Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:17]([CH3:27])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:13][C:12]([CH3:29])([CH3:28])[C:11]1[CH2:30][CH2:31][CH2:32][C:33](=O)[C:10]2=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:17]([CH3:27])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:13][C:12]([CH3:28])([CH3:29])[C:11]1[CH2:30][CH2:31][CH2:32][C:33](=[CH2:1])[C:10]2=1
Reactant: [Li]CCCC
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1=O)C(C)(C)N2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCC2=C1c1cc(O)c(C(C)CCCc3ccccc3)cc1NC2(C)C
Reaction time: 8 h

Procedure:
A 1 N ethereal solution of butyllithium (9 ml.) is added with stirring, under a nitrogen atmosphere to a suspension of 3.57 g. (10 mmoles) of methyltriphenylphosphonium bromide (prepared from methyl bromide and triphenylphosphine) in 50 ml. of ether. 5,6,7,8,9,10-Hexahydro-2-hydroxy-3-(1-methyl-4-phenylbutyl)-6,6-dimethyl-10-oxo-benzo[c]quinoline (600 mg., 1.5 mmoles) dissolved in 100 ml. of ether is added and the mixture is stirred for four hours then allowed to stand overnight at room temperature. Ether is distilled off as tetrahydrofuran is added until most of the ether is replaced. The mixture was then refluxed for six hours, cooled and worked-up as described in Part A of Example 42 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)C2CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method F)=2.00
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([F:10])[CH:9]=2)[CH2:3][CH2:2]1.Cl[C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]3[CH:22]=[C:23]([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[N:24]=[N:25][CH:26]=3)[CH:7]=[C:8]([F:10])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2cc(F)cc(C3CC3)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2cc(F)cc(C3CC3)c2)cnn1

Procedure:
The title compound was prepared from 2-(3-cyclopropyl-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine. (1H-NMR (300 MHz, CDCl3) δ=9.38 (s, 1H), 6.80-7.55 (m, 6H), 5.50 (s, 2H), 2.41 (s, 3H), 1.92-2.02 (m, 1H), 1.02-1.14 (m, 2H), 0.68-0.78 (m, 2H))
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:7][C@@H:6]1[C@@H:2]([O:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
(3R,4S)-Benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (19.6 g, 83 mmol) was dissolved in pyridine (83 ml). To the above solution, Ts-Cl (22.2 g, 117 mmol) was added in portions at rt. After overnight stirring, the reaction mixture was concentrated in vacuo to remove pyridine. The residue was quenched with ice water (200 mL), extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phase was washed with water, 1N HCl, water and sat. NaHCO3, then dried with Na2SO4. After concentration, (3S,4R)-benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (30 g, 92% yield) was obtained as light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.76-7.83 (2H, m), 7.30-7.40 (7H, m), 5.11 (2H, s), 4.57-4.64 (1H, m), 3.56-3.73 (2H, m), 3.38-3.54 (1H, m), 3.08-3.19 (1H, m), 2.33-2.55 (4H, m), 0.97 (3H, dd, J=14.86, 7.15 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 3.60 min; MS(ES+) m/z: 390 (M+H+).
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][C@H:8]([O:11]C(=O)C)[CH2:7]1>CO>[F:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7]1
Reactant: CC(=O)O[C@H]1CCN(CCF)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1CCN(CCF)C1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
4N aqueous sodium hydroxide solution (2 mL) was added to methanol (10 mL) solution of (3S)-1-(2-fluoroethyl)-3-acetoxypyrrolidine (507 mg, 2.89 mmols), and stirred at room temperature for an hour. The reaction liquid was concentrated under reduced pressure, extracted with chloroform and dried over anhydrous sodium sulfate. Concentrating the reaction liquid under reduced pressure, the title compound (135 mg, 35%) was obtained.
Reaction SMILES: OO.[Br:3][C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)C=O.[O-:16]S([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O.C(O)=O.O>[CH3:13][O:12][C:7]1[C:6]([O:14][CH3:15])=[CH:5][C:4]([Br:3])=[CH:11][C:8]=1[OH:16]
Reactant: O=S([O-])[O-]
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COc1cc(Br)cc(O)c1OC
Temperature: 25 °C
Yield: 50 %

Procedure:
A freshly prepared mixture of 30% H2O2 (3.9 g), formic acid (11 mL), and concentrated sulfuric acid (3 drops) was maintained for 1 hour at room temperature. The mixture was then cooled to 5° C. and treated with a solution of 5-bromo-2,3-dimethoxybenzaldehyde (4.15 g) in formic acid (25 mL). The mixture was maintained for 4 hours at 5° C. then placed in the 4° C. freezer overnight. Reaction mixture was then treated with a solution of Na2SO3 (3.4 g) in water (100 mL), stirred, and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with 50 mL water followed by 50 mL brine and then organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in diethyl ether (20 mL) and after addition of 25% aqueous KOH (220 mL) was vigorously stirred under nitrogen. The organic layer was separated, the aqueous phase acidified to a pH of 3 with 2 N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to yield an oily residue which was purified by chromatography on silica in 3:1 hexane/ethyl acetate to provide 2,3-dimethoxy-5-bromophenol in 50% yield. 1H NMR (400 MHz) (CDCl3) δ 3.87 (s, 3H), 3.89 (s, 3H), 5.84 (s, 1H), 6.64 (d, J=4.0 Hz, 1H), 6.80 (d, J=4.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:3]([O:23][C@H:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][O:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:22][C:16](=[O:22])[CH3:15])=[CH:8]1)(=[O:2])[CH3:4]
Reactant: COC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC[C@]12CC[C@H](OC(C)=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 8 h

Procedure:
19-Methoxyandrost-4-ene-3β,17β-diol is dissolved in a mixture of acetic anhydride and pyridine and the solution allowed to stand overnight at room temperature. The solvents are removed under vacuum and the remaining residue crystallized from acetone-hexane to yield 19-methoxyandrost-4-ene-3β,17β-diol diacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=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.C(N(CC)CC)C>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:25])=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ncccc2c1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 6-aminoquinoline (500 mg, 3.47 mmol) and 4-benzyloxybenzoic acid (792 mg, 3.47 mmol) in dichloromethane (25 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.84 g, 4.16 mmol) and triethylamine (0.58 mL, 4.16 mmol), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (218 mg, 18%) was obtained as a white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:13])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([F:13])[CH:6]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium cyanide (1.3 g, 20 mmol) was added to a solution of 4-bromo-2-fluorobenzylbromide (5.00 g, 18.7 mmol) in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate) to give (4-bromo-2-fluorophenyl)acetonitrile in colorless solid form (3.75 g, yield: 94%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccnc1-c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(-c2ncccc2C(=O)O)c1
Reaction time: 20 h
Yield: 92.7 %

Procedure:
Methyl 2-(3′-cyanophenyl)nicotinate (1.21 g, 5.1 mmol) was partially dissolved in MeOH (40 mL), and lithium hydroxide monohydrate (234 mg dissolved in 6 mL H2O, 5.6 mmol) was added. After 20 hours, the resulting solution was diluted with water and extracted with CHCl3. The aqueous was acidified to pH 4 with 1 M HCl and extracted several times with CHCl3. Solid sodium chloride was added to the aqueous solution and the solution was extracted with 5-10% MeOH/CHCl3. The organic extracts were combined, dried over Na2SO4, filtered, and evaporated to yield a white solid (1.06 g, 93%). 1H NMR (CDCl3): δ8.85 (dd, 1H, J=5.1, J′=1.5), 8.35 (dd, 1H, J=7.6, J′=1.4), 7.84 (s, 1H), 7.75 (m, 2H), 7.55 (t, 1H, J=7.7), 7.47 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]>C(OCC)(=O)C.CCCCCC>[CH3:32][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 84 %

Procedure:
Using ethyl (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate obtained in Example 178, the title compound was synthesized in the same manner as in Example 180. Yield: 84%. Melting point: 103-105° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24]>C(Cl)Cl>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Reactant: COCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Methoxyethyl chloroformate (32 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(methoxyethoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH2:20][CH3:21])=O)[CH:5]=1.[C:29]([S-:31])#[N:30].[K+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]=3[CH2:20][CH3:21])[N:30]=[C:29]2[SH:31])[CH:5]=1
Reactant: CCc1c(C(=O)CNc2cc(C(=O)OC)ccc2C)cnn1-c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)c(S)n2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A suspension of 3.75 g (9.94 mmol) of 3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoic acid methyl ester and 2.9 g (30 mmol) of KSCN in 25 mL of HOAc was stirred at 100° C. for 4 h. The mixture was allowed to cool overnight before being filtered and washed with cold MeOH. The solids were dried to provide 2.65 g of 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-mercapto-imidazol-1-yl]-4-methyl-benzoic acid methyl ester as an off-white solid. ESI MS m/z 419 [C23H22N4O2S+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=2)[C:13](/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH3:36])=[N:12][C:11]=1[Cl:37])(C(C)(C)C)(C)C.[F-]>CCCCCC.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([CH2:9][OH:8])=[C:11]([Cl:37])[N:12]=[C:13]2/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH3:36])=[CH:17][CH:18]=1)([O:30][CH3:31])=[O:29]
Reactant: CCC/C=C\c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC/C=C\c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
5-t-Butyldimethylsilyloxymethyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-2-(cis-pent-1-en-1-yl)imidazole (100 mg) was desilylated with fluoride by procedures familiar to one skilled in the art. Flash chromatography in 1:1 hexane/ethyl acetate yielded 65 mg of a viscous, colorless oil. NMR (200 MHz, CDCl3) δ7.85 (d, 1H), 7.55 (t, 1H), 7.42 (t, 1H), 7.28 (m, 3H), 7.05 (d, 2H), 6.11 (d, 1H), 5.92 (d of t, 1H), 5.30 (s, 2H), 4.57 (d, 2H), 3.64 (s, 3H), 2.69 (quart., 2H), 1.62 (t, 1H), 1.47 (sext., 2H), 0.92 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[Na].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1
Reactant: CNc1nc(Br)cc(Br)n1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CNc1nc(Br)cc(Sc2ccccc2)n1
Yield: 65.3 %

Procedure:
0.33 g (0.00124 mol) of (4,6-dibromopyrimidin-2-yl)-methylamine and 0.33 g (0.00248 mol) of thiophenol sodium salt were stirred in 15 ml of 1-methyl-2-pyrrolidone at 120° C. for 4 hrs. The solvent was removed and the residue was partitioned between water and diethyl ether. The ether phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with diethyl ether/hexane 1:3 and subsequently dried in a high vacuum. There was obtained 0.24 g (65%) of (4-bromo-6-phenylsulphanylpyrimidin-2-yl)-methylamine as white crystals; m.p.: 122-124° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 2 equivalents of 4-(1-pyrrolidinyl-methyl)-aniline, melting point 45-50° C. in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])(=[O:3])[NH2:2].[CH:11]([OH:14])([CH3:13])[CH3:12]>>[C:8]([O:14][CH:11]([CH3:13])[CH3:12])(=[O:9])/[CH:7]=[CH:6]\[C:5](=[O:10])[NH:4][C:1](=[O:3])[NH2:2]
Reactant: CC(C)O
Reactant: NC(=O)N1C(=O)C=CC1=O
Product: CC(C)OC(=O)/C=C\C(=O)NC(N)=O
Yield: 95 %

Procedure:
The addition of isopropanol to N-carbamylmaleimide under the conditions of Example C afforded a 95% yield of isopropyl maleurate. M.P.: 113°-14° C.; 1H NMR (CDCl3): δ10.6 (br s, 1H), 8.2 (br s, 1H), 6.3 (AB, 2H), 5.8 (br s, 1H), 5.2 (quintet, 1H), 1.3 (d, 6H); HPLC (20% CH3CN/H2O, C8): Rt=5.6 minutes.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28]S([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: C[Si](C)(C)CCS(=O)(=O)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sulfuryl chloride (43 ml, 539 mmol) was added in 3 min to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 mL) at 0° C. in a flame-dried three-neck round bottom flask. After stirring at 0° C. for 5 min, the ice-water bath was removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) was added in portions over 10 min. The resulting white suspension was stirred at room temperature for 16 h, then it was filtered through a pad of celite. The filtrate was concentrated to ca 50 mL, ethyl acetate/hexanes (1:3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 min and filtered through a pad of celite. Solvents were removed in vacuo and the residue was loaded onto a pre-wetted column with silica gel (300 mL) using 1:3 ethyl acetate/hexanes as the eluent. Solvents were removed and the title compound was obtained as a light tan liquid (41.9 g, 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize decomposition. 1H-NMR (CDCl3, 500 MHz) δ 3.61-3.57 (m, 2H), 1.32-1.27 (m, 2H), 0.10 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([CH:17]3[CH2:22][CH:21]([CH3:23])[N:20]([CH3:24])[CH:19](C)[CH2:18]3)(O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:26]=1.[OH-].[Na+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[CH2:7][CH2:8][C:9]1[C:10](/[C:15]/2=[C:17]2/[CH2:22][CH:21]([CH3:23])[NH:20][CH2:24][CH:18]/2[CH3:19])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1CC(C2(O)c3ccc(Cl)cc3CCc3cccnc32)CC(C)N1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C/C(=C2\c3ccc(Cl)cc3CCc3cccnc32)C(C)CN1
Yield: 6.3 %

Procedure:
A mixture of 8-chloro-11-(1,2,6-trimethyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ol (5.0 g, 14.1 mmol) in 85% H2SO4 (100 mL) was heated in an oil bath (60°-65° C.) for 3 hours. The reaction was cooled and diluted with water followed by basification with 25% aq. NaOH solution. The crude product was extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered and solvent removed. Purification and separation of the E and Z isomers via chromatography (2%→5% MeOH saturated with NH3 in CH2Cl2) gave the title compound (300 mg, 6%).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:8]=[N:9]O)[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ON=Cc1cc(O)ncn1
Solvent: CN(C)c1ccccc1
Product: N#Cc1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Hydroxy-pyrimidine-4-carbaldehyde oxime (9.3 g, 67 mmol) was stirred in 37 ml POCl3 under N2 at 40° C. for 30 min, 60° C. for 30 min, and 80° C. for one h. N,N,-Dimethylaniline was added very slowly by syringe, and stirred for one h at 80° C. After cooling to 0° C., the mixture was poured into a separatory funnel containing 300 g of ice. The mixture was carefully swirled, then extracted with 500 ml t-BuOMe. The organic layer was washed with 1 N HCl (4×100 ml), then several times with NaHCO3, then brine. Acidic and basic aqueous layers were separately back-extracted with t-BuOMe, and the organics again washed with 1 N HCl, saturated aqueous NaHCO3, and brine. The combined organic layers were dried with Na2SO4 and concentrated by rotary evaporator. The residue was filtered through a pad of silica gel, applying in CH2Cl2 and eluting with 10:1 hexanes/t-BuOMe. Fractions were carefully concentrated to obtain 6-chloro-pyrimidine-4-carbonitrile as a (volatile) pale yellow, semi-crystalline solid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.[CH3:21][N:22](C=O)C>>[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([NH:22][CH3:21])=[O:20]
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (0.01 mL, 0.11 mmol) was added slowly to a solution of 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (20 mg, 0.09 mmol) in DMF (3 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess methylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (30 mL) was added to the mixture, which was washed with brine (2×30 mL). The organic layer was dried over MgSO4, and concentrated to yield 4-(2-Fluoro-4-nitrophenyl)-N-methylbutanamide (81) (18 mg, 85%): 1H NMR δ 7.97 (dd, 1H, J=8.4, 2.2 Hz), 7.89 (dd, 1H, J=9.5, 2.2 Hz), 7.40 (dd, 1H, J=8.4, 7.3 Hz), 5.44 (br s, 1H), 2.81 (d, 3H, J=4.9 Hz) 2.79 (t, 2H, J=7.6 Hz) 2.22 (t, 2H, J=7.3 Hz) 1.96-2.04 (m, 2H).