent was removed in vacuo and the pure product was obtained by reduced pressure distillation as a colourless liquid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[N+:14]([C:17]1[CH:18]=[C:19]([CH:24]([CH:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH:20]=[CH:21][C:22]=1[OH:23])([O-:16])=[O:15].[CH3:37][N:38]([CH3:41])[CH:39]=[O:40]>CN(C)C1C=CN=CC=1.O>[N+:14]([C:17]1[CH:18]=[C:19]([CH:24]([CH:27]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:39](=[O:40])[N:38]([CH3:41])[CH3:37])=[CH:34][CH:35]=2)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH:20]=[CH:21][C:22]=1[O:23][C:10](=[O:11])[N:9]([CH3:13])[CH3:8])([O-:16])=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C=O
Reactant: CCC(c1ccc(O)cc1)C(CC)c1ccc(O)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(c1ccc(OC(=O)N(C)C)cc1)C(CC)c1ccc(OC(=O)N(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere, triethylamine (13.8 ml), dimethylcarbamoyl chloride (9 ml) and 4-dimethylaminopyridine (125 mg) were added in that order to a solution of erythro 3-(3-nitro-4-hydroxyphenyl)-4-(4-hydroxyphenyl)hexane (4.21 g) in dry N,N-dimethylformamide (90 ml) at 0-5° C., and the resulting mixture was heated to room temperature and stirred for 2 days. The reaction mixture was diluted with water and extracted twice with a mixed solvent of diethyl ether and ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain erythro 3-(3-nitro-4-dimethylcarbamoyloxyphenyl)-4-(4-dimethylcarbamoyloxyphenyl)hexane (5.14 g, quantitative yield).
Reaction SMILES: [NH2:1]/[CH:2]=[N:3]/[C:4]1[C:9]([C:10]#[N:11])=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:7]=[C:6]([C:25]2[C:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=[CH:27][C:26]=2[O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[N:5]=1.FC(F)(F)C(O)=O>CO.C1(C)C=CC=CC=1>[NH2:11][C:10]1[C:9]2[C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)=[CH:7][C:6]([C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[CH:29][CH:28]=[CH:27][C:26]=3[O:41][CH2:42][CH:43]3[CH2:44][CH2:45]3)=[N:5][C:4]=2[N:3]=[CH:2][N:1]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(/N=C/N)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3c(N)ncnc3n2)cc1
Reaction time: 480 h
Yield: 14.7 %

Procedure:
To a solution of tert-butyl 3-(2-{[(1E)-aminomethylidene]amino}-3-cyano-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-1-piperidinecarboxylate (0.180 g, 0.289 mmol) in MeOH (5 mL) and toluene (5 mL) was added trifluoroacetic acid (0.01 mL). The mixture was allowed to stand for 20 days and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH 50:1 to 20:1) gave tert-butyl 3-(4-amino-7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}pyrido[2,3-d]pyrimidin-5-yl)-1-piperidinecarboxylate as a colorless oil (0.026 g, yield; 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])C)[CH:9]=[CH:10][CH:11]=1.[Se](=O)=O.[C:23]([O-:26])(O)=[O:24].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[C:23]([OH:26])=[O:24])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: O=[Se]=O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cccc(C)c1COc1cccc(C(=O)C(=O)O)c1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)-phenyl)-ethanone (WO 02/100341, 5 g, 20 mmol) in pyridine (20 ml) was added selenium dioxide (3.492 g, 31 mmol) diluted in pyridine (20 ml). The reaction mixture was heated at 100° C. for 3 hours, decanted from selenium metal and concentrated in vacuo to give orange oil, which solidified at room temperature. The solid was dissolved in saturated NaHCO3 (40 ml) and stirred with decolorizing carbon (0.5 g) for an hour at room temperature. The reaction mixture was filtered through celite and aqueous filtrate was acidified using 6N HCl (6 ml). A gray precipitant (6.3 g) was filtered and dried in vacuo at 40° C. for 2 hours. The acidified filtrate was washed with ether (2×75 ml), dried over Na2SO4, filtered, and concentrated to yield a white solid (0.5 g). Recrystallization using carbon tetrachloride afforded 4.9 g of the title compound with pyridine as an impurity. The semipure material (4.2 g) was dissolved in ethyl acetate (150 ml) and washed with 5% HCl (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow solid (3.9 g). The solid was recrystallized with carbon tetrachloride (30 ml) to afford the title compound (3.03 g) as a light yellow solid.
Reaction SMILES: C(O[C:5]([O:9][C:10](=[O:12])[CH3:11])=[CH:6][CH2:7]C)(=O)C.[CH2:13]=CC=C.O=O.[C:19]([OH:22])(=[O:21])[CH3:20]>[Pd]>[C:10]([O:9][CH:5]([CH:6]([O:21][C:19](=[O:22])[CH3:20])[CH3:7])[CH3:13])(=[O:12])[CH3:11]
Reactant: CCC=C(OC(C)=O)OC(C)=O
Reactant: C=CC=C
Reactant: CC(=O)O
Agent: [Pd]
Agent: O=O
Product: CC(=O)OC(C)C(C)OC(C)=O

Procedure:
Diacetoxybutene which had been prepared by catalytically reacting butadiene, acetic acid and an oxygen-containing gas with a palladium-based catalyst at 80° to 100° C, was hydrogenated in the presence of a palladium catalyst carried on activated carbon to produce diacetoxybutane having the composition set forth below. The resulting diacetoxybutane was then hydrolyzed in the presence of a cation exchange resin, DIAION SK1B, (trade mark, manufactured by Mitsubishi Chemical Industries Ltd.) at about 60° C and subjected to distillation to prepare crude 1,4-butanediol, which contained 98.5 % by weight of 1,4-butanediol, 0.7 % by weight of high boiling substances and 0.8 % by weight of other substances.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.CCOCC>[CH3:1][N:2]([CH3:3])[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC
Reactant: O=C(CBr)C(c1ccccc1)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CC(=O)C(c1ccccc1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
Dimethylamine in ethanol (30 ml s of 33% solution) was added to a solution of 3-bromo-1-p-fluorophenyl-1-phenylpropan-2-one (13g.) in dry ether. After 45 minutes, the reaction mixture was extracted with dilute hydrochloric acid and ether. Basification of the acid extract and subsequent isolation through ether in the usual manner gave 3-dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-one isolated as the hydrochloride (5 8g., 53%), m.p. 210° - 220°.