Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[C:26]([NH2:27])=[N:25][C:24]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:23]([Cl:35])[N:22]=1)=[O:20]>C(O)CC(C)C>[CH3:17][O:18][C:19]([C:21]1[C:26]([NH2:27])=[N:25][C:24]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:4]3[N:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=3)[CH2:31][CH2:30]2)=[C:23]([Cl:35])[N:22]=1)=[O:20]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COC(=O)c1nc(Cl)c(NC2CCNCC2)nc1N
Solvent: CC(C)CCO
Product: COC(=O)c1nc(Cl)c(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Temperature: 120 °C
Yield: 49.5 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.74 g, 3.1 mmol) was added to a solution of (36) (1.0 g, 3.2 mmol) in isoamyl alcohol (20 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.75 g (49%) of the compound (1): TLC (Rf =0.50; 10% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 6.93 (s, 1H), 6.82 (s, 1H), 5.44 (d, 1H, J=7.8), 5.21 (br s, 2H), 4.77 (d, 2H, J=13.7), 4.19 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.12 (t, 2H, J=11.3), 2.12 (d, 2H, J=12.6), 1.56 (m, 2H); 13C NMR (CDCl3) δ 166.6, 160.7, 158.4, 155.6, 155.4, 150.8, 149.6, 146.1, 121.5, 110.6, 105.8, 102.8, 101.7, 56.3, 56.1, 51.9, 48.9, 43.0, 31.8; HRMS (FAB) m/z 621.0766 (M+Cs)+ (C21H25N8O4Cl requires 621.0742); Anal. (C21H25N8O4Cl·1/2HCl·1/4CH3OH) C, H, N.
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:14].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:2][CH:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C1CCOCC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC12CCOCC2
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 4-ethylidenetetrahydro-2H-pyran (about 500 mg, step 1) and 3-chloroperoxybenzoic acid (1.11 g, 4.49 mmol) in dichloromethane (50 mL) was stirred at 0° C. to room temperature for 1 h. Then, saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated aqueous sodium thiosulfate solution (50 mL) were added, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo to give 337 mg of the crude title compound as a yellow oil. This was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([F:13])[CH:4]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1COCC1>[CH3:14][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([CH3:12])[C:6]([C:7](/[N:9]=[CH:17]/[N:18]([CH3:20])[CH3:19])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: Cc1cc(N(C)C)cc(F)c1C(N)=O
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)cc(F)c1C(=O)/N=C/N(C)C
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A suspension of 4-Dimethylamino-2-fluoro-6-methyl-benzamide (0.696 g, 3.55 mmol) with dimethylformamide-dimethylacetal (0.551 mL, 3.90 mmol) in THF (3 mL) was heated to 60° C. After 14 h., solvent was removed to give 4-Dimethylamino-N-[1-dimethylamino-meth-(E)-ylidene]-2-fluoro-6-methyl-benzamide as an oil, which eventually crashed out as a white solid (0.890 g, 100%).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][C:5]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][C:5]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:2]
Reactant: COc1ccc(-c2oc3c(OC)cccc3c2C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2oc3c(OC)cccc3c2C(C)O)cc1
Yield: 71.5 %

Procedure:
To a solution containing 75 g of 3-acetyl-7 -methoxy-2-(4'-methoxy phenyl) benzofurane (III bis) in 400 cc of methanol there is slowly added a solution containing 17.5 g of sodium borohydride in 200 cc of methanol. The resulting mixture is heated at reflux, with agitation, for 5 hours. The solvent is removed and the residue is then taken up in 200 cm3 of water, with agitation. The precipitate which forms is then separated by filtration, washed thoroughly with water, and crystallized in alcohol, yielding 54 g of 3-(α-hydroxy ethyl)-7-methoxy-2-(4'-methoxy phenyl) benzofurane (Ia) having a melting point of 100° C. The yield is 72%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33][C:34](OCC)=[O:35])=[CH:28][C:27]=1[O:40][CH3:41]>CCCCO>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:13][C:11]3[N:10]([N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:12]=3)[C:34](=[O:35])[CH:33]=2)=[CH:28][C:27]=1[O:40][CH3:41]
Reactant: Nc1nc(-c2ccc(F)cc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: COc1cc(-c2cc(=O)n3nc(-c4ccc(F)cc4)nc3[nH]2)ccc1Cl
Temperature: 130 °C
Reaction time: 36 h
Yield: 16.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.56 mmol) in n-BuOH (3 ml) was added TsOH (5 mg, 0.03 mmol), and ethyl 3-(4-chloro-3-methoxyphenyl)-3-oxopropanoate (200 mg, 0.78 mmol), and the resulting mixture was stirred for 36 hours at 130° C. in an oil bath. The solids were collected by filtration to give a crude product, which was purified by Flash-Prep-HPLC to afford 5-(4-chloro-3-methoxyphenyl)-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid (33.5 mg, 16%).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17](F)[C:18]=3[CH3:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[CH3:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: Cc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)c(C)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 192 h

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-5,8-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was heated and stirred at 40° C. for 8 days. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. The mixture was left to stand for 3 days, and solids deposited were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (20 mg) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C.O>[Br:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1O
Reactant: BrCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCBr
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 5-hydroxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile (0.4 g) in DMF (8 mL) was added 1-bromo-2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethane (1.0 g) and K2CO3 (0.5 g). The resulting mixture was heated at 80° C. overnight under N2 atmospheres. After reaction finished, the mixture was diluted with water (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.2 g of 5-(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.85 (s, 1H), 7.33 (s, 1H), 4.33-4.28 (m, 4H), 3.95-3.92 (m, 2H), 3.83-3.79 (m, 4H), 3.74-3.72 (m, 2H), 3.69-3.66 (m, 6H), 3.49-3.47 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[N:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.Cl.[OH:22][C:23]1([C:39]([F:42])([F:41])[F:40])[CH2:28][C:27](=[O:29])[NH:26][C:25]2[NH:30][N:31]=[C:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:24]1=2>CS(C)=O.C(OCC)(=O)C>[OH:22][C:23]1([C:39]([F:42])([F:41])[F:40])[CH2:28][C:27](=[O:29])[NH:26][C:25]2[NH:30][N:31]=[C:32]([CH:33]3[CH2:34][CH2:35][N:36]([C:11]4[N:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=4)[CH2:37][CH2:38]3)[C:24]1=2
Reactant: O=C1CC(O)(C(F)(F)F)c2c(C3CCNCC3)n[nH]c2N1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(C(F)(F)F)nn4)CC3)n[nH]c2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
N,N-Diisopropylethylamine (59.8 μL, 0.352 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine (80.2 mg, 0.439 mmol) were added to a solution of 4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one hydrochloride (100 mg, 0.293 mmol) produced in Reference Example 60 in dimethyl sulfoxide (0.5 mL), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, a saturated ammonium chloride aqueous solution, and brine in this order, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=100/0-90/10 (gradient)] to obtain the title compound (39.8 mg, yield: 30%).
Reaction SMILES: B.[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:32][CH3:33])[C:13]1[N:18]=[C:17]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3([O:30][CH2:29][CH2:28][O:27]3)[CH2:23][CH2:22]2)=O)[CH:16]=[C:15]([CH3:31])[N:14]=1.C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:32][CH3:33])[C:13]1[N:18]=[C:17]([CH2:19][N:21]2[CH2:22][CH2:23][C:24]3([O:30][CH2:29][CH2:28][O:27]3)[CH2:25][CH2:26]2)[CH:16]=[C:15]([CH3:31])[N:14]=1
Reactant: CCN(c1nc(C)cc(C(=O)N2CCC3(CC2)OCCO3)n1)c1ccc(C(C)C)cc1Br
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(c1nc(C)cc(CN2CCC3(CC2)OCCO3)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of borane in tetrahydrofuran (1M, 29 mL, 29 mmol) was added dropwise to a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)carbonyl-6-methylpyrimidinamine (1.67 g, 3.3 mmol) in anhydrous THF (7 mL) with stirring under a nitrogen atmosphere. The reaction mixture was heated to reflux temperature and stirred for 20 h, then cooled to ambient temperature. A solution of glacial acetic acid was added dropwise; then the reaction mixture was heated to reflux temperature and stirred for 4 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo; the residue was treated with excess 1N NaOH solution, and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Column chromatography (ethyl acetate) afforded N-(2-bromo-4-( 1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)methyl-6-methylpyrimidinamine as a pale brown oil (860 mg): CI-MS, 489, 491 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([C:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]2[NH:17][C:27](=[O:28])[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CCCCc1n[nH]c(N)c1-c1ccc(C)cc1
Solvent: c1ccncc1
Product: CCCCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
3-Butyl-4-(4-methylphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 215 mg of the target compound is yielded by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:5]2=1.[O:20]([CH2:27][CH:28]1[CH2:30][O:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:30][CH:28]([OH:29])[CH2:27][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[N:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:5]2=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Product: CCOC(=O)c1cc2c3cc(Br)ccc3n(CC(O)COc3ccccc3)c2cn1

Procedure:
Following Representative Procedure 1, the title compound ethyl 6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylate was prepared from ethyl 6-bromo-9H-pyrido[3,4-b]indole-3-carboxylate and phenoxymethyloxirane in 71% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:13][C:14]1[C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][NH:18]2.C([BH3-])#N.[Na+].[OH-].[Na+]>>[CH3:13][C:14]1[C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][CH2:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH2:25]2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][NH:18]2
Reactant: O=Cc1ccncc1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(O[C@@H]2CCC[C@H](NCc3ccncc3)C2)ccc2[nH]ncc12
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Isonicotinaldehyde (42.8 μl, 0.45 mmol) and acetic acid (0.23 mL, 4.08 mmol) were added to a methanolic solution (5 ml) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.41 mmol) obtained in Example 411, and the resulting mixture was stirred for 10 minutes. Then, sodium cyanoborohydride (28.2 mg, 0.45 mmol) was added thereto and stirred for 2 hours. An aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with chloroform (three times), and the extract solution was dried over anhydrous magnesium sulfate. The residue was purified by a silica gel chromatography (ethyl acetate, methanol (5% aqueous ammonia): chloroform=10/100) to obtain N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-4-ylmethyl)amine (58.7 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(CC)CC)C.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>CN(C)C=O>[N:10]1[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:3]2[C:7]([N:6]=[CH:5][NH:4]2)=[N:8][CH:9]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2nc[nH]c12)C(=O)OCC
Yield: 75.4 %

Procedure:
A mixture of 6-aminopurine (13.5 g), triethylamine (10.1 g) and 2-ethoxy-1,1-bis(ethoxycarbonyl)ethene (21.6 g) in dimethylformamide (100 ml) was heated at reflux for 16 hours. It was then cooled and the product which separated was crystallised from dimethylformamide and washed with diethyl ether, to give 2-(purin-6-ylamino)-1,1-bis(ethoxycarbonyl)ethene (23 g), in the form of colourless, fluffy crystals, m.p. 234° C. (with decomposition).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[N:20]1[C:28]([NH2:29])=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:29]1[C:28]1[N:20]=[CH:21][N:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[N:24]2
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Reactant: Nc1ncnc2nc[nH]c12
Solvent: O
Solvent: CO
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2ncnc3nc[nH]c23)C1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (2.66 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added adenine (1.35 g). The mixture was stirred at ambient temperature for one day and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(6-purinyl)morpholin-2-yl]hypoxanthine (3.20 g).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:11].OO>>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: Cl
Agent: OO
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 1.5 h
Yield: 32.2 %

Procedure:
To a solution of 42.5 g (0.3 mole) of 2-hydroxynicotinic acid in 212.5 ml of 37% hydrochloric acid (0.3 mole) was added dropwise 46 ml of a 30% aqueous solution of hydrogen peroxide (0.45 mole) at 25°±3° C. using an ice bath to control the temperature over a 10 minute period. The mixture was seeded with crystals from a previous trial. After 5-10 min. some crystals developed and after 1.5 hr precipitate was collected and rinsed three times with water and dried to give 16.75 g (Fraction 1) (32% yield) of crude 5-chloro-2-hydroxynicotinic acid containing 5-7% starting 2-hydroxynicotinic acid and some 3,5-dichloro-2-hydroxypyridine. After about 4 hr total time from the start, an additional 23 ml of 30% hydrogen peroxide was added to the mother liquor at 25°-30° C. At the 5th hour another 23 ml (0.22 mole) of 30% hydrogen peroxide was added. The solid was then collected and rinsed with water and dried to give 3.77 g (Fraction 2) (7.6% of yield) of crude 5-chloro-2-nicotinic acid containing 10-20% 3,5-dichloro-2-hydroxypyridine and a trace of starting material. The mother liquor was stirred overnight. No new precipitate was present. The mother liquor was then combined with rinsings from Fractions 1 and 2 and the resulting solution was extracted 3 times with methylene chloride. The combined methylene chloride layers were back washed with water, dried and evaporated to give 5.5 g of solid (Fraction 3). Analysis of Fraction 3 by 1HNMR gave many signals. Chemical Ionization Mass Spectroscopy analysis showed compounds m/e 214, 216, 218, 220 corresponding to compounds with multiple (2-3) halogen atoms on pyridine ring. For the trial as a whole, the total yield of 5-chloro-2-hydroxynicotinic acid was about 35% of theory considering the impurities and yield of polychlorinated impurities was about 10% on a theoretical mole base.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[SH:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH:11]1[C:10]([S:9][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:14][N:13]=[N:12]1
Reactant: Sc1nnn[nH]1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cc(Sc2nnn[nH]2)ccn1
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (7.25 g), 5-mercapto-1H-tetrazole (4.93 g) and triethylamine (14.64 g) in dimethylformamide (120 ml) was stirred for one hour at 82° to 85° C. and then cooled in an ice bath. The resulting precipitates were removed by filtration and the filtrate was mixed with water (60 ml). The aqueous solution was adjusted to pH 2 with 2N hydrochloric acid and evaporated to dryness under reduced pressure. The residue was triturated in chloroform (300 ml) and the resulting precipitates were collected by filtration and washed with the same solvent. To the precipitates was added ethanol (650 ml) and an insoluble material was removed by filtration. The filtrate was evaporated to dryness to give 4-(1H-tetrazol-5-ylthio)pyridine (4.03 g), mp. 159° to 161° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[Br:20][C:21]1[CH:22]=[C:23](/[C:27](/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[C:42]#[N:43])=[N:28]\S(C(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=1>>[NH2:43][C:42]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][C:37]=2[F:41])[C:27]([C:2]2[CH:3]=[C:4]([CH3:19])[C:5]([O:17][CH3:18])=[C:6]([CH2:7][OH:8])[CH:16]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=2)[N:28]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)cc1CO[Si](C)(C)C(C)(C)C
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1CO
Yield: 54 %

Procedure:
The title compound was synthesized as described for Example 35i in 54% yield, starting from of (5-bromo-2-methoxy-3-methylbenzyloxy)(tert-butyl)dimethylsilane (1.44 g, 4.17 mmol) and (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.415 g, 3.47 mmol). MS (ES+) m/z 455, 457 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][C:8]=2[NH2:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: c1ccc(-c2cncnn2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1ncnnc1-c1ccccc1
Temperature: -37 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of 6-phenyl-[1,2,4]triazine (18 g, 115 mmol) in anhydrous liquid ammonia (1 l) under an atmosphere of nitrogen at −37° C. was added in one portion potassium permanganate (22.6 g, 143 mmol). The reaction mixture was stirred at −37° C. for 30 min and then the ammonia evaporated. To the residue was added propan-2-ol (800 ml) and the resulting mixture heated under reflux for 10 min, then filtered through hyflo. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 4% MeOH in CH2Cl2+0.5% NH3) to afford 9.8 g (57 mmol, 50%) of 6-phenyl-[1,2,4]triazin-5-ylamine as a yellow solid. δH (360 MHz; CDCl3) 5.58 (2H, br s, NH2), 7.51-7.57 (3H, m, aromatics), 7.68-7.72 (2H, m, aromatics), 8.80 (1H, s, triazine H3); m/z (ES+) 173 (M++H, 100%).