Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)phenol (8.7 g) and sodium hydride (1.2 g) in dimethylformamide (60 ml) was stirred at 25° during 3 h. N-(4-Bromobutyl)phthalimide (12.8 g) was added and the mixture was stirred at 25° during 20 h then at 65° for 3 h. The reaction mixture was poured onto water and extracted with ethyl acetate. The solvent was concentrated and the crystalline impurity was removed by filtration. The filtrate was evaporated in vacuo and the residue was dissolved in ethanol and heated at reflux with hydrazine hydrate (2.5 ml) for 3 h. The mixture was filtered and the filtrate distilled to give the title compound as a colourless oil (4.1 g) b.p. 140°/0.1 mm TLC silica, ethyl acetate/water/isopropanol/0.88 ammonia 25:8:15:2, Rf 0.32.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11](F)[CH:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([NH:24][C:11]1[CH:10]=[C:9]([NH2:8])[C:14]([F:15])=[CH:13][N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(F)ncc1F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Nc1cc(NCc2ccccc2)ncc1F
Yield: 58.4 %

Procedure:
To 1 ml of N-methylpyrrolidone was added 410 mg of 4-amino-2,5-difluoropyridine together with 930 mg of benzylamine, and the mixture was allowed to react in nitrogen atmosphere at 150° C. for 3 days and allowed to cool. After adding 30 ml of chloroform, the mixture was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 15 g; eluent:chloroform:methanol, 1:0 and then, 50:1) to obtain 400 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O-:19])=[O:18])=[CH:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C([O-])C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
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: [K+]
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccc(F)cc3)c2OC1C(F)(F)F
Temperature: 100 °C
Yield: 34 %

Procedure:
To 0.400 g (0.428 mmole) of Wang resin 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 50 mg (0.043 mmole) tetrakis(triphenylphosphine)palladium(0), 0.180 g (1.285 mmole) 4-fluorophenylboronic acid, 0.857 mL K2CO3 (2M soln degassed), and 4 mL degassed DMF. The reaction mixture was heated to 100° C. for 18 hr. The reaction mixture was transferred and washed as follows: DMF (×5), H2O (×5), MeOH (×5), and CH2Cl2 (×5). The resin was treated with 2 mL (TFA:CH2CL2, 1:1) for 30 minutes. The filtrate was collected and treatment was repeated. The resin was washed with CH2Cl2 (×2) and all filtrates were combined and concd. The resulting oil was purified using reverse phase chromatography to afford 0.055 g (34%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 5.66 (q, 1H, J=6.8 Hz), 7.10-7.15 (m, 2H), 7.26 (d, 1H, J=2.4 Hz), 7.37 (d, 1H, J=2.4 Hz), 7.42-7.47 (m, 2H), 7.90 (s, 1H); MS (ES+) 373 (M+1, 100); HRMS (ES−) m/z calcd for (C17H9O3ClF4) 371.0093, found 371.0067.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1[O:14][C@@H:13]1[CH2:15]Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][C@H:13]2[CH2:12][O:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC[C@@H]1CO1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-tert-butyl-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]1O)[CH3:2].[H][H]>[Ni]>[CH2:17]([CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6]1)[CH3:18]
Reactant: [H][H]
Reactant: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1O
Agent: [Ni]
Product: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1

Procedure:
300 Grams of 2,6-di(2-ethylhexyl)-cyclohexanol were hydrogenated with 30 gm of Girdler nickel 49A for six hours at 250° C. and 250 bar of hydrogen pressure. After filtration of the catalyst, 260 gm of 1,3-di-(2-ethylhexyl)-cyclohexane remained with the following characteristics:
Reaction SMILES: Br[C:2]1[N:7]2[C:8]([NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O-:25][CH2:26][CH3:27].[Na+]>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:25][CH2:26][CH3:27])[N:7]2[C:8]=1[NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1ccccc1-c1nc2cccc(Br)n2c1NC1CCCCC1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1cccc2nc(-c3ccccc3Cl)c(NC3CCCCC3)n12

Procedure:
5-bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (152 mg, 0.376 mmol) was added to sodium ethoxide [generated in situ by addition of sodium metal (17.32 mg) to absolute ethanol (10 ml)]. The mixture was heated under reflux for 8 h. Excess solvent was removed in vacuo and the resultant mixture was treated with water before been extracted into ethyl acetate, dried over magnesium sulphate and filtered. Excess solvent was removed under reduced pressure to give an oil that was purified by column chromatography, eluting with hexane:ethyl acetate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]nc(CCC(=O)OC)c3c2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]nc(CCC(=O)O)c3c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 3-{5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-1H-indazol-3-yl}propanoate (Example 123, 20 mg; 0.05 mmol) in ethanol (1 ml) was treated with 10% sodium hydroxide solution (1 ml). After stirring at RT for 2 hours the mixture was acidified to pH 3 with dilute HCl and extracted with EtOAc. The combined organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with EtOAc containing increasing amounts MeOH of to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C([O-])(=O)C.[NH4+:23]>C(O)C>[NH2:23]/[C:4](/[CH2:3][C:2]([F:18])([F:17])[F:1])=[CH:5]/[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(CC(=O)OCc1ccccc1)CC(F)(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: N/C(=C/C(=O)OCc1ccccc1)CC(F)(F)F
Temperature: 80 °C
Yield: 33.9 %

Procedure:
Benzyl 5,5,5-trifluoro-3-oxopentanoate (2.1 g) in ethanol (15 mL) was treated with ammonium acetate (2 g). The mixture was heated at 80° C. for 18 h and was then concentrated in vacuo. Water and DCM were added. The organic phase was separated and washed with sodium bicarbonate solution and water and then dried over sodium sulphate and filtered. The solvent was concentrated in vacuo to yield the title compound as a colourless oil (0.71 g).
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.C(NC(C)C)(C)C.[Cl:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42].Cl>ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[NH:1][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH2:39][Cl:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)C(C)(C)CCl)C3)c1
Temperature: 25 °C

Procedure:
To a solution of N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (40.5 mg, 0.095 mmol; see example 193) in dry dichloromethane (2 ml) containing diisoproylamine (0.025 ml, 0.142 mmol) and under argon was added a solution of 3-chloropivaloyl chloride (0.019 ml, 0.142 mmol) in dichloromethane and stirred at room temperature over night. Added 0.5M hydrochloric acid and extracted with dichloromethane, co extracted aqueous layer with dichloromethane and the combined organic layers were washed with sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the desired N-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide as yellow oil. m=51 mg (quant.) that was used without further purification for the next steps.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2.[Mg]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]2
Reactant: COC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C1Cc2cc(Cl)ccc2N1
Reaction time: 8 h

Procedure:
Methyl 5-chloroindole-2-carboxylate (0.6 g, 2.87 mmol) and magnesium shavings (0.34 g, 14.3 mmol) were suspended in methanol (40 ml) and the mixture was stirred for 8 h. The mixture was filtered, treated with methylene chloride (100 ml) and washed with NH4Cl solution. The organic fraction was dried (Na2SO4) and the solvent removed in order to give a solid which was purified by chromatography on a column of silica gel, using a 7/3 petroleum/ethyl acetate mixture as eluent. The product was isolated in the form of a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[F:26][C:27]([F:42])([F:41])[C:28]1[CH:40]=[CH:39][CH:38]=[CH:37][C:29]=1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:8]2[N:7]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:34]3[CH2:33][CH2:32][N:31]([CH2:30][C:29]4[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=4[C:27]([F:41])([F:42])[F:26])[CH2:36][CH2:35]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3C(F)(F)F)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 52.6 %

Procedure:
A mixture of 7.4 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 5.4 g of 2-trifluoromethylbenzyl piperazine and 2.4 g of sodium carbonate in 260 ml of toluene was reacted as described in Example 146, giving 6.1 g of the desired product, mp 169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:19][CH:20]=O>CO.O>[Cl:12][C:4]1[N:3]2[CH:19]=[CH:20][N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Cl)n2ccnc12
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a stirred suspension of methyl 2-amino-6-chloro-3-pyridinecarboxylate (2 g, 10.72 mmol) and sodium bicarbonate (900 mg, 10.72 mmol) in a mixture of methanol (40 mL) and water (20 mL) was added chloroacetaldehyde (50% wt. solution in water, 2.9 mL, 22.51 mmol). The resultant mixture was heated at reflux for 5 hours when more chloroacetaldehyde (50% wt. solution in water, 1.45 mL, 11.25 mmol) was added and heating at reflux continued for 16 hours. The majority of the solvent was then removed in vacuo and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic phase was separated and the aqueous phase was back extracted with ethyl acetate (150 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-100% ethyl acetate-cyclohexane+0-20% methanol gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (1.32 g).
Reaction SMILES: [OH:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)[CH:11]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([O:1][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]3[CH:13]=[CH:14][C:15]([OH:16])=[CH:10][CH:11]=3)=[CH:19][CH:20]=1)[CH2:3]2
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: O[C@@H]1CN2CCC1CC2
Product: Oc1ccc(Oc2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
3-(S)-Hydroxy-quinuclidine (the product of Reference Example 2D, 127 mg, 1 mmol) was treated with 4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.2) as oil (48 mg, yield, 15%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.55 (m, 1H), 1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.75–2.98 (m, 5H), 3.20–3.30 (m, 1H), 4.45 (m, 1H), 6.62–6.96 (m, 8H) ppm. MS (DCl/NH3) m/z 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccn1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccn1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-2-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[C:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]([OH:5])=[O:4].C(O)C.[OH-].[K+]>O>[CH3:24][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH2:16][CH:15]=[CH:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCC(C)=CCC=CCC=CCCCCCC(C)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(C)=CCC=CCC=CCCCCCCC(=O)O

Procedure:
A mixture of 1.3 g. of methyl 15-methyl-8,11,14-eicosatrienoic acid, 12.8 ml of 95% ethanol, 1.1 g. of potassium hydroxide and 1.1 ml. of water under a nitrogen atmosphere was heated under reflux for 2hours, then water and Skellysolve "B" (mixed hexanes) were added. The aqueous and organic layers were separated and the aqueous layer was made acid with 3N hydrochloric acid, then extracted with ether. The ether extract was washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated leaving a residue comprising 15-methyl-8,11,14-eicosatrienoic acid. The residue was distilled in a short path tube at bath temperatures of about 180°C. and a pressure of about 0.007 mm. The distillate was dissolved in 5% ethyl acetate-benzene and chromatographed over 100 g. of acid washed silica gel. Elution with 600 ml. 5%, 500 ml. 10% and 200 ml. 25% ethyl acetate in benzene, then with 100 ml. of ethyl acetate, collecting 50 ml. fractions, and evaporation of the eluate fractions gave a first peak of 183 mg., followed by a 448 mg. peak comprising 15-methyl-8,11,14-eicosatrienoic acid showing one spot on TLC analysis, and having the following NMR absorptions:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[C:10]2[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1.O.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[C:9]([C:10]1[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:19]
Reactant: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(C(=O)c2cc(F)cc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (2.68 g, 10.2 mmol), 4-methylmorpholine N-oxide monohydrate (2.02 g, 15 mmol) and tetrapropylammonium perruthenate (35 mg, 0.1 mmol) in dry dichloromethane (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue redissolved in ethyl acetate. The organic phase was washed with 10% sodium bisulphite and saturated ammonium chloride, dried and evaporated. Purification of the crude by chromatography over silica gel (EtOAc/hexane) afforded 2.05 g of the title compound (77% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1>CCO.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2cc(N)ccc21
Reaction time: 18 h
Yield: 107.8 %

Procedure:
1-Methyl-5-nitro-1H-benzo[d]imidazole (prepared as described in WO 2005/092899; 1.14 g, 6.43 mmol) in EtOH (50 ml) was stirred under H2 (1 atm) at RT in the presence of 10% Pd/C (50 wt % H2O, 1.37 g, 0.643 mmol). After 18 h, the completed reaction was filtered on Celite, rinsing forward with EtOH. The combined filtrates were concentrated to afford crude 1-methyl-1H-benzo[d]imidazol-5-amine (1.02 g, 108% yield) as a dark orange oil which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.59 (dd, J=2.0 and 8.4 Hz, 1H), 4.73 (brs, 2H), 3.69 (s, 3H); MS (ESI) m/z: 148.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])(=[O:18])[CH3:17]
Reactant: Cc1cc(Br)ccc1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a solution of acetyl chloride (2.8 mL, 26 mmol) in 5 mL of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.9 g of 4-bromo-2-methylphenyl acetate as a light brown oil (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=CNc1cc(N)nc(SC)n1)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNc1cc(NC(C)=O)nc(SC)n1)C(=O)OCC
Reaction time: 16 h

Procedure:
A mixture of EXAMPLE 16A (9.91 g) and acetic anhydride (150 mL) at reflux was stirred for 16 hours, treated with additional acetic anhydride (60 mL), refluxed for 5 hours, cooled and concentrated. The concentrate was dissolved in 9:1 ethanol/ethyl acetate (100 mL), stored at 0° C. for 18 hours, and filtered. 1H NMR (300 MHz, DMSO-d6) δ 10.65 (d, 1H), 8.90 (d, 1H), 7.66 (s, 1H), 4.23 (q, 2H), 4.14 (q, 2H), 2.52 (s, 3H), 2.26 (s, 1H), 2.11 (s, 3H), 1.27 (t, 3H), 1.23 (t, 3H).
Reaction SMILES: CO[C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH3:18])[C:7](=[O:19])[CH2:6]1)=[O:4].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C1(C)C=CC=CC=1>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[CH:5]([C:3](=[O:4])[NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH2:6][C:7](=[O:19])[N:8]([CH3:18])[C:9]=2[CH:16]=1
Reactant: COC(=O)C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Product: CN1C(=O)CC(C(=O)Nc2nccs2)C(=O)c2ccc(Cl)cc21

Procedure:
The mixture of 23.0 g of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, 8.9 g of 2-aminothiazole and 360 ml of toluene is distilled for 20 hours so that after collecting 100 ml of toluene each, this amount is returned to the reaction mixture. It is finally concentrated to a volume of 150 ml, the resulting suspension cooled with ice, filtered and the residue recrystallized from chloroform-acetonitrile, to yield the 8-chloro-1-methyl-4-(2-thiazolylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione of the formula ##SPC3##
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[NH:11][C:10]=1[CH:16]=O)(OCC)=[O:5].S(=O)(=O)(O)O>C(O)C>[Cl:15][C:12]1[NH:11][C:10]2[CH:16]=[N:3][N:2]([CH3:1])[C:4](=[O:5])[C:9]=2[C:13]=1[Cl:14]
Reactant: CNN
Reactant: CCOC(=O)c1c(C=O)[nH]c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A solution of methylhydrazine (4.72 g) and 3-carbethoxy-4,5-dichloro-2-formylpyrrole (4.72 g) in ethanol (50 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.5 ml) was added and the mixture was refluxed for another 21 hours. The reaction mixture was cooled to room temperature and the resulting crystals were collected by filtration. The crystals were rinsed with ethanol and ether and dried in vacuo to provide the title compound as brown powder (3.29 g; yield 81%). H-NMR (DMSO-d6) δ: 3.66(3H,s), 8.11(1H,s).