Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH3:43][O:44][C:45](Cl)=[O:46]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:45]([O:44][CH3:43])=[O:46])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: COC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.99 mL, 7.02 mmol) in 2-methyltetrahydrofuran (33 mL) at −5° C. was added n-BuLi (2.67 mL, 2.5 M in hexanes, 6.69 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and aripiprazole (1.50 g, 3.34 mmol) was added. After a further 10 minutes, methylchloroformate (0.65 mL, 8.36 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature. After 2 hours the reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 10% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was triturated in heptane to remove aliphatic impurities and then filtered to afford Compound-74 (0.824 g) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>CCOCC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2([OH:1])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: CCOC(=O)C1CC(O)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a stirred solution of ethyl 3-oxocyclobutanecarboxylate (2 g, 14.07 mmol) in dry Et2O (30 mL), cooled to −80° C., was added 4-fluorophenyl magnesium bromide (16.88 mL, 16.88 mmol, 1 M in THF) dropwise. The reaction mixture was then allowed to warm to RT and stir for an additional 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 276A as a colorless liquid (1.7 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (dd, J=5.5, 9.0 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.09 (q, J=7.4 Hz, 2H), 2.83-2.71 (m, 1H), 2.61 (s, 2H), 2.55-2.51 (m, 2H), 1.24-1.12 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.CS(O)(=O)=O.[H][H]>[Pd].C.CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 200 ml methanol, methanesulfonic acid (19.2 g, 0.20 mole), and 20.g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 5.7 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and methanol removed under vacuum. The bismethanesulfonate salt of 2,3,5-triamino-4,6-dimethylpyridine so obtained was purified by slurrying with dry isopropyl alcohol, filtering under nitrogen, and vacuum drying over P2O5 at 80°-90° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=O)[N:3]=1.Cl.[NH2:20][OH:21]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[N:20][OH:21])[N:3]=1
Reactant: NO
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=O)n1
Agent: Cl
Solvent: CCO
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=NO)n1

Procedure:
This compound was made from the compound of Example 46 by reaction with hydroxylamine hydrochloride in ethanol, mp. 260°-5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([O:17]CC)=O)[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][NH2:22].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([NH:22][CH3:21])=[O:17])[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 42.3 %

Procedure:
In 1.5 ml of methylene chloride were dissolved 0.5 g of ethyl (3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)acetate and 0.16 g of 40% methylamine-methanol and the mixture was allowed to stand at room temperature for 3 days. The solvent was then distilled off and the residue was recrystallized from methylene chloride-hexane to give 0.2 g of 2-(3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)-N-methylacetamide. This compound has the following physicochemical properties.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:27])[NH:22][CH2:23][CH2:24][O:25][CH3:26])[CH:18]=[C:17]([Cl:28])[C:16]=1[C:29](Cl)=[O:30]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:29]([C:16]3[C:17]([Cl:28])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:27])=[CH:20][C:15]=3[Cl:14])=[O:30])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-(2-methoxyethyl)benzamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 17).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:41][CH2:40][CH2:39]1>>[N:38]1([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1CNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and azetidine according to conditions described in general procedure C. Mp: 196-197° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.17-2.25(m, 2 H), 3.23-3.30(m, 6 H), 3.75-3.78(m, 4 H), 3.87(s, 1 H), 6.14(d, J=5.5 Hz, 1 H), 7.03-7.06(m, 1 H), 7.25(d, J=8.8 Hz, 1 H), 7.40-7.63(m, 5 H), 7.84-7.86 (m, 1 H), 7.99-8.01(m, 1 H), 8.22(d, J=5.5 Hz, 1 H), 10.47(s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:32])=[O:31]
Reactant: COC(=O)c1cccc(CSc2ccc(F)cc2N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 49.4 %

Procedure:
Following General Procedure B, the title compound (601 mg, 50%) was prepared from methyl 3-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (750 mg, 2.58 mmol) and benzofuran-2-sulfonyl chloride (556 mg, 2.58 mmol) in pyridine (5 ml).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[OH:9][C@H:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][NH:12][C@H:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CS(C)=O>[OH:9][C@H:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][NH:12][C@H:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:17][CH:16]=1
Reactant: OCCCCCCCl
Reactant: C[C@H](Cc1ccc(O)cc1)NC[C@H](O)COc1ccccc1
Solvent: CS(C)=O
Product: C[C@H](Cc1ccc(OCCCCCCO)cc1)NC[C@H](O)COc1ccccc1
Reaction time: 1 h

Procedure:
300 ml of 6-chlorohexanol were added to a solution of 602 mg of p-[(R)-2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenol and 246 mg of potassium t-butylate in 10 ml of dimethylsulfoxide and the reaction mixture was stirred at 80° for 1 hour. The reaction mixture was evaporated in a high vacuum and the residue was chromatographed on silica gel with chloroform/n-propanol/saturated ammonia (1000:50:3), whereby there were obtained 500 mg of pure, amorphous 6-[p-[(R)-2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenoxy]hexanol, [α]D20 =-21° (c=0.9 in methanol), ε222 =17230.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:9][C:10](=[S:11])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1cccc2oc(=S)oc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
3-Fluorobenzene-1,2-diol (5.0 g, 39 mmol) and thiophosgene (3.3 mL, 5.0 g, 42 mmol) were combined in chloroform (50 mL), cooled to 10° C. and treated dropwise over 30 min with sodium hydroxide (10% solution; 36 g, 90 mmol) with vigorous stirring. After stirring for 2 h at ambient temperature, the chloroform was removed under vacuum, and the solid formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (100 mL), the solution was washed with water (30 mL) and saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The crude solid was purified by chromatography on silica with 0-30% ethyl acetate-hexane to give the title compound (1.5 g, 77%): mp 58-59° C.; 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 1H), 7.12 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −131.32; EIMS m/z 170.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36]Br)[C:25]=1[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:25]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCCCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 67.9 %

Procedure:
A mixture of 2.62 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.00 g of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methyl ester and 3.70 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was concentrated in vacuo and the residue was purified by liquid chromatography using 30% ethyl acetate-hexane to give 5.10 g (68% yield) of 6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[N+:8]([C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[C:12]=1[NH:13][O:14][CH3:15])([O-:10])=[O:9].[CH2:27](I)[CH3:28]>CCOCC>[N+:8]([C:11]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[C:12]=1[N:13]([CH2:27][CH3:28])[O:14][CH3:15])([O-:10])=[O:9]
Reactant: CCI
Reactant: CONc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(OC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.017 mole of sodium hydride, obtained from 0.82 g. of a 50% dispersion of sodium hydride in mineral oil, was added 50 ml. of dimethylformamide. To the mixture there was added 5.0 g. (0.018 mole) of 2,6-dinitro-N-methoxy-α,α,α-trifluoro-p-toluidine (Example 5), and the mixture was heated for about 45 minutes at temperatures up to about 65° C. The reaction mixture was then cooled to room temperature and there was added thereto, dropwise, 5.3 g. (0.034 mole) of ethyl iodide. The mixture was allowed to stir at room temperature for about 30 minutes and was then heated for about 1 hour at about 80° C., and was checked by TLC. No starting material appeared on the thin layer chromatogram. The reaction product mixture was cooled and allowed to stand overnight at ambient room temperature. The reaction product mixture was worked up by diluting it with ether and washing several times with dilute aqueous hydrochloric acid, once with water, and drying the organic phase over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent removed in vacuo. The residue was chromatographed on a Florisil column using benzene both as solvent and as eluent. The first fractions collected appeared to contain the desired product. The fractions were combined, the solvent was removed in vacuo, and the residue thus obtained was recrystallized from petroleum ether (b.p. 60°-71° C.). The product had a melting point of about 95°-97° C., weighed 1.0 g., and was identified by NMR spectrum and elemental analyses as 2,6-dinitro-N-ethyl-N-methoxy-α,α,α-trifluoro-p-toluidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)[CH3:4].FC(F)(F)S(O[CH2:23][CH:24]([F:26])[F:25])(=O)=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH:24]([F:26])[F:25])=[C:10]([Br:15])[CH:9]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCC(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 60% dispersion in mineral oil (80 mg, 2.0 mmol, 1.0 eq.) was added portionwise to an ice-cooled solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (564 mg, 2.0 mmol, 1.0 eq.) in THF (9.4 mL). The ice bath was removed and the mixture was allowed to warm to r.t. and stirred for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (961 mg, 4.4 mmol, 2.2 eq.) in THF (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was taken up in DCM and water was added. The layers were separated and the aq. phase was extracted with DCM (3×). The comb. org. layers were washed with sat. aq. NaCl soln., dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Product: Cc1cc(C2(c3cc(-c4cccnc4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 37 %

Procedure:
The title compound was synthesized as described for Example 1 in 37% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and pyridin-3-ylboronic acid (30.9 mg, 0.25 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(N)([NH2:20])(=O)=O.O>N1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:20])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Temperature: 117.5 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of 4-methyl-3,5-dinitrobenzoic acid (48.2 kg) (3) and sulfamide (50.1 kg) in pyridine (197 kg) is heated to reflux (about 115-120° C.) for about 1.5 hours. The solution is then cooled to ambient temperature and water is added (178 kg) over about 1 hour. The mixture is then cooled to about ˜5° C. and held at this temperature for about 1 hour. The product slurry is centrifuged and the solids obtained are washed with water (621 L). The product is dried in a vacuum tray dryer at a temperature of about 65° C. and a vacuum of about 10 torr to provide 4-methyl-3,5-dinitrobenzamide (6) (43.8 kg, 91.3% yield).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: COc1ccc(CCC(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)CCc3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Yield: 65 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3-(3,4-dimethoxy-phenyl)-propionyl chloride prepared in the step 1 were used as starting materials, allowed to react at 35-40° C. for 10 hours, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (4:1) to obtain a product as a white solid in a yield of 65.0%, mp: 142-143└. 1H-NMR (CDCl3, 400 MHz) δ: 2.12 (2H, t, J=7.72 Hz), 2.74 (2H, t, J=7.72 Hz), 3.80 (6H, s, 2×OCH3), 3.83 (3H, s, OCH3), 4.18 (2H, s, CH2), 6.51 (1H, dd, J=8.16, 1.96 Hz, ArH), 6.56 (1H, d, J=1.96 Hz, ArH), 6.69 (1H, d, J=8.16 Hz, ArH), 6.83 (2H, d, J=8.68 Hz, ArH), 7.21˜7.33 (5H, m, ArH), 7.42 (2H, d, J=8.68 Hz, ArH), 11.05 (1H, br, CONH); EI-MS m/e (%): 488.1 (M+, 66), 296.0 (100); HREI-MS Calcd. for C28H28N2O4S: 488.1770. found: 488.1764. Anal. Calcd. for C28H28N2O4S: C, 68.83; H, 5.78; N, 5.73. found: C, 68.69; H, 5.67; N, 6.09.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[Ti+3:13].O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O>>[CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[OH:3][Ti+3:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [Ti+3]
Reactant: OCCCCCCO
Agent: CC(C)[O-]
Product: CCCCCC[Ti+3]O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 200 %

Procedure:
0.1 moles of titanium-tri-isopropoxide (Tyzor TPT DuPont, Wilmington, Del.) and 0.1 moles of 6-hydroxy-1-hexanol were added to a 50 ml beaker and stirred at room temperature for 1 minute to form 0.1 mole of hydroxy-hexyl-titanium-tri-isopropoxide. The reaction mixture was heated to 70 degrees C. for 10 minutes to evaporate the isopropyl alcohol formed during the reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>CN(C)C(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCNCC2)nc1
Yield: 50.2 %

Procedure:
Following the general procedure of Example 33, Step 1, and making non-critical variations, 2,5-dichloropyridine (Aldrich; 5.10 g), piperazine (14.8 g), water (50 mL), and N,N-dimethylacetamide (2 mL) give 3.42 g of 1-(5-chloropyridin-2-yl)piperazine; mp 92-107° C.; IR 1480, 1244, 1390, 1589 815 cm-1 ; 1H NMR (CDCl3) δ2.98, 3.47, 6.58, 7.42, 8.11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester [CAS-No. 335255-88-4] according to the general procedure M. Obtained as a light red solid (502 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.O1CCOCC1.[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=2[OH:15])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cccc(B(O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccnc(Cl)n2)c1O
Temperature: 100 °C

Procedure:
To a solution of 3.0 g (20 mmol) of 2,4-dichloro-pyrimidine in a 10:1 mixture of dioxane:water (220 mL) is added 3.3 g (22 mmol) of 2-hydroxy-3-methyl-phenyl boronic acid followed by 6.0 g (57 mmol) of sodium carbonate. Argon is bubbled through the solution for 15 min then 2.4 g (2.1 mmol) of tetrakis(triphenylphosphine)palladium (0) is added. The reaction is heated overnight at 100° C. then cooled to ambient temperature and filtered through diatomaceous earth. The filter pad is washed with EtOAc then placed on a new receiving flask and washed with a 1:1 mixture of MeOH:DCM. The filtrate is concentrated under reduced pressure to B-16 (1.60 g, 36.0%)