Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12.[CH2:18]([CH2:20][NH2:21])[OH:19]>C1(C)C(C)=CC=CC=1>[OH:19][CH2:18][CH2:20][NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12
Reactant: Cc1cc(Cl)c2[nH]nc(-c3ccccc3)c2n1
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2[nH]nc(-c3ccccc3)c2n1
Reaction time: 8 h

Procedure:
A solution of 7-chloro-5-methyl-3-phenyl-1H-pyrazolo[4,3-b]pyridine (D9) (0.63 g) in xylene (15 ml) with ethanolamine (1.5 ml) was heated at reflux for 3 days under nitrogen. The solvent was then removed under reduced pressure and the residue dissolved in water with the minimum amount of methanol with warming. This solution was brought to pH9 by addition of 10% sodium hydroxide and then further diluted with water. The resulting emulsion was left to stand overnight to give the title compound as a pale yellow crystalline solid which was collected, washed with water and dried under vacuum to afford the title compound (0.686 g, 95%), m.p. softening and partial melting at 135° with resolidification and melting at 186°-188°. (Found: C, 64.58; H, 6.42; N, 20.06. C15H16N4O.1/2H2O requires C, 64.96; H, 6.18; N, 20.20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH:8]2[CH2:7][C:6]3[CH:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:5]=3[O:9]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(C4CCCCC4)c3O2)cc1

Procedure:
Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.5 g, 0.017 mol) with p-toluenesulfonyl chloride (4.8 g, 0.025 mol), diisopropylethylamine (4.36 g, 0.034 mol), and 4-(dimethylamino)pyridine (0.12 g, 0.98 mmol) generally according to the procedure described for Intermediate 45 gave (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (4.03 g, 61.99 mmol) generally according to the procedure described for Intermediate 98 provided 3.45 g of (±)-2-(azidomethyl)-5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.75 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 2.70 g (60%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 210-213° C.; Anal. calcd for C15H20ClNOHCl: C, 59.61; H, 7.00; N, 4.63. Found: C, 57.29; H, 7.14; N, 4.78.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1ccc(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(F)cc1Cl
Yield: 96.7 %

Procedure:
1.64 g (6 mmol) of 2-chloro-4-fluorobenzamide were dissolved in 3 ml of dichloromethane and, at 0° C. and under a nitrogen atmosphere, 0.8 ml (9.3 mmol) of oxalyl chloride was added, and the mixture was heated to reflux for 9 hours. The reaction mixture was concentrated under high vacuum and afforded 1.17 g (5.8 mmol) of the desired product, which was employed as solution in dichloromethane (1 mmol in 1.7 ml of solution) in stage b.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].NC(N)=N.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cl)ccc1N
Agent: N=C(N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1N
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
To a suspension of 4-chloro-2-methoxyaniline (1.88 g) in concentrated sulfuric acid (18 mL) was added guanidine nitrate (1.46 g) under ice-cooling over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a saturated aqueous sodium carbonate solution cooled in ice, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.94 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](OC)[N:17]=2)[C:12](=[O:22])[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10]1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:16]1[N:17]=[C:18]2[C:13]([C:12](=[O:22])[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]=1[F:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Yield: 85 %

Procedure:
In 2.5 ml of phosphorus oxychloride was suspended 500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting suspension was subjected to reaction under reflux for 1.5 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the crystalline material thus obtained was washed with 10 ml of diethyl ether to obtain 430 mg (yield 85.0%) of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 216°-219° C. The physical properties of this compound were identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH2:1]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]3[CH:9]2[N:4]([C:5](=[O:14])[CH2:6][CH2:7]3)[C:3](=[O:15])[CH2:2]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[CH2:16]([O:23][C:3](=[O:15])[CH2:2][CH2:1][CH:10]1[CH:9]2[CH:8]([CH2:7][CH2:6][C:5](=[O:14])[NH:4]2)[CH2:13][CH2:12][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC2CCCC3CCC(=O)N1C23
Reactant: OCc1ccccc1
Agent: Cl
Product: O=C1CCC2CCCC(CCC(=O)OCc3ccccc3)C2N1
Temperature: 100 °C

Procedure:
A solution of 0.7 g (0.0033 mol) of decahydro-3H,5H-benzo[ij]quinolizine-3,5-dione (7aα, 10aα, 10bα) in 10 ml of benzyl alcohol is treated with one drop of concentrated hydrochloric acid. The solution is heated at 100° C. for 48 hours and is concentrated at reduced pressure (0.1 mm). The residue is triturated with anhydrous diethyl ether to yield crystalline decahydro-2-oxo-8-quinolinepropanoic acid benzyl ester (4aα, 8aβ, 8aα) with a melting point of 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH3:10][O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[NH:1][C:25](=[O:26])[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:3]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-chloro-5-methoxyphenyl)amino]-1-piperidinecarboxylate (D48) (280 mg) was dissolved in 5 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 0.5 ml) and triethylamine (0.3 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, then water, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, crystallised from diethyl ether, and then further purified by MDAP to yield the title compound, 40 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:14][C:13]=1[C:23]([O:25]CC)=[O:24].CO.O1CCCC1.O.[OH-].[Li+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[S:14][C:13]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1sc(-c2ccncc2)cc1Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(-c2ccncc2)cc1Cc1ccc2ccccc2c1

Procedure:
Ethyl 3-(2-naphthylmethyl)-5-pyridin-4-ylthiophene-2-carboxylate (80.0 mg, 0.214 mmol) was placed in a round bottomed flask equipped with a stirbar. Methanol (3 mL, 70 mmol) and tetrahydrofuran (3 mL, 40 mmol) were added followed by water (2 mL, 100 mmol). The resulting solution was stirred and lithium hydroxide in water (1.0 M, 0.643 mL, 0.643 mmol) was added. The flask was sealed and stirred overnight at RT. LCMS of an aliquot indicated that all starting material had been consumed to give a single product with the correct mass for the desired product. To the stirring reaction was added ˜30 mL water and a few mL saline. The mixture was stirred and acidified to ˜pH 1 with 1N HCl—a gelatinous precipitate formed. The mixture was stirred rapidly and diethyl ether (10 mL) was added—the precipitate became more granular and became suspended mostly in the organic layer. The quench mixture was stirred at room temperature for ˜30 minutes then the solid was collected on a fritted funnel, washed well with water then diethyl ether, then dried in vacuo to yield product 60 mg (81% yield) as a white powder. LC/MS (FA) ES+ 346. 1H NMR (400 MHz, DMSO) δ 13.62-13.20 (s, 1H), 8.63-8.52 (dd, J=4.7, 1.5 Hz, 2H), 7.91-7.80 (m, 3H), 7.80-7.72 (d, J=3.0 Hz, 2H), 7.70-7.63 (dd, J=4.6, 1.5 Hz, 2H), 7.53-7.40 (m, 3H), 4.57-4.48 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][C@@:8]([OH:19])([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[Li+].[OH-].O>CO>[OH:19][C@:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)([CH:9]([CH3:10])[CH3:11])[CH2:7][C:6]([OH:20])=[O:5]
Reactant: CC(C)[C@](O)(CCc1ccsc1)CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@](O)(CCc1ccsc1)CC(=O)O

Procedure:
The title compound was prepared as described in General Method 10 using (S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butyl ester (Example F-1 (S); 8 mmol), LiOH (16 mmol), H2O (5 mL), and MeOH (15 mL).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[C:29]([F:42])[CH:28]=2)=[O:25])[CH2:22][CH2:21]1>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][CH:20]4[CH2:22][CH2:21]4)=[O:25])=[CH:28][C:29]=3[F:42])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Product: CC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Yield: 15 %

Procedure:
Method as described for (S)-1-cyclopropyl-3-(3-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea(example 147) using 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29). Residue was then purified by prep. HPLC at high pH to afford a cream solid (15% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:4][C:3]=1[O:18][CH3:19].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>>[Si:24]([O:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:6][C:7]=1[O:8][CH3:9])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=CC(=O)CC(C)=O)cc(OC)c1O
Product: COc1cc(C=CC(=O)CC(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure of Example 22C, 1-(4'-hydroxy-3',5'-dimethoxyphenyl)-1-hexene-3,5-dione is reacted with t-butylchlorodimethyl silane to afford 1-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxyphenyl)-1-hexene-3,5-dione suitably pure for further use.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[NH:11][C:10]2[C:12]([CH:18]=[O:19])=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[N:8]=1)C.Cl>[OH-].[Na+].O1CCOCC1>[CH:18]([C:12]1[C:10]2[NH:11][C:7]([S:6][CH2:5][C:4]([OH:20])=[O:3])=[N:8][C:9]=2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17])=[O:19]
Reactant: CCOC(=O)CSc1nc2ccc(OC)c(C=O)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2nc(SCC(=O)O)[nH]c2c1C=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
(7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl ester (1.432 g, 4.87 mmol) was dissolved in a mixture of 19.5 mL of 1N sodium hydroxide and 15 mL of dioxane. The solution was stirred at 50° C. for 2 h, cooled to 0° C., and the pH was adjusted to 3.5 by dropwise addition of 6N HCl, keeping the temperature at 0° C. The precipitated yellow solid was filtered, washed with ice cold water and dried. The title compound (1.10 g. 4.15 mmol, 85%) was isolated as a yellow powder.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (69%).
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3Cl)n2)nc1

Procedure:
[4-(2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-chlorobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.O>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:20][O:21][CH3:22]
Reactant: COCCl
Reactant: N#Cc1ccc(F)c(O)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-fluoro-3-hydroxybenzonitrile (25.0 g, 182 mmol), diisopropylethylamine (47.7 mL, 273 mmol) in dichloromethane (530 mL) was added chloromethyl methyl ether (16.6 mL, 219 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, quant.), which was used for the next step without purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15].[F:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>C1COCC1>[F:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])[OH:20]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)cc2F)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
n-Butyllithium (2.5 M, 44.0 mL) was added dropwise into a cold (−78° C.) solution of 1-bromo-4-methoxy-2-methylbenzene (22.0 g, 109.4 mmol), and THF (150 mL). The reaction mixture was stirred at −78° C. for 3 h, and then 2-fluoro-4-methoxybenzaldehyde (16.8 g, 109.4 mmol) in THF (10 mL) was added. The mixture was allowed to warm up to 0° C. stirred for 10 min, and then quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave (2-fluoro-4-methoxyphenyl)(4-methoxy-2-methylphenyl)methanol as a yellow oil (23.6 g, 78% yield). The product was dissolved in acetone (150 mL), cooled to 10° C. and Jones Reagent (79.7 mL) was added dropwise. The reaction stirred for poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave a yellow oil (23.6 g, 78% yield, m.p. 88-90° C.); MS m/e 275 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:12][C:11]([N:13](CC2C=CC(OC)=CC=2OC)[S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](F)=[CH:19][C:18]=2[F:25])(=[O:16])=[O:15])=[N:10][CH:9]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=1[I:46]>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=3[I:46])=[CH:19][C:18]=2[F:25])(=[O:15])=[O:16])=[N:10][CH:9]=1
Reactant: N#Cc1ccc(O)c(I)c1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(F)c(S(=O)(=O)Nc3ncc(Cl)s3)cc2F)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a suspension of potassium carbonate (0.068 g, 0.000492 mol) and N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide (Preparation 334, 0.200 g, 0.000418 mol) in dimethyl sulfoxide (3.0 mL) was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g, 0.000441 mol) and was stirred at 65° C. under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in dichloromethane (1.5 mL), treated with trifluoroacetic acid (1.5 mL) and stirred at room temperature under nitrogen for 16 hours. Reaction was concentrated in vacuo and residue dissolved in ethyl acetate (10.0 mL). The organic extract was washed with saturated aqueous sodium bicarbonate solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified using ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:39, by volume) to afford the title compound as an orange solid, 165 mg, 35% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:4]1=2)[CH3:2].O.NN>CCO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[N:3]([CH2:1][CH3:2])[C:4]=2[CH:14]=1
Reactant: CCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1C(=O)CCCc2ccc(N)cc21
Yield: 101 %

Procedure:
To a solution of 1-ethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (920 mg, 3.9 mmol, WO2002100327A2) in EtOH (13 mL) was sequentially added 10% Pd/C (155 mg) and hydrazine-monohydrate (3 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine to afford 8-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (805 mg, 100%) that had the following properties: LC/MS (ESI+): 205 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 6.97 (d, J=7.8, 1H), 6.55 (s, 1H), 6.52 (d, J=7.8, 1H), 3.95 (br s, 2H), 3.67 (br s, 2H), 2.60 (br s, 2H), 2.29 (m, 2H), 2.11 (m, 2H), 1.15 (t, J=6.2, 3H).
Reaction SMILES: COC1C=C(C[N:12]2[C:16](=[O:17])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[C:14]([CH3:28])[C:13]2=[O:29])C=CC=1OC.C(O)(C(F)(F)F)=O.OS(O)(=O)=O>C1(OC)C=CC=CC=1>[CH3:28][C:14]1[C:13](=[O:29])[NH:12][C:16](=[O:17])[C:15]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)C(C)=C(c3ccc(C(F)(F)F)cc3)C2=O)cc1OC
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(c2ccc(C(F)(F)F)cc2)C(=O)NC1=O
Yield: 79.4 %

Procedure:
A solution of 1-{[3,4-bis(methyloxy)phenyl]methyl}-3-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (P3, 100 mg), anisole (107 μL), TFA (4 mL) and H2SO4 (catalytic amount) was heated at 90° C. overnight. The solution was then concentrated in vacuo, dichloromethane was added and the organic phase was washed with NaHCO3 (aqueous saturated solution), dried on sodium sulphate and evaporated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 to give the title compound (50 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[N:6]=[C:5]([S:7][CH3:8])[CH2:4][S:3]1.[N:10]([O-])=[O:11].[Na+].C(O)(=O)C>O>[N:10](=[C:4]1[S:3][C:2]([CH3:9])([CH3:1])[N:6]=[C:5]1[S:7][CH3:8])[OH:11]
Reactant: O=N[O-]
Reactant: CSC1=NC(C)(C)SC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSC1=NC(C)(C)SC1=NO
Reaction time: 3 h

Procedure:
6.4 g (0.04 mol) of crude 2,2-dimethyl-4-methylthio-3-thiazoline are dissolved in 40 ml of water and the solution is treated with 3.6 g (0.052 mol) of sodium nitrite and subsequently treated dropwise at 10° C. with 6.1 ml (0.11 mol) of acetic acid. After stirring the mixture for 3 hours, 3.6 g of sodium nitrite and 6.1 ml of acetic acid are added theretoand the mixture is allowed to stir for an additional 16 hours. The mixture is then diluted with water and the precipitated crystals are filtered off,to yield 5-oxo-2,2-dimethyl-4-methylthio-3-thiazoline oxime, m.p. 168°-171° C.