Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:8])[CH:4]([OH:7])[CH2:5][Cl:6].O1CC[CH2:12]OO1.S(=O)(=O)(O)O>ClCCCl>[Cl:1][CH2:2][CH:3]1[CH:4]([CH2:5][Cl:6])[O:7][CH2:12][O:8]1
Reactant: C1COOOC1
Reactant: OC(CCl)C(O)CCl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: ClCC1OCOC1CCl
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A three-neck 500-mL flask equipped with a thermometer, a mechanical stirrer, an addition funnel, a condenser, and a positive nitrogen atmosphere was charged with 1,4-dichloro-2,3-butanediol (50.0 g, 0.314 mole), trioxane (9.43 g, 0.314 mole), and 1,2-dichloroethane (EDC) (300 mL). The 1,4-dichloro-2,3-butanediol was not totally dissolved. Concentrated sulfuric acid (46.3 g, 0.455 mole) was then added dropwise over eight minutes. During the addition period, a slight exotherm was noticed and the flask was immersed in an ice bath to maintain the reaction temperature at 21.5° C. to 25.5° C. for 2.1 hours. The reaction mixture was permitted to settle overnight. The acid layer was removed, washed once with 30 mL EDC, and discarded. The combined EDC solutions were quenched with 2% NaHCO3 (600 mL), washed with deionized water (400 mL), 1% NaHCO3 solution (400 mL), deionized water (400 mL, twice), and stripped in vacuo. The resulting light yellow liquid weighed 48.9 g (89.5% yield), and contained 1.8% EDC and 98.2% dl- and meso-(4,5-dichloromethyl)-1,3-dioxolane, as determined by GC analysis and proton NMR (CDCl3) δ (s, --OCH2O--), 4.1 (m, ClCH2CHCHCH2Cl), 3.6(d, ClCH2CHCHCH2Cl).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:22]([N:24]([CH2:27]C)[CH2:25][CH3:26])[CH3:23].C(#[N:31])C>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:31]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:22][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCN(CC)CC
Reactant: CC#N
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.0 g (3.35 mmole) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 1.36 g (13.35 mmole) of triethylamine and 60 ml of acetonitrile is refluxed for eight hours and stirred at room temperature for 16 hours. The precipitate is removed by filtration, washed with acetonitrile, and dried in vacuo at 45° C. to give 5-amino-1-cyclopropyl-6,8-difluoro-1,4 -dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, mp 247°-248° C.
Reaction SMILES: N#N.C[CH:4]([OH:7])[CH2:5][CH3:6].[H-].[Na+].[C:10]([C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2F)[N:18]=1)=[O:15])([CH3:13])([CH3:12])[CH3:11].[CH3:31]N(C)C=O>O>[C:10]([C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[O:7][CH2:4][CH:5]([CH3:31])[CH3:6])[N:18]=1)=[O:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(-c2cccc(NC(=O)C(C)(C)C)n2)c(F)c1
Reactant: CCC(C)O
Reactant: CN(C)C=O
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cccc(NC(=O)C(C)(C)C)n2)c(OCC(C)C)c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a 125 mL three-necked round-bottomed flask equipped with septum, condenser and N2 inlet were added 2.4 mL (26.2 mmol) 2-butanol and 20 mL dry dimethylformamide. The solution was heated to 80° C., and 1.2 g (60% in oil, 30 mmol) sodium hydride was added. The reaction was heated at 80° C. with bubbling for 1 hour, then a solution of 2.5 g (8.7 mmol) N-t-butylcarbonyl-6-(2-fluoro-4-methylphenyl)-pyridin-2-ylamine in 20 mL dry dimethylformamide was added, and the reaction heated at 80° C. for 24 hours. The reaction was cooled, poured into water, and extracted into ethyl acetate. The organic layer was washed thoroughly with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 2.4 g (75%) of the product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19](OC)[C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:25](C1NC=CN=1)(C1NC=CN=1)=[O:26].[O:37]1CCC[CH2:38]1>>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH2:4][C:3]3[C:2](=[C:22]([O:37][CH3:38])[CH:21]=[CH:20][CH:19]=3)[NH:1][C:25]2=[O:26])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C1CCOC1
Reactant: COc1cccc(N)c1CNC1CCN(Cc2ccccc2)CC1
Product: COc1cccc2c1NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A stirred solution of (2-amino-6-methoxy-benzyl)-(1-benzyl-piperidin-4-yl)-amine (0.2 g, 0.62 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with carbonyl diimidazole (99 mg, 0.62 mmol). The reaction was stirred for 30 min at 0° C. and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 150 mg (68%) of the desired product. LC/MS: tR=1.41 min, 352.30 (MH)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]3[CH:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=2)[CH2:2]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]3[CH:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=2)[CH2:2]1)=[O:24]
Reactant: CCOC(=O)c1cc(OC2CNC2)c2cc(C)oc2c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC2CN(C(=O)N(C)C)C2)c2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate (200 mg, 0.73 mmol) in dissolved in DCM with containing TEA (0.4 mL, 2.9 mmol) was added dimethylcarbamic chloride (0.1 mL, 1.09 mmol). The mixture solution was stirred at room temperature for 2 hrs. The reaction was diluted with DCM, washed with NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (20/80 to 60/40) to provide the product (138 mg, 55%) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.54 (m, 3 H) 2.49 (s, 3 H) 2.88 (s, 6 H) 4.06-4.20 (m, 2 H) 4.33-4.53 (m, 4 H) 5.04-5.18 (m, 1 H) 6.52 (s, 1 H) 7.01 (s, 1 H) 7.80 (s, 1 H); MS (ESI, pos): 347.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>C(#N)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4]1
Reactant: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Yield: 70 %

Procedure:
Methyl 4-oxo-3,4-dihydroquinazoline-7-carboxlate 300 mg (1.37 mmol) was dissolved in acetonitrile (20 mL) followed by addition of K2CO3 (100 mg), KI (80 mg) and 2-flourobenzyl chloride (0.2 mL, 1.65 mmol). The mixture was refluxed over night. The reaction mixture was concentrated and the residue was purified by flash chromatography (Et2O:DCM, 1:1) to give methyl 3-(2-flourobenzyl)4-oxo-3,4-dihydroquinazoline-7-carboxylate in 70% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:8]=2[CH3:16])=[N:3]1.[H][H]>O1CCCC1.[Pd]>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:16])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cc1c(C2=NC(C)(C)CO2)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(N)cccc1C1=NC(C)(C)CO1
Yield: 95 %

Procedure:
To 29.82 g of 4,5-dihydro-4,4-dimethyl-2-(2-methyl-3-nitrophenyl)oxazole in 500 ml of tetrahydrofuran is added 0.5 g of 10% palladium on barium sulfate. The mixture is exposed to hydrogen gas until the appropriate quantity of hydrogen is taken up, filtered and the solvent evaporated to give 24.7 g of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylbenzenamine as a gum which crystallizes on cooling; mp 45° C.
Reaction SMILES: [NH2:1][C:2]1C(C#N)=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[OH-:17].[K+].[CH2:19]([OH:22])[CH2:20]O>>[NH2:1][C:2]1[C:20]([C:19]([OH:22])=[O:17])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: OCCO
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)cnc1N
Reactant: [OH-]
Agent: [K+]
Product: Nc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
An alkaline hydrolysis procedure may also be used to synthesize the desired compound. Accordingly, 2-amino-5-(4-chlorophenyl)-3-pyridinecarbonitrile (2.0 grams) and KOH (2.0 grams) in 30 ml ethylene glycol were heated at 150° C. in an oil bath. After 3 hours the reaction was complete and the alkaline solution was poured into ice water and acidified to give the desired solid. The final product was again confirmed by NMR, yield 2.3 grams, m.p. 300°-315° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-tolueneslufonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:23]3)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
A mixture of 2-oxindole (29 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 81 mg (95%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27]2)[CH2:18][CH2:17]1)=[O:15])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCBr)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.5 g, 40.7 mmol) in dimethylformamide (100 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.6 g, 40.0 mmol) in dimethylformamide (100 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 3-bromo-propyl ester (15.0 g, 37.4 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. overnight. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from industrial methylated spirits to afford a white crystalline solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].C(Cl)(=O)C.[C@@H:39]1([N:47]2[CH:55]=[C:53]([CH3:54])[C:51](=[O:52])[NH:50][C:48]2=[O:49])[O:46][C@H:43]([CH2:44]O)[C@@H:41]([OH:42])[CH2:40]1.CN(C1N=CC=CN=1)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([O:32][CH2:44][C@H:43]2[O:46][C@@H:39]([N:47]3[CH:55]=[C:53]([CH3:54])[C:51](=[O:52])[NH:50][C:48]3=[O:49])[CH2:40][C@@H:41]2[OH:42])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Agent: CN(C)c1ncccn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Yield: 84.4 %

Procedure:
Compound 30 (3.5 grams, 7.73 mmol) was coevaporated with toluene (2×) and then dissolved in anhydrous toluene (85 mL). Acetyl chloride (33 mL, 464 mmol) was added to the solution and the reaction mixture was heated to reflux and stirred under argon. After 4 hours the reaction mixture was concentrated in vacuo and the crude product was coevaporated with pyridine and then dissolved in anhydrous pyridine (42 mL). Thymidine (1.5 grams, 6.18 mmol), which had been coevaporated with pyridine and dissolved in anhydrous pyridine (42 mL), was then added to the solution containing the crude product. A catalytic amount of dimethylaminopyrimidine (DMAP) was added and the reaction mixture was stirred under argon overnight and the solvent was evaporated. The residue was redissolved in dichloromethane and washed with a 5% aqueous solution of sodium bicarbonate followed by water. The organic phase was dried (MgSO4), evaporated and purified by column chromatography (silica gel; EtOAc/hexane, 1/1) to afford 3.53 grams (84%) of compound 31 as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 3 H), 2.22-2.46 (m, 2 H), 2.50-2.63 (m, 4 H), 3.35-3.58 (m, 2 H), 3.85-4.09 (m, 5 H), 4.51-4.60 (m, 1 H), 5.02 (dd, J=1.5, 10.4 Hz, 2 H), 5.14 (dd, J=1.5, 17.3 Hz, 2 H), 5.68-5.83 (m, 2 H), 6.12-6.45 (m, 5 H), 6.82 (d, J=9.0 Hz, 4 H), 7.18-7.46 (m, 9 H), 7.58 (s, 1 H), 8.44 (s, 1 H); Anal. Calcd for C41H44N2O7·2H2O (712.8384): C, 69.08; H, 6.79; H, 3.93. Found: C, 69.34; H, 6.44; N, 3.91.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>ClC1C=CC=CC=1Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccccc1C1=CCCCCCC1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: C1=C(c2ccccc2N2CCNCC2)CCCCCC1
Temperature: 200 °C
Reaction time: 9 h
Yield: 53.2 %

Procedure:
To a solution of 2-cyclooct-1-enylphenylamine (140 mg, 0.695 mmol) in 1,2-dichlorobenzene (2 mL) was added bis(2-chloroethyl)amine hydrochloride (149 mg, 0.835 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 9 hours, the mixture was air-cooled to room temperature. Aqueous solution of potassium carbonate, ethyl acetate and methanol were added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 100 mg of the title compound as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:20])[NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:20])[NH:19][C:12]([NH:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:13]
Reactant: CN(C)N
Reactant: O=C=NCc1cccc(-c2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)NC(=O)NCc1cccc(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
To a solution of 2.56 g of this crude 3-phenylbenzylisocyanate in 8 ml of toluene was added dropwise 0.78 g (13 mmol) of N,N-dimethylhydrazine with ice-cooling. The mixture was removed from an ice bath and stirred for 1.5 hours. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 1.40 g (5.20 mmol) of 1,1-dimethyl-4-(3-phenylbenzyl)semicarbazide.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[C:1]1([C:7]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:8]([CH3:9])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1OC1(c1ccccc1)c1ccccc1
Yield: 98.8 %

Procedure:
A solution of 2.00 g (10.3 mmol) 1,1-diphenylpropene and 2.09 g (10.4 mmol) 85% m-chloroperbenzoic acid in 15 ml dichloromethane was stirred in the dark at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated K2CO3 solution and the organic layer was washed with brine and dried over Na2SO4. This was concentrated to give 2.14 g (98%) of 2,2-diphenyl-3-methyloxirane as a colorless oil.
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.FC1C=CC(F)=C2C=1C(OCC1C=CC=CN=1)=NN1C(C3C=[C:42](C)[O:41]N=3)=NN=C12.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:41][CH3:42])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: Cc1cc(-c2nnc3c4c(F)ccc(F)c4c(OCc4ccccn4)nn23)no1
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0.14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (6 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES+) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES+) 438 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:12])C.[C-]#N.[Na+].Cl.[CH3:17][NH:18][CH3:19]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([N:18]([CH3:19])[CH3:17])[C:10]#[N:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC
Reactant: CC#N
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CN(C)C(C#N)c1ccc(F)cc1
Yield: 90.5 %

Procedure:
Into a 1 l four-necked flask equipped with a thermometer, a stirrer and a dropping funnel, 49.6 g (0.4 mol) of 4-fluorobenzaldehyde and 480 ml of acetonitrile were charged, and a solution comprising 29.4 g (0.64 mol) of sodium cyanide, 81.6 g (1 mol) of dimethylamine hydrochloride and 200 ml of water, was dropwise added over a period of 15 minutes at from 20 to 30° C. with stirring, and then reacted at the same temperature for 18 hours. After completion of the reaction, the mixture was subjected to liquid separation. The organic layer was separated, and acetonitrile was distilled off. The residue was extracted with 400 ml of ethyl acetate, washed with a 5% sodium hydrogen carbonate aqueous solution and water, and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the obtained oily substance was distilled under reduced pressure to obtain 64.5 g (yield: 90.5%) of the desired compound (boiling point: 100-101° C./1 KPa). The NMR spectrum data thereof are as follows.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:12])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>CO.C1(C)C=CC=CC=1.[Rh]>[CH:1]1([C@@H:7]([CH3:12])[CH2:8][C:9]([Cl:16])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](CC(=O)Cl)C1CCCCC1

Procedure:
(S)-3-phenylbutyric acid was hydrogenated using Rh/C in MeOH at 60 psi and 60° C. for 3.2 hours. The reduced product was then converted to the title acid chloride by treating with 1 eq of oxalyl chloride, and a catalytic amount of DMF, in toluene for 90 minutes, followed by evaporation of the volatile materials.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][O:6][N:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C(N(CC)C(C)C)(C)C>C(O)C.C(#N)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:3]([C:4]2[C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: ON=C(Cl)c1nonc1N1CCOCC1
Reactant: Nc1ccc(F)c(Br)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: ON=C(Nc1ccc(F)c(Br)c1)c1nonc1N1CCOCC1
Reaction time: 62 h
Yield: 48.7 %

Procedure:
A solution of N-Hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidoyl chloride (40 mg, 0.17 mmol) and 3-bromo-4-fluoroaniline (49 mg, 0.26 mmol) in ethanol (1 mL) was treated with a solution of N,N-diisopropylethylamine (45 μL, 0.26 mmol) in acetonitrile (1 mL) and stirred for 62 h. The reaction mixture was purified by preparative HPLC to give the desired product (32 mg, 48%). LCMS for C13H14ClFN5O3 (M+H)+: m/z=386.0, 388.0.