Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH2:9])[CH3:8]>O.CO>[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH:9][C:2]#[N:1])[CH3:8]
Reactant: COC(C)(OC)C(C)N
Reactant: N#CBr
Solvent: O
Solvent: CO
Product: COC(C)(OC)C(C)NC#N

Procedure:
Cyanogen bromide (424 mg., 4 m moles) was added to a solution of 2,2-dimethoxy-1-methylpropylamine (266 mg., 2 m moles) and KHCO3 (400 mg., 4 m moles) in a mixture of water (2 ml.) and methanol (4 ml.). After 15 minutes the mixture was poured in to water (150 ml.) and the mixture extracted with CH2Cl2. The extract was washed with water and brine, dried (MgSO4) and evaporated to dryness to give 2,2-dimethoxy-1-methylpropylcyanamide as a pale yellow oil (280 mg., 88%) having the following n.m.r. spectrum in CDCl3 : 1.15 (s, 3H); 1.18 (d, 3H); 3.15 (s, 6H); 3.0-3.6 (m, 1H); 4.0 (m, 1H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(C=O)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CN4CCOCC4)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
In a 20 mL vial was added 1-cyclohexyl-2-(5-(4-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carbaldehyde (28 mg, 0.047 mmol.), morpholine (10 mg, 0.11 mmol) and methylene chloride (2 mL). A catalytic amount of acetic acid was added and the reaction mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (30 mg, 0.14 mmol) was then added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated to give the title compound (15 mg) which was used directly in the next step.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/c1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc2ccccc12
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of ethyl (2E)-3-(1-naphthyl)propenoate (37.6 g, 166 mmol) in ethanol (500 ml) was added 10% palladium carbon (4 g) and the mixture was stirred under hydrogen atmosphere for 5 hours. The insoluble matter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 37.7 g (yield: 99.7%)
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]3[C:18]([CH3:29])([CH3:28])[C@@H:17]([O:30]C(=O)C)[C@@H:16]([O:34]C(=O)C)[C:15]([CH3:39])([CH3:38])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>CO>[CH3:28][C:18]1([CH3:29])[C@@H:17]([OH:30])[C@@H:16]([OH:34])[C:15]([CH3:38])([CH3:39])[C:14]2[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][CH:6]=3)[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]1=2
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)C3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)c2cc(/C=C/c3ccc(C(=O)O)cc3)c(Cn3cccn3)cc2C(C)(C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A mixture of 1.0 g (2.2 mmol) of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-6,7-cis-diacetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid methyl ester. in 20 ml of methyl alcohol and 10 ml of 1 N LiOH was heated at reflux. After 1 h, cooled to room temperature, concentrated under reduced pressure, acidified with 2 N HCl, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and adsorbed onto silica gel. The product was purified by flash chromatography (gradient elution: 20-60% ethyl acetate/hexane with 0.2% acetic acid) to give 560 mg of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-6,7-cis-dihydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid.(mp 238.3-241.5) 148.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:27]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:25]O)[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.CCN(S(F)(F)[F:40])CC.O.C(=O)(O)[O-].[Na+]>ClCCl>[F:40][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:15]1[CH2:16][CH2:17][CH2:18][N:13]2[N:12]=[C:11](/[CH:10]=[CH:9]/[C:7]3[CH:6]=[CH:5][C:4]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:3]([O:2][CH3:1])[N:8]=3)[N:27]=[C:14]12
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CO)ccc1-n1cnc(C)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CF)ccc1-n1cnc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
{2-{2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}methanol (350 mg) was dissolved in dichloromethane (40 mL). This was added dropwise to a solution of DAST (1.04 mL) in dichloromethane (6 mL) cooled to −78° C., and the reaction solution was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: NH silica, elution solvent: ethyl acetate:methanol=9:1) to obtain a racemate of the title compound (70 mg). The resulting racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 7 minutes and positive optical rotation (20 mg) and the title optically active compound with a retention time of 9 minutes and negative optical rotation (20 mg), where the retention time is an analysis result in CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (Lot. IB00CD-FD026, mobile phase: ethanol, flow rate: 0.5 mL/min).
Reaction SMILES: [CH2:1]([N:8]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:9]1[CH2:13][CH:12]([C:14](=[O:43])[CH2:15][N:16]([C:24]2[N:25]=[C:26]3[CH:32]=[CH:31][N:30]([S:33]([C:36]4[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=4)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=2)C(=O)OC(C)(C)C)[CH:11]([CH3:44])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:45]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:13][CH:12]([C:14](=[O:43])[CH2:15][NH:16][C:24]2[N:25]=[C:26]3[CH:32]=[CH:31][N:30]([S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=4)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=2)[CH:11]([CH3:44])[CH2:10]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)C(=O)OC(C)(C)C)cnc32)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
tert-Butyl 2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (6.19 g, 8.75 mmol) was dissolved in HCl (4 N in 1,4-dioxane, 25 mL). The reaction mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc (100 mL each). The organic phase was washed with brine (80 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield 1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (5.2 g, 98%) as a brown amorphous solid: LC/MS (Table 1, Method a) Rt=3.00 min; MS m/z 608 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:24]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: N
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391 mg., 0.001 mole) in tetrahydrofuran (15 ml.) is cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution is allowed to warm to ambient temperature and stand for 24 hours. It is then concentrated in vacuo. The residue is suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give 0.229 g. of crude product of melting point 227°-228.5° C. Recrystallization of this material from ethyl acetate gives three crops of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: 0.142 g. of melting point 228°-229.5°, 0.053 g. of melting point 228.5°-229.5° C. and 0.021 g. of melting point 228°-229.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 165, 179 mg, 0.38 mmol) in ethanol and THF was hydrolyzed with 1M NaOH to give rise to the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[H-].[Na+].[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1>CN(C=O)C.CCOC(C)=O>[Cl:14][C:15]1[N:16]=[N:17][C:18]([O:8][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidin-4-ol (106 mg, 0.67 mmol) in DMF (6.7 mL) was added 60% wt NaH (35 mg, 0.87 mmol). The solution was stirred at RT for 30 min, then 3,6-dichloropyridazine (100 mg, 0.67 mmol) was added and the reaction was stirred for 1 h. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-chloro-6-(2,2,6,6-tetramethylpiperidin-4-yloxy)pyridazine, intermediate 1-3 (135 mg). The crude material used without further purification. LCMS Rt=1.22 min (condition B); MS (M+1)=270.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53 (s, 1H), 7.37 (d, J=9.1 Hz, 1H), 6.91 (d, J=9.1 Hz, 1H), 5.68-5.78 (m, 1H), 2.20 (dd, J=12.4, 4.0 Hz, 2H), 1.32 (s, 6H), 1.27-1.29 (m, 2H), 1.20 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)[C:16]([S-])=[S:17].[K+]>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[O:13][C:16]([SH:17])=[N:14][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Sc1nc2cc(-c3ccccc3)ccc2o1

Procedure:
4-Phenyl-2-aminophenol, 11.4 mmol (2.10 g) was dissolved in ethanol, 30 ml, and added potassium ethyl xanthate, 11.4 mmol (1.82 g). The reaction mixture was refluxed overnight, cooled, and excess of ethanol was distilled off, then the reaction mixture was poured into crushed ice. The pH was adjusted to 5 by the addition of acetic acid. The white precipitate formed was filtered and dried to give the crude 5-phenylbenzo[d]oxazole-2-thiol, 2.32 g (90%) that was directly used in the next step without any purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1)#[N:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:26])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(CO)cn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Cyano-5-hydroxymethylpyridine (13.4 g) and pyridine (8.7 g) were dissolved in toluene (150 ml), and a solution of p-toluenesufonyl chloride (19.1 g) in toluene (50 ml) was added dropwise at room temperature to the solution. After the addition, the mixture was gradually heated, and stirred at 70° to 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and washed with water. The organic layer was dried. Toluene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2-cyano-5-pyridylmethyl chloride (7.7 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(Br)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
1.00 g (5.02 mmol) of 6-bromo-9H-purine (purchased from Aldrich; cat. no. 104981) was suspended in 10 mL of DMF and potassium carbonate (2.08 g, 15.05 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then 1-(chloromethyl)-4-methoxybenzene (1.40 mL, 10.06 mmol) were added. The reaction mixture was stirred at 45° C. overnight. Then the mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 50% hexane/AcOEt) to yield 447 mg (28%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24](O)=[O:25])[N:22]=1)=[CH:5]2.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([NH:39][CH3:37])=[O:25])[N:22]=1)=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
The compound (44 mg, 0.11 mmol) prepared in Example 31 was dissolved in N,N-dimethylformamide (2 ml). Methylamine (0.08 ml, 2M in THF, 0.17 mmol), EDC (36 mg, 0.19 mmol) and HOBT (30 mg, 0.22 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18 mg, Yield 37%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH2:3][C:2]2([CH3:13])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(C)(C)CCO2
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCOc2ccc(CBr)cc21

Procedure:
A mixture of 5.0 g (28.4 mmole) of 4,4,6-trimethylchroman, 5.55 g of purified N-bromosuccinimide and 200 ml of carbon tetrachloride was heated under reflux for 12 hours. The succinimide was removed by filtration and the solvent was removed by evaporation in vacuo to give the title compound as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:34][C:13]([F:12])([F:33])[C:14]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:10]2/[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:19][CH2:18]1
Reactant: O=C1N=C(NCCCO)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-1,3-thiazol-2(5H)-one (900 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.75 g) in 2-propanol (20 mL) was added piperidinium acetate (750 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. After evaporation of the solvent, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.17 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][N:11]=1>C1C=CC=CC=1>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:11][N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1ccc(O)cc1
Solvent: c1ccccc1
Product: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A pressure bottle was charged with 4-aminophenol (0.453 g, 0.416 mmol), 1-chloro-4-phenylphthalazine (1.00 g, 0.416 mmol) and 16.8 mL of benzene. The bottle was sealed and heated to 100° C. for 25 h. The reaction mixture was concentrated. The crude material was dissolved in methanol and was purified by Gilson reverse phase liquid chromatography, 5-75% ACN/H2O/0.1% TFA over 14 min. The product-containing fractions were combined, brought to basic pH by addition of 1M NaHCO3, and extracted with dichloromethane. The organic portion was dried with MgSO4, filtered and concentrated to provide 4-(4-phenylphthalazin-1-ylamino)phenol as a yellow solid. MS m/z=314 [M+H]+. Calc'd for C20H15N3O: 313.35.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[CH3:23][C:5]1[NH:4][C:3](=[O:2])[N:8]([C:30](=[O:33])[CH2:31][CH3:32])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)CC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (750 mg., 2.35 mmole) and dry pyridine (0.57 ml., 7.05 mmole) in dichloromethane (5.0 ml.) at -20° (methanol/ice bath) under argon is treated dropwise via gas-tight syringe with propionyl chloride (0.26 ml., 2.82 mmole). The reaction mixture is stirred for 2.0 hours and evaporated. The solid yellow residue is dissolved in methanol (25 ml.) and tetrahydrofuran (15 ml.) and treated with 5N hydrochloric acid (6.0 ml.). After stirring at room temperature for 1.0 hour, the reaction mixture is evaporated. The residue is partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is flash chromatographed to give the title compound as a white foam (567 mg.). This foam is combined with material from another batch (290 mg.) and recrystallized from dichloromethane/isopropyl ether to give large shiny white crystals (784 mg., m. p. 152°-154°). TLC(silica gel; 50% ethyl acetate:hexanes) Rf =0.57.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15](O)([CH2:17][CH2:18][C:19]([CH3:22])(O)[CH3:20])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:14][C:15]1([CH3:16])[C:2]2[CH:1]=[C:13]3[C:5]([C:6]4[CH:7]=[C:8]5[C:19]([CH3:22])([CH3:20])[CH2:18][CH2:17][C:15]([CH3:16])([CH3:14])[C:9]5=[CH:10][C:11]=4[CH2:12]3)=[CH:4][C:3]=2[C:19]([CH3:22])([CH3:20])[CH2:18][CH2:17]1
Reactant: CC(C)(O)CCC(C)(C)O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Temperature: -8 °C
Yield: 53 %

Procedure:
In a 500 ml three-necked flask purged with nitrogen, 9.72 g (58.6 mmol, 1 eq) of fluorene and 19.61 g (134 mmol, 2.3 eq) of 2,5-dimethyl-2,5-hexanediol were placed at room temperature. Then, 85 ml of dehydrated dichloromethane was added. After stirring by a magnetic stirrer, the mixture was cooled to −8° C. with an ice bath (light brown slurry). To the slurry, 38.9 g (292 mmol, 5.0 eq) of pulverized anhydrous aluminum chloride was added over a period of 70 minutes, followed by stirring at 0° C. for 2 hours. The ice bath was removed, and the solution was stirred at room temperature for 19 hours (dark brown solution). After disappearance of fluorene was confirmed by gas chromatography, the dark brown solution was poured into 150 ml of ice water to perform quenching (yellowish brown slurry) After the soluble component was extracted with 500 ml of diethyl ether, the organic phase was neutralized with a saturated sodium hydrogencarbonate aqueous solution and washed with water. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator. The residue was transferred onto a Kiriyama funnel, washed 6 times with 10 ml of hexane and vacuum dried to obtain a white powder (12.0 g, yield: 53%)