Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH2:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH:51][C:22]([C:10]1[N:11]=[C:12]([CH2:19][O:20][CH3:21])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a mixture of 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid (120 mg, 0.37 mmol), NEt3 (109 μl, 0.78 mmol), and CH2Cl2 (7 ml) cooled with an ice bath was added ClCO2iBu (52 μl, 0.39 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (79 mg, 0.39 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a yellow oil (141 mg); MS-(+)-ion: M+1=471.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[N:24]1([CH2:31][CH2:32][CH2:33][NH:34][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:9][C:10]=3[CH3:23])[CH2:19][CH2:18]2)=[O:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCCCCC1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)NCCCN2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylic acid (0.25 g, 0.75 mmole), 3-(Azepan-1-yl)propan-1-amine (0.33 g) and DIPEA (0.32 mL) in DMF (5 mL) was added EDC (0.153 g). The reaction solution was stirred at room temperature overnight. The solvent removed and EtOAc (100 mL) was added. The organic layer was washed with saturated sodium bicarbonate (50 mL), water (50 mL) and dried over anhydrous magnesium sulfate. After filtration, the residue after concentration of the filtrate was crystallized from EtOAc/Hexane to provide the N-(3-(azepan-1-yl)propyl)-1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxamide as white solid (0.30 g, 85%). H1NMR (300 MHz, CDCl3), ppm: 7.94 (d, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 3.44 (s, 2H), 3.36 (m, 2H), 2.99 (d, 2H), 2.67 (m, 4H), 2.60 (t, 2H), 2.39 (s, 3H), 2.07 (m, 3H), 1.83 (m, 4H), 1.65 (m, 10H). MS (ESI+) M/z: 473, 475 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH3:15])[CH2:9]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2CCCOC(C)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CCCOC(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of 4-(4-methoxy-benzyl)-2-methyl-[1,4]oxazepan-3-one (2.00 g, 8.02 mmol) in tetrahydrofuran (24 ml) was added 1M borane-tetrahydrofuran complex in tetrahydrofuran (27.3 ml, 27.3 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours. After cooling to 0° C., methanol (20 ml) and 6N sodium hydroxide (20 ml) was added carefully. The resulting mixture was refluxed for 2 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=1/1) to afford 4-(4-methoxybenzyl)-2-methyl-[1,4]oxazepane as colorless oil (1.66 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:23]([C:30](OCC)=[O:31])#[C:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:25]([C:24]1[N:3]2[C:4]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:7][CH2:8][C:2]2=[N:1][C:30](=[O:31])[CH:23]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2-amino-7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine was heated in ethanol with diethyl acetylenedicarboxylate to give 1-carboethoxy-9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:14]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCO)CC1

Procedure:
A suspension of 3.4 g (12.72 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 125 ml ethanol and 810 mg of PtO2.H2O was hydrogenated (1 atm) for 7 h. The reaction was filtered (Celite) and evaporated to give 3.5 g (quantitative) of trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 271 (M).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40]>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=1)[C:14]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[O:15])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)C(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. The resulting solution was added dropwise to a solution of 168 mg (1.88 mmol) of 2-amino-2-methyl-1-propanol in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 364 mg (74% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccccc1F
Solvent: Cc1ccccc1C
Product: O=C(O)c1cccnc1Nc1ccccc1F

Procedure:
50 g of 2-chloronicotinic acid and 31 ml of 2-fluoroaniline in 180 ml of xylene are refluxed for 5 hours. The precipitate is filtered off and washed with xylene and then with water to yield the desired compound.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][OH:5]>C(O)C.O1CCCC1.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][CH2:7][CH2:6][N:2]([CH3:1])[CH2:3][CH2:4][OH:5])[CH2:10][CH2:11][CH2:12]2
Reactant: CN(CCO)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCO)CCCN1CCCc2cc(N)ccc21
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)amino)ethanol (76 mg, 0.259 mmol) in ethanol (2 mL) and tetrahydrofuran (2.0 mL) was added palladium, 10 wt % on activated carbon (27.6 mg, 0.026 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (balloon pressure) for 2 h. The reaction mixture was then filtered through a pad of celite (washed with methanol) and concentrated to give a dark oil. The crude product was used directly in the subsequent reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=2[N:7]=[N:6]1.CO.C(=O)([O-])[O-:19].[K+].[K+].Cl>C(O)=O.O.[Ni].[Al]>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:19])=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)nnn2CCCO
Agent: [Ni]
Agent: Cl
Agent: [Al]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: O=Cc1ccc2c(c1)nnn2CCCO
Temperature: 75 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazole-5-carbonitrile (Intermediate 97, 9.6 g, 47.5 mmol) in aqueous Formic Acid (106 mL of a 75% solution in water) was added Niquel-Aluminium alloy (10.6 g, 0.12 mol). The mixture was stirred overnight at 75° C. The solids were removed by filtration through Celite® and the solvent was removed under reduced pressure. The crude obtained was treated with MeOH (415 mL) and potassium carbonate was added (49 g, 0.35 mol). After 1 h the solution was acidified with 2N HCl until neutral pH and MeOH evaporated under reduced pressure. The aqueous phase was extracted with CH2Cl2 (3×200 mL) and the resulting organic layer washed with water (2×50 mL), dried and evaporated under reduced pressure to afford the title compound as a solid (6.05 g, 60% yield), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1.[ClH:39].CCOCC>C(O)C>[ClH:39].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of (S)—N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.360 g, 0.656 mmol) in ethanol (25 mL) was added an aqueous 6N solution of HCl (2 mL). The reaction was heated at 80° C. for 2 hours, then cooled to ambient temperature, stirred for 30 minutes, then cooled to 0° C. Ether (25 mL) was slowly added to initiate precipitation/crystallization. The reaction was stirred 30 minutes, then filtered. The solids were washed with ether several times, then hexanes, and dried overnight under vacuum at 50° C. to afford (S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.205 g, 0.406 mmol, 61.9% yield) as a light yellow powder/fine crystals. Mass Spectrum (apci) m/z=469.2 (M+H−HCl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[N:4][C:5]([F:30])=[C:6]([Cl:29])[C:7]=1[CH:8](C(OCC1C=CC=CC=1)=O)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O>CS(C)=O>[Cl:29][C:6]1[C:5]([F:30])=[N:4][C:3]([F:31])=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c(Cl)c(F)nc(F)c1Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1c(Cl)c(F)nc(F)c1Cl)OCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m).
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:14]([CH3:16])[CH3:15])[C:5]=1[OH:17].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:14]([CH3:16])[CH3:15])[C:5]=1[OH:17])=[O:31]
Reactant: CC(C)c1cc(C(C)(C)C)cc(CN)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
0.4 g (0.0012 mol) of 2-aminomethyl-4-(1,1-dimethylethyl)-6-isopropylphenol hydrochloride is reacted with 0.17 g of hexamethylenetetramine in 2.5 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH:6]=[CH:5][N:4]=1
Reactant: FC(F)(F)c1ncc(Cl)cn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2cnc(C(F)(F)F)nc2)ccn1
Yield: 46.1 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol) were reacted according to the procedure of Example 3 (step a) to provide the title compound (1.0 g, 46%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
2.0 Grams (0.00855 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.65 g (0.0116 mole) of powdery potassium hydroxide, the resulting mixture was stirred at 30° C. for 30 minutes. To this solution was added 2.32 g (0.00855 mole) of tert-butyl 4-bromomethylbenzoate, and reaction was carried out at from 50° to 60° C. for 1 hour. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain crude crystals. The crystals were recrystallized from methanol to obtain 2.4 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1>>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)=[CH:23][CH:24]=1)[CH3:30]
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1
Yield: 33.4 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 1-bromo-4-ethoxybenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 265 mg (yield 33%). Melting point was 117 to 119° C. (ethanol-water).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[Na+].OO>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[C:1]1([CH:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]([NH2:9])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Cc1ccc(CC(C#N)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(CC(C(N)=O)c2ccccc2)cc1
Yield: 98 %

Procedure:
221.3 Grams of 2-phenyl-3-(p-tolyl)-propionitrile (II-1), 40 g of a 25% aqueous sodium hydroxide solution, 291.5 g of a 35% aqueous hydrogen peroxide solution and 2.78 g of tetra-n-butylammonium chloride were mixed at 50° C. for 4 hours in 663.9 g of methanol. After the reaction was completed, methanol was distilled off and the formed precipitate was filtered out and washed with water to obtain 234.5 g of 2-phenyl-3-(p-tolyl)-propionamide (m.p.: 150°-151° C.) (I-1) in a yield of 98%.
Reaction SMILES: OC1C2[C@@H]3CC(=NO)CC[C@H]3C(C)(C)OC=2C=C(C(C)(C)CCCCCC)C=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[C:42]([O:45][C:46]1[C:55]2[CH:54]3[CH2:56][C:57]([N:60]([C:64](=[O:66])[CH3:65])[C:61](=[O:63])[CH3:62])=[CH:58][CH2:59][CH:53]3[C:52]([CH3:68])([CH3:67])[O:51][C:50]=2[CH:49]=[C:48]([C:69]([CH3:77])([CH3:76])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:47]=1)(=[O:44])[CH3:43]>O.C(OCC)C>[C:42]([O:45][C:46]1[C:55]2[C@@H:54]3[CH2:56][C:57]([N:60]([C:64](=[O:66])[CH3:65])[C:61](=[O:63])[CH3:62])=[CH:58][CH2:59][C@H:53]3[C:52]([CH3:67])([CH3:68])[O:51][C:50]=2[CH:49]=[C:48]([C:69]([CH3:76])([CH3:77])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:47]=1)(=[O:44])[CH3:43]
Reactant: CCCCCCC(C)(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1CC=C(N(C(C)=O)C(C)=O)CC21
Agent: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=NO)C[C@@H]21
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCC(C)(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)[C@@H]1CC=C(N(C(C)=O)C(C)=O)C[C@@H]21
Temperature: 25 °C

Procedure:
A solution of 2.59 g. of dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-hydroxyimino-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran in 25 ml. of acetic anhydride and 75 ml. of pyridine was stirred under a nitrogen gas atmosphere and heated to reflux for twenty-four hours. After cooling the reaction mixture to room temperature, the solvent was removed therefrom by evaporation under reduced pressure to provide an oily residue. The residue was dissolved in 50 ml. of diethylether and 50 L ml. of water and stirred for one hour. The mixture was filtered and the organic layer was separated. The ethereal solution was washed with 1 N hydrochloric acid, water, saturated sodium chloride solution and dried. Removal of the solvent afforded 3.57 g. of a dark oil which was then chromatographed over 100 g. of Woelm Activity I silica gel, eluting with fifty percent hexane-diethyl ether. The fractions containing the major product were combined and concentrated to dryness to provide 3.12 g. of predominantly dl-1-acetoxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(N,N-diacetylamino)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran, with a minor quantity of the Δ9 compound. m/e: calc. 497; found 497.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1>CC#N.O>[NH2:22][C:17]1[N:16]=[C:15]([Cl:14])[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[N:18]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: COC(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc(Nc2nc(N)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Methyl 3-aminobenzoate (0.69 g, 4.55 mmol) and a 1N NaOH aqueous solution (0.91 mL, 0.91 mmol) were added to a solution of 4,6-dichloro-1,3,5-triazin-2-amine (0.75 g, 4.55 mmol) in a 1:1 MeCN/water mixture (40 mL) at 0 C. The mixture was stirred at 0 C for 1 h and room temperature for 3 days. The acetonitrile was removed under vacuum and the resulting white solid in water was filtered and dried under vacuum to provide the title compound (1.1 g, 87%). Method B HPLC-MS: MH+ requires m/z=280/282 Found: m/z=280/282, Rt=1.69 min (95%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC1CCOCC1
Product: O=C(O)c1ccc(OCC2CCOCC2)nc1
Yield: 60 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 60% yield starting from ethyl 6-chloronicotinate and tetrahydro-2H-pyran-4-ylmethanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.13 (dd, 1 H), 6.89 (d, 1 H), 4.19 (d, 2 H), 3.86 (dd, 2 H), 3.09-3.50 (m, 2 H, obscured by H2O), 1.95-2.10 (m, 1 H), 1.59-1.70 (m, 2 H), 1.25-1.40 (m, 2 H); MS (ESI) m/z 236[M−H+].