Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH:32]5[CH2:34][CH2:33]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:23])[F:21])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 76 %

Procedure:
As described for Example 48b, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using cyclopropylamine instead of cyclopropanemethylamine, to the title compound (80 mg, 76%) which was obtained as a white solid. MS: m/e=474.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[F:1][CH:2]([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([Cl:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc(OC(F)F)cc1
Solvent: ClC(Cl)Cl
Product: FC(F)Oc1ccc(C(Cl)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
55 g of 4-difluoromethoxybenzhydrol are dissolved in 440 ml of chloroform, the mixture is cooled to 0° C. and 17.5 ml of thionyl chloride in 220 ml of chloroform are added. The mixture is allowed to stand for 24 hours at room temperature and excess thionyl chloride and chloroform are removed by distillation. 47 g (80%) of 4-difluoromethoxybenzhydryl chloride are obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>N1CCCNC1=O>[N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][C:22]=2[NH:21][CH2:12][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc2cccnc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=C1NCCCN1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2cccnc12)C(F)(F)F
Yield: 77.5 %

Procedure:
200 mg (0.68 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl)-2-(trifluoromethyl)oxirane (WO 00/32584) and 99 mg (0.68 mmol) of 8-aminoquinoline are heated in 0.2 ml of 3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU) for 20 hours to 130° C. After the reaction mixture is purified on silica gel with hexane-ethyl acetate (0-20%), 230 mg of the product is obtained.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:35]=[CH:34][CH:33]=[CH:32][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]5C=NN(C)[CH:30]=5)=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1>>[OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:35]=[CH:34][CH:33]=[CH:32][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([CH:26]=[CH2:30])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCOC[C@@H]5O)cnc4c4ccccc34)cn2)cn1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: C=Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1

Procedure:
3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-vinylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one in Example 4, substituting potassium vinyltrifluoroborate for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:3]=1[NH2:4].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].COC>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>[C:10]1([C:2]2[CH:8]=[CH:7][C:6]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)=[CH:5][C:3]=2[NH2:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1cc(-c2ccccc2)ccc1-c1ccccc1
Yield: 81 %

Procedure:
2,5-dibromoaniline (50 g, 199.27 mmol, 1.0 equivalent), phenylboronic acid (58.31 g, 478.25 mmol, 2.4 equivalents), tetrakis(triphenylphosphine)palladium(0) (6.91 g, 5.98 mmol, 0.03 equivalent), sodium carbonate (238.48 g), dimethyl ether (750 milliliters), and water (750 milliliters) were loaded, and the mixture was refluxed for 7 hours. After that, the precipitate was separated by filtration and removed, and ethyl acetate was added to the resultant reaction solution so that an organic layer was extracted. The extracted organic layer was washed with a saturated salt solution, dried with anhydrous sodium sulfate, and concentrated. The resultant residue was purified by short column chromatography (methylene chloride) and silica gel chromatography (methylene chloride:hexane=1:1→2:1). An appropriate amount of hexane was added to the purified residue, and the resultant precipitate was separated by filtration. The resultant precipitate was dried, whereby a white solid was obtained (39.4 g, yield: 81%).
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]([CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH:18](O)[C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1)([OH:11])=[O:10]>O>[C:9]([CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH:18]2[C:1]3[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=3[O:21][C:19]2=[O:20])=[CH:16][CH:15]=1)([OH:11])=[O:10]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)COc1ccc(C(O)C(=O)O)cc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccc(OCC(=O)O)cc1)C(=O)O2
Yield: 81 %

Procedure:
A mixture of 41.6 g (0.39 mol) of p-cresol and 29.0 g (0.13 mol) of 4-carboxymethoxymandelic acid is maintained at 185° C. under a nitrogen atmosphere for 90 minutes, during which the water formed is distilled off. Excess p-cresol is then distilled off under reduced pressure. Crystallisation of the residue from 75 ml of xylene gives 31.4 g (81%) of 3-(4-carboxymethoxyphenyl)-5-methylbenzofuran-2-one, melting point 198°-203° C. (compound (101), Table 1).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(N)CCCCC1>CO>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (691 g, 1.77 mol) and ethyl acetate (7.0 liters) were added to an aqueous solution of citric acid (10%, 6.3 liters) and the organic phase was separated, washed with water (7.0 liters) and concentrated in vacuo to a yellow oil. A solution of the oil and 5% rhodium on carbon (51.6 g) in methanol (7.0 liters) was stirred at ambient temperature, under hydrogen (150 p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added cyclohexylamine (202 ml, 1.77 mol) and the methanol solution was stripped and replaced with methylethyl ketone by distillation at atmospheric pressure, to a volume of 5.5 liters. The mixture was allowed to cool to ambient temperature where it was stirred for 48 hours and then filtered. The residue was washed with methylethyl ketone (2×500 ml) and then dried in vacuo at 45° C. for 4 hours to leave the title compound as a colourless solid (495 g, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][C:25]([NH2:28])=[N:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[N:26][C:25]([NH:28][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:24]2)=[CH:21][CH:22]=1
Reactant: Nc1ncn(-c2ccc(Cl)cc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-chloro-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=18%). MS ISP (m/e): 376.2 (100) & 378.2 (35) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:14])[CH3:13]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 14.7 (70.9 mmol) of 2-bromonaphthalene and 6.40 g (81.5 mmol) of acetyl chloride in 55 mL of nitrobenzene was added dropwise to a vigorously stirred solution of 10.4 g (78 mmol) of anhydrous AlCl3 in 25 mL of nitrobenzene at 25°-30° C. over a period of 1.3 h. After being stirred for 1 h more at 25° C., the reaction mixture was poured onto 200 g of ice and 30 mL of concentrated HCl. The product was extracted with Et2O (300, 200, and 100 mL). The extracts were washed with brine and saturated NaHCO3, dried (MgSO4), and concentrated at reduced pressure to afford a brownish oil. Short-path distillation (45°-55° C./25 mm) was used to remove nitrobenzene. The crystalline residue was dissolved in hot hexane (300 ml), filtered, and concentrated at reduced pressure to give 16.3 g (92% yield) of crude 2-acetyl-6-bromonaphthalene. Two crystallizations from hexane afforded 5.3 g (21% yield) of pure product, which had only one spot by TLC (10% EtOAc/hexane) Rf 0.22, mp 99°-101.5° C.; IR (mull) 1670, 1623, 1365, 1355, 1265, 1225, 1175, 880, 820, 800 cm-1 ; 1H NMR (CDCl3) δ 2.71 (s, 3, CH3CO), 7.5-8.2 (m, 4, 3,4,7,8-ArH), 8.03 (s, 1, 5-ArH), 8.44 (s, 1, 1-ArH).
Reaction SMILES: [C:1]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]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)=[N:9][O:10][C:11]=2[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH3:32][O:33][C:34](=[O:41])[C@@H:35]([NH:40][C:12]([C:11]1[O:10][N:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:19][CH:20]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13])[CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2noc(C(=O)O)c2-c2ccccc2)cc1
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1-c1ccccc1
Yield: 83 %

Procedure:
The title compound was prepared from 4-phenyl-3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 83% yield. Mass (ES−): 525 (M−−1); 1H NMR (DMSO-d6) δ: 0.75, 0.81 (2×d, 6H), 1.35-1.58 (m, 3H), 3.66 (s, 3H), 4.49 (m, 1H), 6.96 (t, 1H), 7.27 (t, 2H), 7.44 (d, 2H), 7.54 (m, 3H), 7.56 (d, 2H), 7.66 (d, 2H), 7.82 (m, 2H), 8.72 (br, 1H), 8.95 (br, 1H), 9.31 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(O)=O.[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:17])[CH2:15][Cl:14])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CNC(=O)CCl
Temperature: 0 °C

Procedure:
Twenty-seven and nine-tenths grams (g) (0.2 mole) of glycine ethyl ester --HCl was combined with about 100 grams of ice in a reaction flask. Solid NaHCO3 (33.6 g) (0.4 mole) was then added to this mixture followed by dropwise addition of 23.0 g (0.2 mole) of chloroacetyl chloride with stirring. The temperature of the reaction mixture was maintained between -10° and -5° C. by ice addition. The solid precipitate that formed was separated from the reaction mixture by filtration, washed with ice water and air dried. The yield was 15 g (41.7%) of a solid having a melting point of 60°-62° C. which was identified as the title compound by infrared (IR) spectroscopy analysis.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>ClCCl>[C:5]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([Br:9])=[CH:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH2:21]1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)C1(c2ccc(Br)cc2)C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a reaction flask under nitrogen atmosphere there was placed 26.6 g (0.2 Mol) of aluminum chloride, which was then covered with 150 ml of dichloromethane. There was then added dropwise 15.6 g (0.2 Mol) of acetyl chloride in 200 ml of dichloromethane, while cooling the reaction mixture. To this was added dropwise 23.3 g (0.1 Mol) of 4-bromobiphenyl in 200 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, and it was then heated to reflux for 4 hours, after which it was left at room temperature overnight under nitrogen atmosphere. There was then added 50 g of ice and the aqueous layer was separated. The organic layer was washed twice with 50 ml of saturated sodium chloride solution, then dried over magnesium sulfate and evaporated. The crude product was crystallized from 3:1 petroleum ether:benzene to give 16.9 g in the first crop, m.p. 126°-128° C.; and 3.9 g in the second crop.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:15][C:16]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24][CH3:25])=[O:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(CS)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(C(=O)CBr)c(OC)c1
Product: COc1cc(OC)c(C(=O)CSCc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1

Procedure:
According to Scheme 5, (4-methoxy-3-nitrophenyl)methanethiol 10 (an aromatic mercaptan according to Formula IIb) is reacted with 2-bromo-1-(2,4,6-trimethoxyphenyl)ethanone (a compound according to Formula IIa) to form 2-(4-methoxy-3-nitrobenzylthio)-1-(2,4,6-trimethoxyphenyl)ethanone 11 (a sulfide according to Formula II). Suitable reaction conditions for this reaction are as described above for the reaction of a Formula IIa compound and a Formula IIb compound.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.N[OH:13]>O1CCCC1>[OH:13][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1
Reactant: NO
Reactant: CN(C)C=Nc1cnccn1
Solvent: C1CCOC1
Product: ONC=Nc1cnccn1
Temperature: 80 °C

Procedure:
A solution of N,N-dimethyl-N′-pyrazin-2-ylimidoformamide (189 g) from Step A in tetrahydrofuran (400 mL) was treated drop wise with 50% aqueous solution of hydroxylamine (245.7 mL) at 0° C., then warmed up to 80° C. for 2.5 h. Tetrahydrofuran was removed by rotoevaporation and the resulting aqueous mixture kept cold in a refrigerator. The resulting solid was filtered and rinsed with cold diethyl ether to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH3:8])[C:7]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(Br)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a mixture of 1-bromo-2,4,5-trimethylbenzene (5.0 g, 25.0 mmol) and acetyl chloride (2.45 ml, 34.5 mmol) in dichloromethane (50 ml) was added aluminium chloride (4.42 g, 33.1 mmol) in dichloromethane (50 ml) and the reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water and the two layers were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and filtered through silica. The filtrate was concentrated in vacuo to give the title compound (5.50 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Product: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Yield: 80 %

Procedure:
A suspension of 2-amino-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (1.96 g, 10 mmol) in acetic anhydride (200 ml) was refluxed for 2 hours till a clear solution was obtained. The solvents were evaporated in vacuo till crystallization started. The precipitate was filtered off and dried under vacuum yielding the pure title compound (2 g, 80%) which was characterised as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[CH:12]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[N:4]=[C:5]4[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]4[CH:12]=3)[CH2:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1cccn2cc(CCl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccn2cc(CN3CCN(c4ccc(Cl)cc4)CC3)nc12
Temperature: 75 °C
Yield: 41.2 %

Procedure:
A mixture of 2-(chloromethyl)-8-methylimidazo[1,2-α]pyridine (0.297 g), 1-(4-chlorophenyl) piperazine dihydrochloride (Aldrich; 0.534 g), triethylamine (0.8 mL), THF (6 mL), and DMF (2 mL) is heated at 75° C. for 4 hours. Diisopropylethylamine (0.3 mL) is added and the mixture is stirred another hour, at which time the mixture is concentrated under reduced pressure and the residue is partitioned between saturated aq. sodium bicarbonate and dichloromethane. The organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96). The appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/hexane to give 0.231 g of the title compound; mp 102-104° C.; MS m/z 340; IR (mineral oil) 1495, 1338, 2819, 1227, 743 cm-1 ; 1H NMR (CDCl3) δ2.61, 2.78, 3.22, 3.85, 6.68, 6.82, 6.94, 7.18, 7.58, 7.95.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2Cl)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Product: CCOC(=O)N1CCc2nc3ccccc3c(N3CCCC3)c2CC1
Yield: 18 %

Procedure:
1,2,4,5-Tetrahydro-11-pyrrolidino-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 1,2,4,5-tetrahydro-11-chloro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and pyrrolidine analogous to Example 204.
Reaction SMILES: CN(C)CCN(C)C.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)=[O:12]>C1COCC1.[BH4-].[Zn+2].[BH4-]>[OH:20][CH2:19][CH:16]1[CH2:15][CH2:14][CH:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1
Reactant: COC(=O)C1CCC(C(=O)Cl)CC1
Agent: CN(C)CCN(C)C
Agent: [BH4-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Zinc borohydride solution (67 ml of a 0.35M solution, Ref. W. J. Gensler et al J. Amer. Chem. Soc. 1960, 82, 6074) and tetramethylethylenediamine (TMEDA) were successively added to a stirred solution of 4-methoxycarbonylcyclohexylcarbonyl chloride (1.02 g) in THF (18 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The organic phase was then washed with dilute hydrochloric acid and brine before drying over anhydrous magnesium sulphate and then evaporation in vacuo. Methyl 4-hydroxymethylcyclohexanecarboxylate was obtained as a semi-crystalline oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]2([CH3:20])[CH3:19])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)C1(C)C
Yield: 60.2 %

Procedure:
A mixture of 30 g of 1-(2,2-dimethyl-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, 150 ml of water and 17 g of sulfuric acid is heated to +80° C. Within a period of 1.5 hours an aqueous solution of 114 g of ammoniaperoxodisulfate is added dropwise. The reaction mixture is cooled to +7° C. and the pH-value is adjusted to pH 3 by addition of a 30% sodium hydroxide solution. The mixture is twice extracted with 200 ml of methylene chloride. The combined organic extracts are dried with sodium sulfate and concentrated to dryness. The residue is taken up with a small amount of methylene chloride and diluted with diethyl ether. The resulting suspension is filtered and the filtrate is concentrated and crystallized from a diethyl ether/hexane mixture affording 19 g of 1-(2,2-dimethyl-3-oxo-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, mp. 104°-108° C.