Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])(=[O:3])C.[Na+].CO[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)CBr)=[CH:10][CH:9]=1.[C:25](O)(=O)C>>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]=[CH:11][C:10]2[CH:9]=[CH:8][C:13]([O:3][CH3:1])=[CH:12][CH:25]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(CBr)c2ccc(OC)cc2)cc1
Agent: [Na+]
Product: COc1ccc(C=Cc2ccc(OC)cc2)cc1
Temperature: 190 °C
Yield: 69.4 %

Procedure:
The Parr bomb described in EXAMPLE 6 above was employed. To a solution of 20.0 grams (0.24 mole) of anhydrous sodium acetate dissolved in 200 milliliters of glacial acetic acid was added the entire crude 1,1-bis(4-methoxyphenyl)-2-bromoethane (66.0 grams, 0.21 mole based on pure product) from EXAMPLE 8 above. The bomb was flushed and then pressurized to 110 psig with dry nitrogen. The contents were heated, with stirring, to 190° C. over a 30-minute period, maintained at that temperature for 1 hour, and allowed to cool over a 2-hour period. The solid which crystallized was collected by suction filtration, washed successively with 50 milliliters of acetic acid, followed by 300 milliliters of warm water in a beaker. The crystalline material was collected and dried under vacuum to yield 33.3 grams (69.4 percent based on bromoacetal employed in EXAMPLE 8 above) of 4,4'-dimethoxystilbene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[N:36]1[CH:40]=[N:39][C:38]([CH3:41])=[N:37]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCBr)n1
Reactant: CNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCN(C)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methylethane-1,2-diamine (0.2 g, 0.623 mmol) in DMF (3 mL) was added TEA (0.095 g, 0.935 mmol) followed by 1-(2-(2-bromoethoxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (Preparation J, 0.245 g, 0.233 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, with 10% methanol in chloroform) to get N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methyl-N2-(2-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)ethyl)ethane-1,2-diamine (0.04 g, 13.12%) as a dark brown solid. LC-MS (M+H)+=567.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, s), 7.14-7.08 (3H, m), 6.99-6.95 (2H, m), 6.41 (1H, s), 6.32 (1H, d, J=8.4 Hz), 4.39 (2H, br s), 4.14 (1H, t, J=8.8 Hz), 3.93-3.88 (4H, m), 3.22-3.09 (6H, m), 2.55-2.54 (1H, m), 2.46 (3H, s), 1.99-1.98 (1H, m).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][C:16]=1[N+:24]([O-:26])=[O:25])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of 1.0 g (4.0 mmol) 4-ethoxalylaminobenzonitril in 4 ml glacial acetic acid was added 4 ml acetic anhydride. At 0° C. a solution of 1 ml 100% nitric acid in 2 ml glacial acetic acid was added dropwise, and after 15 min. further 1 ml 100% nitric acid was added. Stirring was continued at 0° C. for 1 h. The reaction mixture was poured into 50 ml ice-water to give 0.95 g (81%) of 4-ethoxalylamino-3-nitrobenzonitril. M.p. 151.8° C.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=O.C(Cl)(Cl)Cl>O1CCCC1>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=[CH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 0.95 g of phenyllithium (19% solution in dibutylether) (2.15 mmol). To this mixture, 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added under cooling. After the mixture was well-stirred, 0.38 g (1.98 mmol) of 2,4,6-trimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the reaction mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 508 mg (yield: 92%) of 2-[2-(2,4,6-trimethoxyphenyl)vinyl]thiophene as a colorless crystal.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([O:26]CC2C=CC=CC=2)[C@H:15]([CH3:34])[O:14][C@H:9]1[O:10]CC=C)(=[O:6])C.CCOC(C)=O>CO>[CH3:34][C@@H:15]1[O:14][CH:9]([OH:10])[C@H:8]([OH:7])[C@H:17]([OH:18])[C@H:16]1[OH:26].[OH2:6]
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O
Product: O
Reaction time: 2 h

Procedure:
After adding 0.5 M NaOMe (222.7 mL, 111.0 mmol, 1 eq.) to the allyl glycoside 76 (47.5 g, 111.0 mmol) in solution in MeOH (150 mL), the reaction mixture is stirred for 2 h and its development is monitored by TLC (Chex/EtOAc, 7/3). After observing the disappearance of 76 (Rf=0.6) and the appearance of a more polar product (Rf=0.35), the reaction mixture is neutralized by adding DOWEX (H+) ion-exchange resin, then filtered on a frit. The resin is washed with DCM/MeOH mixture and the solvents are evaporated. The yellow oil obtained is purified by silica gel chromatography (Chex/EtOAc, 8/2→7/3) to give the alcohol 58 in the form of a colorless oil (39.2 g, 92% or 61% starting from commercial L-rhamnose 27).
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([OH:30])[CH2:19][O:20][C:21]4[CH:29]=[CH:28][C:24]([CH2:25][C:26]#[N:27])=[CH:23][CH:22]=4)[CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]([C:33]1[C:34]([NH2:41])=[N:35][C:36]([NH2:40])=[N:37][C:38]=1[NH2:39])=O.C(OCC[O-])C.[Na+].O>C(OCCO)C>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([OH:30])[CH2:19][O:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]5[N:31]=[C:33]6[C:34](=[N:41][C:26]=5[NH2:27])[N:35]=[C:36]([NH2:40])[N:37]=[C:38]6[NH2:39])=[CH:28][CH:29]=4)[CH2:13][CH2:12]3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: N#CCc1ccc(OCC(O)CN2CCN(C34CC5CC(CC(C5)C3)C4)CC2)cc1
Agent: CCOCC[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: Nc1nc(N)c2nc(-c3ccc(OCC(O)CN4CCN(C56CC7CC(CC(C7)C5)C6)CC4)cc3)c(N)nc2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A mixture of 4-[3-[4-(1-adamantyl)-1-piperazinyl]-2-hydroxypropoxy]benzylcyanide (3.44 g, 8.4 mmol), 5-nitroso-2,4,6-triamino-pyrimidine (1.08 g, 7.0 mmol) and 0.2N sodium-(2-ethoxyethoxide) in 2-ethoxyethanol (35 ml) was stirred at 120° C. for 30 minutes. After cooling to about 90° C. 100 ml of water was added and the mixture was cooled to room temperature followed by stirring in an ice-water bath for 30 minutes. The precipitate was collected, washed with water and acetonitrile to give the title compound (3.23 g) as a yellow powder, mp. 287°-289° C. (dec.), yield: 84.6%.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH3:10])[CH:5]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: CNc1cc(Cl)nc(N)[n+]1[O-]
Reactant: C1CCNC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(N2CCCC2)nc(N)[n+]1[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
3.4 g of 2-amino-4-methylamino-6-chloropyrimidine 3-oxide are suspended in 70 ml of ethanol. 4.15 g of pyrrolidine are added. The reaction mixture is refluxed for 7 hours. After it has returned to room temperature, 1.30 g of potassium hydroxide are added as an 85% solution in 15 ml of ethanol. After 1 hour's stirring the mixture is filtered on paper. The filtrates are evaporated to dryness. The residue obtained is recrystallized from 50 ml of a 9/1 acetonitrile-water mixture. 2.40 g of 2-amino-4-methylamino-6-pyrrolidinopyrimidine 3-oxide are obtained.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14]C=1)([CH3:9])([CH3:8])[CH3:7].S(Cl)(Cl)(=O)=O>O>[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][C:1]=1[Cl:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)c1cc(O)ccc1Cl
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Into 30 ml of carbon tetrachloride were dissolved 9 g of 3-tert-butylphenol and the mixture was heated up to 70° C. With stirring at this temperature, 10.5 g of sulfuryl chloride were added dropwise to the mixture. After completion of this dropwise addition, the reaction mixture was subjected to stirring over a period of 48 hours at 70° C. After cooling the reaction mixture down to room temperature, the reaction mixture was poured into cold water and the resultant product was extracted with carbon tetrachloride. After drying over anhydrous calcium chloride, carbon tetrachloride of the extraction solution was distilled off under reduced pressure, and the residue was purified through a column chromatography (employing silica gel as carrier and benzene as developing solvent) to give 1.3 g of 3-tert-butyl-4-chlorophenol, having the following properties.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13](O)=O)=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N:22]1C=CC=CC=1>>[CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]#[N:22])=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ncc(Br)cc1C(=O)O
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Product: CC(C)OC(=O)c1ncc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (630 mg, 2.187 mmol) in pyridine (8 ml) at 0° C. was added methane sulfonyl chloride (0.34 ml, 4.37 mmol, 2 equiv.) and the reaction mixture was stirred for 1 hour at 25° C. Then NH3 gas was purged in to reaction mixture at 0° C. and stirred at 25° C. for 30 minutes. The excess NH3 was evaporated off in vacuo. The reaction mixture was cooled to 0° C., a fresh lot of methane sulfonyl chloride (1.35 ml, 17.49 mmol, 8 equiv.) was added drop wise to the mixture and stirring was continued at 25° C. for another 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc (2×40 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The resulting crude material was purified by column chromatography over normal silica gel (10% EtOAc in hexane) to give 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (320 mg, 54%) as yellow oil.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16]Br)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][O:26][C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CO>O>[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[C:23]4[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=4[O:26][CH:25]=3)[CH2:28][CH2:29]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Reactant: Nc1nc(-c2ccc(F)cc2)c(CCBr)s1
Agent: Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccc(F)cc2)c(CCN2CCC(c3coc4cc(F)ccc34)CC2)s1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 0.917 g of 2-amino-5-(2-bromoethyl)-4-(4-fluorophenyl)thiazole hydrobromide, 0.511 g of 4-(6-fluorobenzofuran-3-yl)piperidine hydrochloride, 1.5 ml of diisopropylethylamine and 3 ml of methanol was stirred with heating under reflux for 12 hours. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with chloroform. The extract solution was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, after which ether was added to the residue and the crystals were collected by filtration. The crystals were recrystallized from ethanol to obtain 0.57 g of 2-amino-4-(4-fluorophenyl)-5-[2-[4-(6-fluorobenzofuran-3-yl)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:16]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([O-:18])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[N+:16]([C:19]1[CH:20]=[C:21]([NH:22][CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:23]=[CH:24][CH:25]=1)([O-:18])=[O:17]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 10 h
Yield: 71.1 %

Procedure:
To a solution of N-Boc-hexahydro-1H-azepin-4-one (141 mg) and 3-nitroaniline (91 mg) in methylene chloride (3 mL), sodium triacetoxyborohydride (210 mg) and acetic acid (38 μL) were added at room temperature, and the mixture was stirred at the same temperature for 10 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain tert-butyl 4-((3-nitrophenyl)amino)azepane-1-carboxylate (C25, 157 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:9]=2[C:24]([OH:26])=O)=[CH:4][CH:3]=1.O[N:28]1[C:32]2C=CC=[CH:36][C:31]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.C(N)CC>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[C:24]([NH:28][CH2:32][CH2:31][CH3:36])=[O:26])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1nc(C(C)C)c(C(=O)O)c(-c2ccc(F)cc2)c1CC=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCN
Product: CCCNC(=O)c1c(C(C)C)nc(C(C)C)c(CC=CO)c1-c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 37 %

Procedure:
To a stirring solution of 4-(4-fluorophenyl)-5-(3-hydroxy-2-propenyl)-2,6-bis(1-methylethyl)-3-pyridinecarboxylic acid (4.0 g, 0.0112 mol) was added 1.51 g of 1-hydroxybenzotriazole (0.0112 mol) followed by 2.31 g of DCC (0.0112 mol). The resulting mixture was stirred 25 minutes, then 1.84 ml of n-propylamine (0.0224 mol) was added. The resulting mixture was stirred for 72 hrs and then was taken up in ethyl acetate (500 ml), filtered, washed with water (2×250 ml), washed with 30% saturated NaHCO3 (1×150 ml), washed with brine (1×150 ml), dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica (1:1 hexane:ethyl acetate) to yield 1.65 g of the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH3:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])(=[O:1])[CH2:14][CH3:15]
Reactant: CCC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCC(=O)C(=Cc1cccc(Cl)c1)C(=O)OCc1ccccc1

Procedure:
1.59 g (7.71 mmol) of benzyl 3-oxovalerate, 1.08 g (7.71 mmol) of 3-chlorobenzaldehyde and 65.7 mg (0.771 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 50 ml of benzene for 6 hours while water was removed. Benzene was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:27]=[N+:28]=[N-:29].[Na+].CCOC(C)=O>CN(C=O)C>[N:27]([C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:28]=[N-:29]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (135 mg, 0.33 mmol, prepared according to Example 30, Step 16.1) and sodium azide (108 mg, 1.66 mmol) in DMF (1 mL) was heated at 60° C. and stirred for 4 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (144 mg, 0.33 mmol, quant.) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=2.77.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:12][C:13](=[O:14])[NH:8][N:9]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
To a solution of 2-benzyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (6.4 g, 15.7 mmol) in toluene (100 mL) at 90° C. was added aluminum chloride (5.23 g, 39.3 mmol) in one portion. After addition, the reaction mixture was stirred at 90° C. for 20 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to reduce the volume to about 50 mL, then water (150 mL) was added. The resulting mixture was sonicated for 5 min, then stirred at room temperature for 10 min. The resulting suspension was filtered, the collected solid was washed with water (20 mL×3), hexanes (20 mL×3) and dried in a 50° C. vacuum oven for 16 h to afford 4.2 g (76%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.27 min, (M+H)+=317.0. 1H NMR (CDCl3, 400 MHz): δ 11.6 (S, 1H), 7.17-7.40 (m, 6H), 6.90-7,10 (m, 3H).
Reaction SMILES: [Cl:1][C:2]12[N:10]=CN[C:7]1([N+]([O-])=O)[C:6](Cl)=[N:5][C:4](SC)=[N:3]2.N.CO>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[CH:6][CH:7]=1.[NH2:10][C:2]1[N:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: CSC1=NC2(Cl)N=CNC2([N+](=O)[O-])C(Cl)=N1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccncn1
Product: Nc1ccncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Method XLXVII: Compound FJ. 4,6-dichloro-5-nitro-2-methylmercaptopurine (1.0715 g, 4.502 mmol) was dissolved in 25 mL THF and cooled to 0° C. NH3/MeOH was added (3.5 Equiv) and the mixture was allowed to stir cold for 1 h. Aminoester (1.22 g, 4.37 mmol) was then added dropwise as a solution in 10 mL THF over 10-15 minutes, and the resulting mixture was allowed to warm to room temperature. After 3 h, the reaction was quenched with the addition of water, diluted with EtOAc and the pH was adjusted to =8 using solid K2CO3. The mixture was washed with water, washed with brine then dried with sodium sulfate and concentrated in vacua. The crude product was then chromatographed on silica with a CH2Cl2 and 20% MeOH/CH2Cl2 gradient over 10-15 column volumes. Sometimes mixtures of 6-chloropyrimidine and 6-aminopyrimidine products are obtained (1.02 g) and are sequentially treated with excess NH3 in MeOH in THF over 45 minutes at room temperature and rechromatographed as above to give pure 6-aminopyrimidine product (716 mg). LCMS-ESI+: calc'd for C16H21N6O4S: 392.43 (M+H+); Found: 393.0 (M+H+).
Reaction SMILES: COCCOC.[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH:23]([CH2:26][CH3:27])[CH:24]=O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Zn].O>[CH2:26]([CH:23]1[CH:24]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][CH2:22]1)[CH3:27]
Reactant: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: CCC1C=C(c2ccccc2)c2ccccc2SC1
Yield: 77.3 %

Procedure:
To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl3. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO4 and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.