Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=1.[OH-].[Na+]>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[CH:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O

Procedure:
108.9 g (0.316 mol) of rac-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 750 ml of concentrated hydrochloric acid. 215 g (0.95 mol) of stannous chloride are added portionwise to the solution while cooling with ice and stirring and the mixture is stirred at room temperature for 3 hours. The mixture is subsequently neutralised at 0° C. with 10 N sodium hydroxide and the aqueous phase is extracted with methylene chloride/ethanol (4:1). The organic phase is washed with water, dried and evaporated. Recrystallisation of the residue from ethyl acetate/petroleum ether yields rac-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 180° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:25]#[N:26])([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 72.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-fluoro-phenyl)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Reaction SMILES: Cl.[NH2:2]O.N.[C:5]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:39])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:38])[C@@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:9][CH:8]=1)#[N:6]>C(O)C>[C:5]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:39])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:38])[C@@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:9][CH:8]=1)(=[NH:2])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)nc1
Reactant: NO
Agent: Cl
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C(=N)N)nc1
Reaction time: 0.17 h

Procedure:
1.15 g (16.5 mmol) of hydroxylamine hydrochloride were suspended in 5 ml of ethanol, 1.2 g of 25% strength ammonia solution were added, and the mixture was stirred for 10 min. After addition of 45 ml of ethanol, the precipitated salt was filtered off with suction and 3.14 g (6.6 mmol) of the above compound (stage c) were added to the solution. The hydroxyamidine compound separated out after a short time and, after stirring for 30 minutes, was filtered off with suction and washed with a little cold water and ethanol. The residue moist with ethanol was dissolved in 40 ml of ethanol and 8 ml of glacial acetic acid, 250 mg of 10% Pd/C were added and hydrogenation was carried out at about 50° C. After 5 hours, TLC (CH2Cl2/MeOH/50% strength acetic acid, 20/5/1) showed no detectable starting material.
Reaction SMILES: [CH3:1]C(C)[O-].[Na+].[Na].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[NH:11][C:12]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(OC)(OC)(=O)=O>C(O)(C)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[N:11]([CH3:1])[C:12]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: N#CCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)[nH]1
Reactant: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
To a refluxing solution of sodium isopropoxide in isopropanol (prepared by refluxing 0.69 g. (0.030 mole) of sodium in 70 ml. of isopropanol) is added 7.0 g. (0.025 mole) of 4-chloro-5-(p-chlorobenzoyl)-pyrrole- 2-acetonitrile prepared according to Example VIII, after which a solution of 3.78 g. (0.030 mole) of dimethyl sulfate in 10 ml. of isopropanol is added dropwise. When addition of the dimethyl sulfate solution is complete, the whole is refluxed for a half-hour and then poured into 1 liter of ice water. Filtration of the resulting mixture yields a grey solid, which is washed well with water and is then chromatographed with benzene on alumina. The chromatographed material is finally recrystallized from isopropanol to yield 4-chloro-5-(p-chlorobenzoyl)-1-methyl- pyrrole-2-acetonitrile as a beige solid; m.p. 139°-142° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccnc(Cn3ncc(N)n3)c2)OCCO1
Product: CC(=O)c1ccnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by N, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[N+:17]([O-])([OH:19])=[O:18]>>[CH3:16][C:10]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:8][C:7]([F:6])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
116 ml of sulfuric acid is introduced and mixed in portions at −15° C. with 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid. A mixture of nitrating acid (4.79 ml of fuming nitric acid and 21.8 ml of concentrated sulfuric acid) is added in drops to this mixture, specifically at −15 to −10° C. during a period of 90 minutes. After three more hours of stirring, the reaction mixture is poured into ice water and stirred vigorously for about one-half hour. The precipitated crystallizate is suctioned off, washed neutral with water and dried. The yield is 8.56 g (45.1%) of a mixture of various regioisomers and by-products. This mixture is incorporated into the next stage (esterification) and purified in this stage.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][CH2:2][C:3](=[O:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: O=C1CCCN1CC(O)CCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CCl)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(3-Chloro-2-hydroxypropyl)pyrrolidin-2-one (0.380 g, 2.14 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. Dess-Martin periodinane (0.907 g, 2.14 mmol) was added and the mixture agitated at ambient temperature for 2 hours. The mixture was loaded on silica gel chromatographic column and eluted with 1% methanol/dichloromethane to provide the title compound.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][C:38]1[CH:39]=[C:40]([NH:45][C:46](=[O:48])[CH3:47])[CH:41]=[C:42]([CH3:44])[CH:43]=1>C(Cl)Cl.CO>[Br:1][C:43]1[C:42]([CH3:44])=[CH:41][C:40]([NH:45][C:46](=[O:48])[CH3:47])=[CH:39][C:38]=1[CH3:37]
Reactant: [Br-]
Reactant: CC(=O)Nc1cc(C)cc(C)c1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
Benzyltrimethylammonium tribromide (BTMA-Br3) (7.8 g, 20.21 mmol) was added to a solution of N-(3,5-dimethyl-phenyl)-acetamide (3.0 g, 18.38 mmol) in CH2Cl2/MeOH (90 ml/90 ml) at room temperature in an Ar atmosphere. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 was then added to the resulting residue. The organic layer was washed with H2O, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=1:1) to give N-(4-bromo-3,5-dimethyl-phenyl)-acetamide (4.0 g, yield 90%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:13][C:10]1[N:11]=[CH:12][C:7]([CH2:6][N:1]=[N+:2]=[N-:3])=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(CCl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(CN=[N+]=[N-])cn1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
NaN3 (11.2 g, 172 mmol) was added to a solution of the 5-(chloromethyl)-2-methylpyridine (12.2 g, 86.2 mmol) in dimethylformamide (120 ml) while cooling on ice and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was poured into semi-saturated aqueous sodium hydrogencarbonate, extraction was performed with ethyl acetate and the extract was washed with water and saturated aqueous NaCl. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (8.9 g, 26%, two steps) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:22]#[N:23])=[CH:15][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])[CH3:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1ccc([N+](=O)[O-])cc1C

Procedure:
A mixture of 2-methyl-4-nitroaniline (38.0 g, 250 mmol), ethyl (ethoxymethylene)cyanoacetate (50.8 g, 300 mmol), and 200 ml of toluene was refluxed for 24 h, cooled, diluted with 1:1 ether-hexane, and filtered. The resulting white solid was washed with hexane-ether and dried to give 63.9 g, mp 180-210° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:11][C@@H:10]1[C@@H:12]([CH3:13])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3]([NH2:17])=[N:4][C:5]2=[O:16])[C@@H:8]1[OH:9])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
5'-Deoxy-5-fluorocytidine (245 mg) was dissolved in dry pyridine (5 ml). To the solution was added benzoyl chloride (130 μl) with stirring at 0° C. The reaction mixture was stirred for 1 hour at 0° C. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane - methanol) followed by recrystallization from ethyl acetate to give colorless crystals of 3'-O-benzoyl-5'-deoxy-5-fluorocytidine (51 mg). mp 127°~129° C.; MS 350 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1.O>CN(C=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:3][CH:2]([CH3:4])[CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: CC(C)[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 61 %

Procedure:
3.38 g of sodium isopropoxide are added to a solution of 2.6 g of 2.4-dichloro-5-nitropyridine in 39 ml of DMF. The reaction medium is stirred at ambient temperature for 1 h 15 and 3.18 g of sodium isopropoxide are added. The reaction medium is stirred for a further 15 minutes and then the mixture is poured into 200 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a heptane/ethyl acetate mixture (90/10 to 80/20). 1.78 g of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are obtained in the form of a pale yellow solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([C:7]([NH:9][NH2:10])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.O>CCO>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[N:10][NH:9][C:7]([C:2]1[C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NNC(=O)c1ccccc1-c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a stirred solution of biphenyl-2-carboxylic acid-hydrazide (0.212 g, 1.0 mmol) in 20 mL EtOH was added 3-trifluoromethyl-benzaldehyde (0.174 g, 1.0 mmol) in 5 mL EtOH at room temperature. The mixture was refluxed for 4 h and cooled to room temperature, then was diluted by 100 mL of water. The precipitate was collected, washed with MeOH, and dried to yield the title compound (0.320 g, 87%). 1H NMR (acetone-d6): 11.60 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=12 Hz, 1H), 7.35 (d, J=12 Hz, 1H), 6.97˜7.15 (m, 10H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH2:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1.CCOC(C)=O>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]4([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[CH2:1][CH2:35]4)[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccn4)CC3)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide (36 mg, 0.32 mmol) was added to a solution of trimethyl-sulfoxonium iodide (440 mg, 0.48 mmol) in DMSO to make a 1M solution of ylide. This reaction mixture was stirred for 10 min at RT, then a portion of it (0.64 mL, 0.64 mmol) was added to a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridine-2-yl)vinyl)-benzo[d]thiazole (134 mg, 0.32 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight, EtOAc was added, and the mixture was washed with water several times, then dried over MgSO4. After concentrating under vacuum, the resulting oil was purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridine-2-yl)-cyclopropyl)benzo[d]thiazole. MS (ESI) m/z: Calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:11][N:10]=1)=[O:8]>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:11][N:10]=1)=[O:8]
Reactant: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 8 g of sodium borohydride and 350 ml of methanol, cooled to -2°, the solution of 20 g of 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester in 60 ml of dimethylformamide sufficiently warm for dissolution is added all at once and the container of the latter is washed with 15 ml dimethylformamide and 20 ml methanol containing 0.5 g of sodium borohydride. The mixture warms to about 20°, is cooled to 0° for 40 minutes and stirred at 25° for 15 minutes. It is cooled again to 0° and 9 ml of 12 N hydrochloric acid, 2 ml of acetic acid and 200 ml of ice water are added in this order. The resulting solution is diluted with crushed ice to about 1,000 ml, extracted with ethyl acetate and diethyl ether, the extract dried and evaporated. The residue is first recrystallized from diethyl ether/hexane and then from ethyl acetate/diethyl ether, to yield the 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester of the formula ##STR9## melting at 111°-113°.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[NH:32]1[CH:36]=[C:35]([CH2:37][NH2:38])[N:34]=[N:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[NH:32]1[CH:36]=[C:35]([CH2:37][NH:38][C:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:23]=[CH:24][C:2]=3[Cl:1])[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[O:20])[N:34]=[N:33]1
Reactant: NCc1c[nH]nn1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1c[nH]nn1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a solution of 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105, 200 mg, 0.458 mmol), (1H-1,2,3-triazol-4-yl)methanamine (74 mg, 0.549 mmol) and N,N-diisopropylethylamine (406 μL, 2.29 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (1 mL) was added HATU (261 mg, 0.687 mmol). The reaction was stirred at room temperature for 2 hours. Further HATU (87 mg, 0.229 mmol) was added and the reaction continued for 3 hours. The reaction solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was further extracted with ethyl acetate (2×10 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by elution through an SCX-2 column using MeOH followed by 7N NH3 in MeOH followed by silica gel column chromatography eluting with 1% NH3(aq) and 8% MeOH in DCM to afford the title compound as white solid (51 mg, 21%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][NH2:9]>ClC1C=CC=CC=1>[CH3:8][NH:9][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CN
Reactant: O=C1C=CC(=O)O1
Solvent: Clc1ccccc1
Product: CNC(=O)/C=C\C(=O)O

Procedure:
The same reactor as used in Example 7 was adopted. This reactor was charged with a solution 53 g of maleic anhydride in 200 g of chlorobenzene. Then, methylamine gas was blown in gradually and piecemeal at 30° C. at a rate of 4.3×10-3 mol/min. over a period of two hours to produce a white slurry of N-methyl maleinamic acid. Subsequently, the slurry and 22.5 g of ortho-phosphoric acid (purity 89% by weight), 0.1 g of phenothiazine, and 0.02 g of zinc acetate added thereto were heated at 134° C. for two hours to effect reaction. Thereafter, the resultant reaction mixture was cooled to 40° C., filtered, and distilled under a vacuum to expel chlorobenzene. Consequently, there was obtained 45 g of light yellow N-methyl maleimide having purity of 92.1% by weight. The yield of the product is calculated to be 72.5 mol% based on methylamine as the raw material.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-]>C(O)C>[CH:24]1([CH2:23][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8]3)[CH2:3][CH2:2]2)[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc2c(c1)ccn2C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 1-N-(piperidin-4-yl)-indole (0.6 g, 3 mmol) in dry ethanol (4 mL) was added anhydrous potassium carbonate (680 mg, 4.9 mmol). After stirring for 15 minutes at ambient temperature, bromomethylcyclopropane (0.29 mL,4.5 mmol) was added. Stirring was continued overnight. An additional amount of carbonate (0.22 g) and bromomethylcyclopropane (0.14 mL) was added. After 3 hours, the reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined organic phase was washed with water, dried, evaporated, and purified by column chromatography on silica gel eluting with methylene chloride/ethanol (98:2). Evaporation of the eluting solvent gave the title compound as an oil (480 mg, 63% yield).
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]2=[N:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][CH:20]([Br:25])[C:13]2=[N:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCC2Br
Temperature: 25 °C

Procedure:
A mixture of methyl 3-(benzoyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, N-bromo-succinimide (1.2 eq.) and dibenzoylperoxide (70%, 0.13 eq.) in carbon tetrachloride was stirred under reflux for one hour. The mixture was cooled to room temperature, the succinimide was filtered off and the solvent was removed under reduced pressure. Methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate was obtained after flash chromatography (eluent petroleum ether/ethyl acetate, 1:1) as a pale yellow oil.