Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:2]=[CH:3]4)[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Reactant: CCOC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of 5-[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D43) (85 mg, 0.246 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ethyl 3-bromo-2,2-dimethylpropanoate (D98) (103 mg, 0.492 mmol) and Cs2CO3 (120 mg, 0.369 mmol). The resulting mixture was stirred at 80° C. for 48 h then cooled to room temperature and diluted with EtOAc. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [30-50% EtOAc/cyclohexene] gave the title compound (20 mg, 16%) as a yellow solid. MS (ES) C26H27N5O4 requires 473, found 474 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:12]=1[Cl:11])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cccc(Cl)c1C(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc(Cl)c1C(=O)Nc1ccccc1C(N)=O
Temperature: 0 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
2-Amino-benzamide (6.9 g, 50.8 mmol) was dissolved in 50 mL of pyridine and cooled to 0° C. 2-Chloro-6-methoxy-benzoyl chloride was added dropwise to the solution. After complete addition, the reaction was left to stir at room temperature for three days, which resulted in formation of a brown, cloudy solution. The reaction mixture was then poured into 150 mL of ice water. The precipitate was filtered and washed twice with water, twice with THF and finally twice with CH2Cl2 to obtain N-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide (13.3 g, 43.7 mmol, 86%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14]
Reactant: OCCCCCCCCCCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
To 12-bromododecanol (5 g) dissolved in methylene chloride (30 ml) were added Celite (5.0 g) and pyridinium chlorochromate (5.2 g), and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give 12-bromododecanal (4.4 g). To 12-bromododecanal (4.4 g) dissolved in methylene chloride (50 ml) was added (carbomethoxymethylene)-triphenylphosphorane (6.75 g), and the mixture was stirred for 4 hours. Then, the reaction mixture was concentrated, and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give the methyl ester of 14-bromo-2-tetradecenoic acid (4.91 g). The product was dissolved in acetonitrile (30 ml), and 1M tetra-n-butylammonium chloride in THF (27 ml) and potassium fluoride (7.6 g) were added. The mixture was heated under reflux for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethylacetate 100:1 to give the methyl ester of 14-fluoro-3-tetradecenoic acid (3.3 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]=[CH:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][O:16]4)=[CH:30][CH:29]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (6.92 g, 33.5 mmol) and 4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (7.25 g, 35.2 mmol) in 110 mL methylene chloride was added magnesium sulfate (14.2 g, 117.3 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction was filtered and concentrated to afford 13.3 g of the crude title compound of Step A which was used without further purification. MS 395.2 (M+1)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[O:13])=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl)piperazine-1-carboxylate (0.048 g, 0.13 mmol) in methanol (2.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.025 g, 0.17 mmol). Then, the mixture was added with 7 drops of piperidine, and the mixture was stirred at 50° C. for 4 hours. The solid formed was removed by filtration, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl}piperazine-1-carboxylate (0.054 g, 85%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH2:24]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][CH:2]1[CH3:1]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CCOC(=O)CN1C(=O)CCC1C
Product: CC1CCC(=O)N1CC(=O)NCCN1[C@H](C)CCC[C@@H]1C

Procedure:
From 9.26 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate (British Pat. No. 1,309,692) and 8.6 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine, following the procedure of Example 9, there is obtained cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-methyl-5-oxo-1-pyrrolidineacetamide; m.p. 115°-116° C. after crystallization from cyclohexane.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](Cl)=[O:13]>>[OH:13][C:12](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC#N
Reactant: Cn1cccc1C(=O)Cl
Product: Cn1cccc1C(O)=C(C#N)C#N

Procedure:
[Hydroxy(1-methylpyrrol-2-yl)methylene]methane-1,1-dicarbonitrile was synthesized in the same manner using malononitrile and 1-methylpyrrole-2-carbonylchloride. The ESI/MS data for this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:45]=[O:46])C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10]([CH:45]=[O:46])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C=O
Temperature: -77 °C
Reaction time: 0.02 h

Procedure:
To a solution of THF (35 mL) was added 1-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (200 mg, 0.35 mmol). The solution was cooled to −77° C., and then 2.5 M n-BuLi in hexanes (0.70 mL, 1.75 mmol) was added. The reaction was stirred for 1 min and then DMF (0.16 mL, 2.1 mmol) was added. The solution was stirred for an additional 5 min, and the ice bath was removed. The reaction was allowed to warm to rt over the following 1 h. EtOAc was added to the solution followed by water. The solution was separated and the aqueous layer was back extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and evaporated yielding the title compound as crude material (216 mg, 119%). MS [M+H]+=521; LCMS RT=3.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[SH:8].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ccncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 3-bromopyridine-4-thiol (step A, 4.75 g, 25 mmol), ethyl 2-bromoisobutyrate (9.75 g, 50 mmol), and sodium carbonate (7.95 g, 75 mmol) in DMF (50 mL) was stirred at 60° C. for 1 hour. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with water (2×100 mL) and saturated sodium chloride (100 mL). The aqueous washes were back extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by normal phase chromatography (a gradient of 0-25% ethyl acetate in hexane) to yield ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate as a pale yellow oil (6.6 g, 88%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2([CH3:14])[CH3:13].[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.O>[CH3:13][C:6]1([CH3:14])[C:7]2[C:3](=[C:2]([O:1][C:18](=[O:19])[NH:17][CH3:16])[C:10]([CH3:11])=[CH:9][C:8]=2[CH3:12])[CH2:4][CH:5]1[CH3:15]
Reactant: CN=C=O
Reactant: Cc1cc(C)c2c(c1O)CC(C)C2(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1c(C)cc(C)c2c1CC(C)C2(C)C
Temperature: 70 °C
Yield: 63.7 %

Procedure:
34 g of 4-hydroxy-1,1,2,5,7-pentamethyl-indane, 14.3 g of methyl isocyanate and a few drops of triethylamine were dissolved in 102 ml of ligroin and the solution was stirred under slight reflux (about 70° C.) overnight. After cooling to 30° C., the mixture was stirred with 40 ml of water and the colorless crystals were filtered off and dried. Recrystallization from ligroin and toluene gave 27.7 g of N-methyl-carbamic acid 1,1,2,5,7-pentamethylindan-4-yl ester of melting point 130.5°-131° C.
Reaction SMILES: COC1C=C(C=CC=1OC)[CH2:6][N:7]([C@H:18]([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[H-].[Na+].C(N(CC)CC)C.C(Cl)(Cl)=[O:46]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][C@H:18]([N:7]2[CH2:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:10][C:6]2=[O:46])[CH3:30])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)CC(O)c2cccc(Cl)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@@H](C)N2C[C@@H](c3cccc(Cl)c3)OC2=O)cc1OC
Reaction time: 1 h

Procedure:
A solution of 0.8 g. of (R)-N-(3,4-dimethoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine in 10 mL of toluene is added to a slurry of 64 mg. of sodium hydride (60% oil slurry) in 5 mL of toluene at room temperature. The reaction mixture is stirred for one hour, 0.11 mL of triethylamine is added, and the reaction mixture is stirred for an additional 30 minutes. A 1.93M solution of phosgene (0.9 mL) is added and the reaction mixture is stirred for one hour and quenched with 10% hydrochloric acid. Additional toluene is added and the mixture is sequentially washed with dilute hydrochloric acid, 3N sodium hydroxide, and brine, after which it is dried over magnesium sulfate and concentrated to yield (R,R)-3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-(3-chlorophenyl)oxazolidin-2-one which is further purified by recrystallization from 1:7 ethanol:heptane to yield white crystals. Gas chromatography indicates the chemical purity is 99.9% and HPLC indicates the optical purity is 99.6%. 1H NMR (250 MHz, CDCl3) d 1.26 (d, 3H, J=6.7 Hz), 2.65-2.85 (m, 2H), 3.25 (m, 1H), 3.8-3.9 (m, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 4.34 (m, 1H), 5.35 (m, 1H), 6.6-7.4 (m, 7H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25](=O)[NH:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:17])[CH3:18])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=3)[N:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 3.43 mmol) was dissolved in m-xylenes (18 mL) and heated at 135° C. Solid ammonium acetate (1.70 g, 22.0 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (674 mg, 1.19 mmol): LCMS-ESI+: calc'd for C25H34BrN5O5: 564.5 (M+). Found: 564.2/566.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([O:29][CH3:30])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 35.7 %

Procedure:
Sodium hydride (60% in oil, 50.8 mg, 1.27 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (250 mg, 1.06 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (226 mg, 1.59 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (166 mg, 0.378 mmol, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[CH:7]=[CH:6][C:5]=1[S:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16])([O-])=O>CO.[Ni].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[CH:7]=[CH:6][C:5]=1[S:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccccc1Sc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccc(CCl)cc1N
Reaction time: 17 h
Yield: 95.4 %

Procedure:
A solution of 9.0 g (27.8 mmol) of methyl S-(2-nitro-4-chloromethylphenyl)thiosalicylate in 100 mL of methanol was hydrogenated over Raney nickel (1.12 g) at room temperature and 30 psi pressure with stirring for 17 hours. The residue obtained on evaporation of the methanol was dissolved in chloroform, filtered, dried over MgSO4, filtered, and concentrated in vacuo to provide methyl S-(2-amino-4-chloromethylphenyl)thiosalicylate as a white solid (8.16 g, 55.6%), 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H, —OCH3), 4.40 (s, 2H, —NH2), 6.77 (dd, 1H, J=1.2 Hz), 6.79 (dd, 1H, J=2.1 Hz), 6.84 (dd, 1H, J=2.4 Hz), 7.15-7.20 (m, 1H), 7.28-7.34 (m, 1H), 7.40 (d, 1H, J=8.1 Hz), 8.006 (dd, 1H, J=1.5 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].Cl.[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:29]([O:28][C:26]([C@@H:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:24]1)=[O:27])[CH3:30]
Reactant: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Reactant: CCOC(=O)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2C)c2ccc(F)cc2C)C1

Procedure:
1-[2-(2-Bromethoxy)-1-(2-methylphenyl)ethenyl]-4-fluoro-2-methylbenzene (1.15 g, 0.0033 mol), the (R)-enantiomer of ethyl nipecotate hydrochloride (see example 1) (1.92 g, 0.0099 mol) and dried potassium carbonate (2.28 g, 0.0165 mol) were stirred in acetone (100 ml) at reflux temperature for 54 h.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]2[C:17]([O:19][C:20](=O)[C:5]=12)=[O:18])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.O>C(O)(=O)C>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:18])[N:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=3)[C:20](=[O:19])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:16]
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic anhydride (23.3 g, 81.5 mmol) and ethyl (4-aminophenyl)acetate (14.8 g, 82 mmol) were refluxed under nitrogen in acetic acid (160 ml) overnight. The mixture was cooled to room temperature and poured into water (1 L). The white solid was filtered, washed with water and dissolved in dichloromethane (800 ml). The solution was washed with water, brine and dried (MgSO4) and the solvent evaporated under vacuum to give ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as an off-white solid (33 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[N+:10]([O-:14])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[C:26]([O:35][CH3:36])[CH:25]=1)=O.Cl>N1C=CC=CC=1>[CH3:36][O:35][C:26]1[CH:25]=[C:24]([C:22]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([C:8]3[C:9]([C:15]([F:17])([F:16])[F:18])=[N+:10]([O-:14])[CH:11]=[CH:12][CH:13]=3)[O:7][CH:21]=2)[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]=1[O:33][CH3:34]
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1OC
Reactant: CCOC(=O)CC(=O)c1ccc[n+]([O-])c1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cc(OC)c(OC)c([N+](=O)[O-])c2)coc1-c1ccc[n+]([O-])c1C(F)(F)F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3-(3-ethoxy-3-oxopropanoyl)-2-(trifluoromethyl)pyridine-1-oxide (1.39 g, 5 mmol) in pyridine (25 mL) was added 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)ethanone (1.67 g, 5.5 mmol). The reaction mixture was heated to 70° C. and stirred for 5 hours, then cooled to room temperature and poured onto 6 N aqueous HCl (100 mL). The precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane/isopropanol to give crude 3-(4-(3,4-dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.05 g (43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1csc(-n2ccnc2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Yield: 37.6 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and 3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H19) (235 mg, 0.8 mmol) according to the general procedure K. Obtained as a white solid (98 mg).