Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:27](=[O:29])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:11][C:10]=1[C:27]([OH:29])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 78.8 %

Procedure:
1-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-ethanone [prepared as per WO 2004/072051] (2.02 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 ml), a solution of sodium hydroxide (2.08 g, 52.0 mmol) in water (30 ml) was added and the mixture was stirred and treated dropwise with bromine (0.8 ml, 15.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. The 1,4-dioxane was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 30% ethyl acetate in petroleum ether afforded 2,4-bis-benzyloxy-5-tert-butyl-benzoic acid (1.6 g, 79%) as a pale yellow oil. 1H NMR (DMSO-d6) 12.18 (1H, br s), 7.69 (1H, s), 7.52 (4H, t), 7.45-7.33 (6H, m), 6.93 (1H, s), 5.24 (2H, s), 5.23 (2H, s), 1.32 (9H, s). MS: [M+H]+ 391.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CCO>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:16]1[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=[N:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(Cl)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(N2CCNCC2)n1

Procedure:
A solution of (6-chloro-pyrazin-2-yl)-(3-fluoro-benzyl)-carbamic acid tert-butyl ester (1.14 g, 3.39 mmol) and piperazine (1.75 g, 20 mmol) in EtOH (34 mL) was stirred at reflux for 19 h. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in Ethyl Acetate and washed with H2O (4×50 mL), brine, dried (Na2SO4), and concentrated to dryness. The crude product was chromatographed on Silica Gel (90 g) using 5% MeOH in CH2Cl2 as the eluant to give the title compound I-4c (1.09 g) as a pale yellow oil.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C(Cl)(Cl)Cl>[C:36]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)(=[O:39])[CH2:37][CH3:38]
Reactant: CCC(=O)Cl
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (6.5 g, 0.021 mole) and triethylamine (2.5 g, 0.025 mole) in chloroform (75 ml) was slowly dropped propionyl chloride (2.3 g. 0.025 mole) in chloroform (10 ml). After stirring at ambient temperature two hours the reaction mixture was concentrated to an oil which was dissolved in ether then washed with water, dilute HCl, again twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (7.2 g, 95%, m.p. 98°-105° C.). A sample was twice recrystallized from hexanes to yield 3-propionyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 109°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH2:55]>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH:55][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1F
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (200 mg, 1.28 mmol) in DMF (3 ml) at ambient temperature were added HATU (536 mg, 1.41 mmol) and DIEA (268 μL, 1.54 mmol). The reaction was stirred for 30 minutes and then 2-(2,4-dichlorophenyl)ethanamine (193 μL, 1.28 mmol) was added. The reaction was stirred overnight, then concentrated and diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography) to give N-(2,4-dichlorophenethyl)-2-fluoro-4-hydroxybenzamide (0.420 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@H:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:5]([OH:6])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]>O1CCCC1.O>[CH3:25][C:24]([Si:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH2:9][C@H:7]1[O:8][C@H:3]([CH2:2][NH:1][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:36])[CH2:4][C@@H:5]1[OH:6])([CH3:27])[CH3:26]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN)C[C@@H]1O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A slurry of 3.15 g of product from Example 283 and 1.35 g of potassium carbonate in 15 ml of tetrahydrofuran at 0° C., under argon, is treated with 2.11 g of p-nitrobenzyl chloroformate and the reaction is stirred vigorously at 0° C. for 4 hours. The reaction mixture is diluted with 100 ml of water, extracted with 3×100 ml of ethyl acetate, dried, concentrated in vacuo and purified by chromatography (Silica Gel: 5-50% ethyl acetate/hexane) to give 3.49 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].CC(=O)CC>C(OCC)C>[Cl:20][CH2:19][CH2:18][O:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9]
Reactant: ClCCBr
Reactant: Oc1c(Br)cc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate (60 g, 0.43 mol), 1-bromo-2-chloroethane (32.5 g, 0.23 mol) and 2-butanone (500 mL) was heated to reflux for 2 hours and allowed to cool to ambient temperature. The solids were filtered and the solvent was removed under vacuum to afford an oil. The oil was dissolved in diethyl ether (300 mL) and washed with water, dried over anhydrous magnesium sulfate, charcoalized, and filtered through Solka floc to afford 65.9 g (97.2%) of an oil; MS EI m/e 330/332/334/336 (M+ ; 1H NMR (CDCl3) δ 3.89 (2H, t, J=6.1 Hz), 4.23 (2H, t, J=6.1 Hz), 7.28 (2H, d, J=7.5 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 96 h

Procedure:
A mixture of 800 mg of 2-butyl-3-(2'-cyano-biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]-pyridine, 515 mg of trimethyltin azide and 20 ml of toluene is boiled for 96 hours and evaporated. Chromatography of the residue (silica gel; methylene chloride/-methanol 9:1, then 85:15 and 80:20) yields 2-butyl-4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine , m.p.167°. The corresponding K salt is prepared therefrom in conventional manner.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C([O-])(O)=O.[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[Cl-].[Na+]>CO>[CH3:12][S:13]([NH:1][NH:2][C:3]([NH:5][NH:6][S:13]([CH3:12])(=[O:15])=[O:14])=[O:4])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)NNC(=O)NNS(C)(=O)=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A mixture of 45 g (0.5 mole) carbohydrazide, 84 g NaHCO3 (1.0 mole) and 50 ml methanol was stirred as 114.5 g (1.0 mole) methane sulfonyl chloride was added over 30 minutes. The temperature rose from 25° to 40° C. The stirring was continued for 15 minutes (temp. 44° C). The mixture was then heated to 65° C for two hours, and was then cooled to 25° C and the solid product (including sodium chloride was filtered and washed with methanol and dried. Yield: 146 g. The material was first suspended in water to remove sodium chloride and then filtered, washed with water and dried. Yield: 81 g, m.p. = 207° C dec.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[NH2:10][C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:16]=[C:15]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Reactant: CCCC[C@H](N)CCO
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
(S)-3-Aminoheptan-1-ol (0.135 g) was added to a stirred solution of the product from step (iii) (0.12 g) in NMP (2 mL). The mixture was heated at 150° C. for 48 h, and then at 170° C. for a further 8 h. The mixture was allowed to cool, diluted with water (10 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried and evaporated. The crude product was purified by column chromatography, to give the subtitle compound, 0.11 g.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[CH2:19]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:17][CH2:15][CH2:2][CH2:3][CH3:4])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cccc21
Reactant: CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CCCCOc1cccc2c1C(=O)c1c(OCCCC)cccc1C2=O
Temperature: 25 °C
Yield: 154.4 %

Procedure:
A suspension of 1,8-dihydroxyanthraquinone (35.0 g, 0.14 mol), butyltosylate (93 g, 0.6 mol), and sodium carbonate (38 g, 0.36 mol) in 700 mL of o-dichlorobenzene was heated at reflux for 6 days. The mixture was cooled to room temperature, filtered, and the solvent was removed by steam distillation. The residue was recrystallized from isopropanol to provide 38.1 g (74% yield) of 1,8-dibutoxyanthraquinone, which has the structural formula: ##STR48##
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:11])[CH3:10].[NH4+].[Cl-]>CCOCC.[Cu]I>[C:9]([CH:12]([C:17]([CH3:19])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)C(C(C)=O)=C(C)C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C(C(C)=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 146 mg (0.8 mmol) of anhydrous CuI (I) in 5 mL of anhydrous ether are added, at 0° C., under a stream of argon, 3.6 mL (10.9 mmol) of a 3M solution of phenyl magnesium bromide in Et2O. After stirring for 30 minutes at 0° C., 1 g (6.4 mmol) of methyl 2-acetyl-3-methylbut-2-enoate is added in a single portion. The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The reaction mixture is then treated with 100 mL of saturated NH4Cl solution, the phases are separated by settling, and the organic phase is again treated with 100 mL of saturated NH4Cl solution. The aqueous phases are extracted with 4×100 mL of DCM. The organic phases are combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. After purification by chromatography on silica gel, eluting with a 95/5 cyclohexane/EtOAc mixture, 1 g of methyl 2-acetyl-3-methyl-3-phenylbutanoate is obtained in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)[C:5]([O:8]C)=[N:6][CH:7]=1.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:12][CH2:13][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:16]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]cc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Yield: 49.3 %

Procedure:
In ethanol (8 ml) was dissolved 245 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine. To the mixture was added 7 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 7 hours. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. Ether was added to the resulting oil to be crystallized, and 116 mg of the title compound was obtained as a slight yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10](=[CH2:16])[CH:11]=[CH:12][C:13](=O)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[S:19][CH2:20][CH2:21][N:22]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:22]3[CH2:21][CH2:20][S:19][C:18]3=[N:17][C:13]3[C:12](=[CH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:11][S:10][CH2:16][C:14]2=3)=[CH:5][CH:4]=1
Reactant: C=S1C=CC(=O)C=C1c1ccc(OC)cc1
Reactant: NC1=NCCS1
Solvent: CC(C)=O
Product: COc1ccc(C=C2CSCC3=C2N=C2SCCN2C3c2ccc(OC)cc2)cc1

Procedure:
A mixture of tetrahydro-3,5-bis[(4-methoxyphenyl)-methylene-4H-thiopyran-4-one (4.9 g, 14 mmole) and 2-amino-2-thiazoline (1.8 g, 17.6 mmole) in acetone (300 ml) is heated at reflux temperature overnight. The precipitate (4.7 g) collected is a mixture of starting ketone and intermediate aminol (4-[(4,5-dihydro-2-thiazolyl)amino]tetrahydro-3,5-bis[(4-methoxyphenyl)methylene]thiopyran-4-ol) in a ratio of 4:6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:3][C:4]=1[CH3:9]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cc(N)ccc1O
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(O)c(C)c3)c2cc1OC
Yield: 100.4 %

Procedure:
An analogous reaction to that described in example 17, but starting with 4-amino-2-methylphenol (6.98 g, 56.7 mmol) and 4-chloro-6,7-dimethoxyquinazoline hydrochloride (14.79 g, 56.7 mmol), yielded 4-(4-hydroxy-3-methylanilino)-6,7-dimethoxyquinazoline (17.72 g, 90% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:13][CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:21])[CH3:22])[CH:16]=1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2Cl)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 75.7 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 2,4-dichlorophenylboronic acid (0.55 g) and 1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.00 g), the amorphous title compound (0.85 g) was obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([N:12]2[CH2:15][CH:14]([N:16]([CH3:25])[CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:13]2)[CH:9]=[CH:8][CH:7]=1.C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:25][N:16]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:14]1[CH2:13][N:12]([C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[CH2:15]1
Reactant: CN(CCN1CCOCC1)C1CN(c2cccc(C3OCCO3)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CN(CCN1CCOCC1)C1CN(c2cccc(C=O)n2)C1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a mixed solution of 1-(6-(1,3-dioxolan-2-yl)pyridin-2-yl)-N-methyl-N-(2-(morpholin-4-yl)ethyl)azetidine-3-amine (157 mg, 0.451 mmol) described in Production Example 29-3, acetonitrile (5.00 mL) and water (0.500 mL) was added p-toluenesulfonic acid monohydrate (386 mg, 2.03 mmol). The resultant mixture was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, and then the solvent was evaporated under a reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the resultant solution was extracted with dichloromethane three times. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure to give a crude product (122 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[C:17](=O)[CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: CCCN1CC(c2ccc(Cl)c(OC)c2)OCC1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CCOC(c2ccc(Cl)c(OC)c2)C1
Yield: 99.1 %

Procedure:
Borane-tetrahydrofuran complex (1 M in THF) (3.5 mL, 3.5 mmol) was added dropwise to a solution of the product from example 52 (0.33 g, 1.16 mmol) in dry THF (3 mL) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2.5 hours then cooled and quenched by addition of methanol (1 mL). The reaction mixture was concentrated in vacuo and the residue suspended in 4N HCl (aq., 8 mL) and refluxed for 2 hours. The reaction mixture was cooled and extracted with dichloromethane (2×10 mL). The organic layers were discarded. The aqueous layer was rendered basic (pH 9-10) by addition of solid potassium carbonate before re-extracting with dichloromethane (2×15 mL). The dichloromethane extracts were washed with water (10 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (0.31 g, 1.15 mmol, 99%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t, 3H), 1.45-1.60 (m, 2H), 2.00 (t, 1H), 2.20 (t, 1H), 2.35 (t, 2H), 2.80 (d, 1H), 2.90 (d, 1H), 3.80 (t, 1H), 3.90 (s, 3H), 4.03 (dd, 1H), 4.55 (d, 1H), 6.85 (dd, 1H), 7.00 (s, 1H), 7.30 (dd, 1H). LRMS (APCl): m/z 270 (MH+).
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[ClH:28].[C:29](#[N:31])[CH3:30]>C(O)C>[ClH:28].[ClH:28].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH2:20][N:31]4[CH2:11][C:12]5[C:30](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:29]4)[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: CC#N
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1Cc2ccccc2C1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added αα′-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g: eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240-243° C.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([N:14]=NC3C=CC=CC=3)[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.CO.[H][H]>[Pd].O>[Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([NH2:14])[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: C[N+]1(C)CCCc2c(N=Nc3ccccc3)ccc(O)c21
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C[N+]1(C)CCCc2c(N)ccc(O)c21

Procedure:
Into a stainless steel autoclave, one introduces 36.2 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-8-hydroxyquinolinium bromide (i.e. 0.1 mole), 200 ml of methanol and 3 g of 5% palladium on charcoal. The reduction is carried out at a pressure of 3-5 kg/cm2 of hydrogen and a temperature of 50°-60°C. After cooling, one adds a sufficient quantity of water to dissolve the entire mass, then one filters off the catalyst. One evaporates the filtrate to the dry state. The residue is extracted by means of ether so as to remove the aniline. One washes, with acetone, the clear brown compound that is obtained.