Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:25]([O:28][C@@H:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C@H:31]([NH2:40])[CH2:30]1)[CH:26]=[CH2:27].[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>CC#N>[CH2:25]([O:28][C@H:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C@@H:31]([NH:40][CH2:13][C@@H:11]([OH:12])[C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:30]1)[CH:26]=[CH2:27]
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: C=CCO[C@H]1C[C@@H](N)c2cc(OC)ccc21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Temperature: 30 °C
Reaction time: 60 h
Yield: 16 %

Procedure:
Step E (1): A mixture of benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate (1.0 g, 3.0 mmol), cis-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine (657 mg, 3.0 mmol) and LiClO4 (1.60 g, 15 mmol) in CH3CN (10 mL) with was stirred at 30° C. for 2.5 days. The resulting mixture was poured into brine/NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1-20% MeOH (containing 0.1% triethylamine)/chloroform linear gradient) to give two pure diastereomers 265 mg (16% yield) of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer A, first to elute) and 270 mg (16% yield)of benzyl (2S,3R)-4-((1R,3S)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (diastereomer B, second to elute). Data for diastereomer A: HRMS (M+H)+=553.2534; 1H NMR (500 MHz, DMSO-d6) δ 7.21-7.35 (m, 4H), 7.14-7.21 (m, 2 H), 7.03 (t, J=9.46 Hz, 1H), 6.87-6.99 (m, 3H), 6.83 (dd, J=8.24, 2.14 Hz, 1H), 5.88-6.00 (m, 1H), 5.30 (dd, J=17.09, 1.83 Hz, 1H), 5.14 (dd, J=10.53, 1.98 Hz, 1H), 4.96-5.02 (m, 1H), 4.83-4.95 (m, 2H), 4.75 (t, J=6.41 Hz, 1H), 4.01-4.13 (m, 2H), 3.91-4.00 (m, 1H), 3.72-3.76 (m, 3H), 3.64-3.72 (m, 1H), 3.44-3.53 (m, 1H), 3.06 (dd, J=13.73, 3.05 Hz, 1H), 2.65-2.75 (m, 1H), 2.54-2.65 (m, 2H), 1.92-2.02 (m, 1H), 1.57-1.67 (m, 1H). Data for diastereomer B: HRMS (M+H)+=553.2509; 1H NMR (500 MHz, DMSO-d6) δ 7.20-7.37 (m, 4H), 7.12-7.22 (m, 2H), 6.98-7.13 (m, 1H), 6.86-7.00 (m, 3H), 6.82 (dd, J=8.24, 2.14 Hz, 1H), 5.80-6.05 (m, 1H), 5.30 (dd, J=17.40, 1.83 Hz, 1H), 5.14 (d, J=10.38 Hz, 1H), 4.80-5.03 (m, 3H), 4.74 (t, J=5.95 Hz, 1H), 3.99-4.15 (m, 2H), 3.95 (t, J=6.10 Hz, 1H), 3.62-3.77 (m, 3H), 3.49 (d, J=4.88 Hz, 1H), 3.03 (dd, J=13.89, 3.20 Hz, 1H), 2.54-2.80 (m, 4H), 2.01-2.18 (m, 1H), 1.59-1.76 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[CH2:36][C:32]1[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=1
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3ncc[nH]3)ccc2C1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 89.4 %

Procedure:
The compound (104 mg) obtained in Example 17-7 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (42.9 mg) and sodium cyanoborohydride (49.0 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 16.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (115 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26](OC)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:31]>CO>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([NH2:31])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Solvent: CO
Product: NC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Reaction time: 168 h

Procedure:
1 g of methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate (Example 1) is dissolved in 20 ml of an approximately 10% strength solution of ammonia in methanol, and the solution is left to stand in a closed vessel at room temperature for 7 days. The solvent is removed by distillation in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase ethyl acetate/cyclohexane 1:4).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=2)[CH:8]=1)[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C1COCC1.CN1C(=O)CCC1>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[N:15]=[C:16]([NH:20][C:24](=[O:27])[CH:25]=[CH2:26])[CH:17]=[CH:18][CH:19]=2)[CH:8]=1
Reactant: COc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C=CC(=O)Nc1cccc(Nc2cc(Oc3cccc(OC)c3)ncn2)n1
Reaction time: 2 h

Procedure:
To a stirred solution of N2-(6-(3-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (100 mg, 0.323 mmol) in THF/NMP (1 mL/0.5 mL) was added acryloyl chloride (0.029 g, 0.3 mmol) under N2 atmosphere at −10° C. The stifling was continued at the same temperature for 2 h and the reaction mixture was concentrated under reduced pressure to give a residue that was further purified by column chromatography (SiO2, 60-120, chloroform/methanol) to give N-(6-(6-(3-methoxyphenoxy)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-90) as a pale yellow solid. 1H NMR (DMSO-d6) δ ppm: 3.75 (s, 3H), 5.79 (dd, J=1.8 & 10.08 Hz, 1H), 6.30 (dd, J=1.8 & 16.96 Hz, 1H), 6.65 (dd, J=10.12 & 16.96 Hz, 1H), 6.74-6.76 (m, 2H), 6.82 (td, J=1.52 & 9.24 Hz, 1H), 7.04 (d, J=7.92 Hz, 1H), 7.33 (t, J=8.28 Hz, 1H), 7.70 (t, J=7.96 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.90 (s, 1H), 8.34 (s, 1H), 10.20 (s, 1H), 10.48 (s, 1H); LCMS: m/e 364 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([NH:15]/[C:16](/[CH3:21])=[CH:17]\[C:18]([O-:20])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2=[C:14]3[C:13](=[CH:12][CH:11]=[C:9]2[N:10]=1)[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]3[OH:20]
Reactant: C/C(=C/C(=O)[O-])Nc1ccc2nc(-c3ccco3)[nH]c2c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(O)c2c(ccc3nc(-c4ccco4)[nH]c32)n1
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a preheated (230°) solution of Dowtherm (500 ml) is added portion-wise 3-[[2-(2-furyl)-5-benzimidazolyl]amino]crotonate (38.5 g, 0.1 mole). After the addition is complete the reaction mixture is kept at 230° for 15 minutes, then decanted into a beaker to form, upon cooling, a tan precipitate. The precipitate is filtered and washed with hexane to give 20 g (74 percent) of tan solid. Recrystallization from CH3NO2 gives m.p. 280°-282°. Anal. Calcd. for C15H11N3O2 -1/4H2O: C, 66.78; H, 4.30; N, 15.58. Found: C, 66.56; H, 4.43; N, 15.40.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[C:27]([OH:34])[C:26]=2[CH3:35])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].Cl>CN(C=O)C.O>[NH2:12][C:13]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[C:27]([O:34][CH2:2][CH2:3][O:4][CH3:5])[C:26]=2[CH3:35])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COCCBr
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1c(C)c(C(=O)c2ccc(N)c(C(=O)OC)c2)n2ccccc12
Yield: 40.4 %

Procedure:
0.161 g (1.16 mmol) of 1-bromo-2-methoxyethane and 0.359 mg (1.16 mmol) of caesium carbonate are added, under an inert atmosphere at ambient temperature, to 0.313 g (0.97 mmol) of methyl 2-amino-5-{[1-hydroxy-2-methylindolizin-3-yl]-carbonyl}benzoate in 10 ml of DMF. The reaction medium is stirred for 24 hours at ambient temperature, hydrolysed with water, and then acidified with a 1N aqueous solution of hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic phase obtained is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 150 mg of a yellow oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:31][CH3:32])[CH2:24][C:25](N(OC)C)=[O:26])=[CH:4][CH:3]=1.[CH3:33][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:31][CH3:32])[CH2:24][C:25](=[O:26])[CH3:33])=[CH:4][CH:3]=1
Reactant: CCC(CC(=O)N(C)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-N-methoxy-N-methylpentanamide (148.6 mg, 0.30 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (3.0 M in diethyl ether, 0.3 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hr and at room temperature for 1 hr. Methylmagnesium bromide (3.0 M in diethyl ether, 0.3 mL, 0.9 mmol) was added to the reaction mixture at room temperature. After the mixture was stirred at room temperature for 2 hr, aqueous ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture to give the title compound (96.0 mg, 0.213 mmol, 71%) as colorless crystals.
Reaction SMILES: P([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(O)(O)=O.C([Li])CCC.[CH2:18]([O:20][C:21]([C:23]1[S:27][C:26]2[CH:28]=[C:29]([CH:32]=O)[CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])[CH3:19]>C1COCC1>[CH2:18]([O:20][C:21]([C:23]1[S:27][C:26]2[CH:28]=[C:29]([CH:32]=[CH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])[CH3:19]
Reactant: CC(C)(C)OC(=O)CP(=O)(O)O
Reactant: CCOC(=O)c1cc2ccc(C=O)cc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C=CC(=O)OC(C)(C)C)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a stirred solution of tert-butyl phosphonoacetate (1.7 g, 7.27 mmol) in THF (20 mL) was slowly added n-butyllithium (1.6 M, 5 mL) with cooling to −78 degrees Celsius. After stirring for 30 minutes at −78 degrees Celsius, this solution was added into a solution of 6-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (1.83 g, 7.27 mmol). The resulting solution was stirred at −78 degrees Celsius for 30 minutes before being allowed to warm to room temperature. The solution was subsequently cooled back to −78 degrees Celsius and quenched with sat. aq NH4Cl. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate. After being filtrated and concentrated, the residue was purified by flash column chromatography to give 1.7 g (71%) of 6-(2-tert-butoxycarbonyl-vinyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester. MS: calc'd 333 (MH+), exp 333 (MH+). 1H NMR (d6-DMSO, 400 MHz), 8.38 (s, 1H), 8.18 (s, 1H), 8.02 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.4 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.66 (d, 1H, J=16.0 Hz), 4.36 (q, 2H, J=7.2 Hz), 1.49 (s, 9H), 1.34 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][NH:14][CH3:13])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cccc(F)c12
Reactant: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2cccc(F)c12

Procedure:
According to the procedure of Preparation 13 (c),except substituting 4-fluoro-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=3[F:35])[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: O=Cc1ccccc1F
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2F)CC1
Yield: 8.2 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 2-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (6.1 mg, 8.2%) as light yellow oil. MS m/e=573.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[C:5]([CH3:16])=[CH:4][S:3][C:2]=2[NH:1][C:17](=[O:19])[N:18]=1
Reactant: Cc1csc(N)c1C(=O)c1ccccc1F
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2[nH]c(=O)nc(-c3ccccc3F)c12
Temperature: 200 °C

Procedure:
A mixture of 18.5 g of 2-amino-3-(o-fluorobenzoyl)-4-methylthiophene, 26.6 g of ethyl carbamate and 1.61 g of zinc chloride is heated at 200°C for 30 minutes. After cooling, the reaction mixture is washed with chloroform, then with water, and filtered to give crude crystals of 4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one having a melting point of 258° - 261°C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[O:4][N:3]=1.C([O-])(=O)C.[Na+].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>C1C=CC=CC=1>[C:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: Cc1cc(CCCCCCCO)on1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCCCCCCCc1cc(C)no1
Yield: 70 %

Procedure:
To a mixture of 7-(3-methylisoxazol-5-yl)heptan-1-ol (1.97 g, 0.01 mol) and anhydrous sodium acetate (0.080 g) in benzene (20mL) was added a solution of diketene (1.84 g, 0.022 mol) in benzene (6 mL) dropwise. The mixture was refluxed for 12 h. After the removal of benzene under reduced pressure, the crude product was purified by elution from a silica gel column using dichloromethane-hexane (9:1 v/v) as eluant to give 5-(7-acetoacetoxyhept-1-yl)-3-methylisoxazole (21) (70%) as a yellow oil. IR (neat) 1740 (CO2), 1718 (CO)cm-1 ; NMR (CDCl3) 1.12-1.95 (m, 10H, (CH2)5), 2.35 (S, 6H, Me-Het, CO-Me), 2.70 (t, J=9 Hz, 2H, CH2 --Het), 3.49 (S, 2H, CO--CH2 --COMe), 4.14 (t, J=6 Hz, 2H, O--CH2), 5.80 (S, 1H, H-Het). Analysis found: C, 64.11; H, 8.31; N, 4.72. Required: C, 64.02; H, 8.24; N, 5.00 (C15H23NO4). ##STR8##
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[BH4-].[Na+].[CH3:17]O.Cl>C1COCC1>[CH3:17][C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=[CH:2][CH:3]=1)[CH2:7][OH:9]
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
To a refluxed solution of methyl 5-methyl-2-nitrobenzoate (50 g, 0.256 mol) and sodium borohydride (29 g, 0.768 mol) in THF (400 mL) was added dropwise methanol (60 mL) over 2.5 h. After the addition was completed, the mixture was refluxed for 1 h and allowed to cool at room temperature. The excess reagent was decomposed by addition of diluted hydrochloric acid (300 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 43.0 g of the title compound (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18]C(NCCN)=S)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CO>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][N:10]3[CH2:11][CH2:12][N:8]=[CH:9]3)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(NC(=S)NCCN)ccc2c1ncn2C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(NN2C=NCC2)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea (2.89 g) and mercuric acetate (3.32 g) in methanol (200 mL)/chloroform (100 mL) is stirred at room temperature for 2 hours. The resulting black mixture is filtered on Celite and the filtrate rotary evaporated. The residue is purified by flash chromatography on a short pad of silica gel, eluting with 10% methanol/chloroform containing 1% ammonium hydroxide. The product-containing fractions are collected and rotary evaporated to afford 1-tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncn1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
p-Anisaldehyde (320 g, 2.35 mol, 1.0 equiv; Aldrich, St. Louis, Mo.) and 4-aminopyrimidine (246 g, 2.58 mol, 1.1 equiv; AK Scientific, Inc., Union City, Calif.) were dissolved in anhydrous DCM (8.0 L). To this solution under N2 atmosphere at room temperature was added a solution of Ti (Oi-Pr)3Cl (1348 g, 5.17 mol, 2.2 equiv; Aldrich) in anhydrous DCM (1 L) in one portion and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 10° C. and NaBH(OAc)3 (1495 g, 7.05 mol, 3.0 equiv; Aldrich) was added in portions over 30 min followed by the addition of acetic acid (10 mL). (Note: A mild exotherm of 10-19° C. was observed). Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction was monitored using LC/MS. Product formation was observed along with many other peaks. Upon completion the reaction mixture was quenched slowly and carefully pouring over a well-stirred saturated aqueous NaHCO3 (30 L). The crude product was then extracted with dichloromethane (3×12 L) and the organic extracts were combined, washed with brine (5 L), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was initially triturated with hexanes to obtain a solid. The crude solid was further triturated with MTBE to remove most of the impurities. The crude product was purified using column chromatography eluting with MeOH/ethyl acetate (2:98 to 5:95) to afford N-(4-methoxybenzyl)pyrimidin-4-amine (INTERMEDIATE OO) as a white solid with >99% purity (129 g, 26% yield). 1H NMR (400 MHz, DMSO) δ ppm 8.40 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 6.98-6.77 (m, 2H), 6.48 (s, 1H), 4.43 (s, 2H), 3.72 (s, 3H). m/z (ESI) 216.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25]O)=[CH:24][C:19]=2[O:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][O:18][C:19]=3[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.0 g, 4.8 mmol), benzo[1,3]dioxol-5-yl-methanol (1.4 g, 9.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 9.5 mmol) in THF (30 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (1.9 mL, 9.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the filter was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid dimethyl ester (1.7 g, 102% crude yield). The product was used in the next step without further purification.