Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(CO)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
2.0 g of 2-(4-chlorophenyl)-3-methylbutanol in 10 ml of a 20% mixture of dimethylformamide and toluene was added over a 5 minute period to sodium hydride (0.8 g, 50% in oil) in 20 ml of toluene at 110°-120° C, and the mixture was stirred for 15 minutes. 3.0 g of 3-phenoxybenzyl bromide in 15 ml of toluene was then added over a 15 minute period and the mixture was gently refluxed for 2 hours, then was cooled and 10 ml of mineral spirits was added. The mixture was poured into ice/hydrochloric acid, extracted with ether, washed with sodium bicarbonate solution and dried (MgSO4). The solvent was removed to give an orange oil, which was chromatographed on silica gel using 1:1 methylene dichloride:hexane as eluent to give 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:37][CH2:38][CH2:39][F:40])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Reactant: FCCCBr
Product: COc1ccc(CC2c3cc(OC)c(OCCCF)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH2:36])[C@H:27]([O:37][C:38](=[O:40])[CH3:39])[C@H:26]1[O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2].[CH3:45][C:46]([CH:48]1[C:54](=[O:55])[CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51][C:49]1=[O:50])=O>CO>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH:36][C:46](=[C:48]2[C:54](=[O:55])[CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51][C:49]2=[O:50])[CH3:45])[C@H:27]([O:37][C:38](=[O:40])[CH3:39])[C@H:26]1[O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](NC(C)=C3C(=O)CC(C)(C)CC3=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 55.2 %

Procedure:
A mixture of 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl amine (157 mg, 0.24 mmol) and 2-acetyldimedone (81 mg, 0.45 mmol) in MeOH (5 ml) was refluxed for 5 h. The reaction mixture was evaporated, and the residue was purified by chromatography using CHCl3/EtOAc 1:1 as the mobile phase, to give 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl]-β-D-glucopyranosyl amine (27) (106 mg, 54%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:21][OH:22]>C(O)C>[OH:22][N:21]=[CH:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1

Procedure:
To a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (10.0 g) in ethanol (110 ml) is added dropwise hydroxylamine (50% in water, 2.48 ml). The mixture is heated to reflux for 2 hours. Volatile substances are subsequently removed under reduced pressure. This gives tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (10.5 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]N3C(=O)CCC3=O)=O)=[CH:11][CH:10]=2)=[N:4][N:3]=1.[CH3:25][NH:26][CH3:27].CO.CNC>CO>[CH3:25][N:26]([CH3:27])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)=[CH:24][CH:23]=1
Reactant: CNC
Reactant: Cc1nnc(SCc2ccc(C(=O)ON3C(=O)CCC3=O)cc2)s1
Solvent: CO
Product: Cc1nnc(SCc2ccc(C(=O)N(C)C)cc2)s1

Procedure:
A slurry of 3.0 grams of 1-((4-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)benzoyl)oxy)-2,5-pyrrolidinedione (0.0083 mole) was treated with 50 ml of methanol saturated with dimethylamine. After the mixture of methanol-dimethylamine went into solution, the reaction mixture was concentrated and a viscous oil obtained. Crystals formed upon drying the viscous oil in vacuo. Further purification gave the product N,N-dimethyl-4-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)benzamide, confirmed by nuclear magnetic resonance, as a white solid having a melting point of 75°-80° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1cnccn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnccn1
Yield: 59 %

Procedure:
A solution of 2-pyrazinecarboxylic acid (2.00 g, 16.1 mmol) and H2SO4 (catalytic) in MeOH (50 mL) was heated at reflux for 45 minutes, then concentrated in vacuo. The residue was partitioned between EtOAc (40 mL) and saturated NaHCO3(aq) (20 mL). The organic phase was washed with saturated NaHCO3(aq) (20 mL) and brine (10 mL), then dried (MgSO4) and concentrated in vacuo to give colourless crystals (1.32 g, 59%). 1H NMR (CDCl3) □ 4.04 (s, 3H), 8.72 (dd, 1H, J=2.4, 1.2 Hz), 8.77 (d, 1H, J=2.4 Hz), 9.32 (d, 1H, J=1.2 Hz).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:18]([NH:17][C:10]1[C:11]([Br:16])=[CH:12][C:13]([Br:15])=[CH:14][C:9]=1[Br:8])=[O:19]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1c(Br)cc(Br)cc1Br
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Br)cc(Br)cc1Br
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base (4.0 g.; 0.05 mole -- assuming 100% conversion) by adding 5 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 16.79 g. (0.0472 mole) of 2,4,6-tribromophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene, is added with stirrng. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo to give a solid residue of 1-(1-methyl-2-pyrrolidylidene)-3-(2,4,6-tribromophenyl)urea. Recrystallizations from acetone yields the pure product, m.p. = 165°-167.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (78 mg, 0.40 mmol) and diisopropylethylamine (0.094 ml, 0.52 mmol) in methylene chloride (2.5 ml) was added 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 135 mg, 0.35 mmol), portionwise. After stirring overnight, the reaction was concentrated, in vacuo, to ½ volume and then purified on a Biotage™ Flash 12M column using 0-3% ethyl acetate in methylene chloride to afford 8A-1 (200 mg, quantitative) as a solid: +APcI MS (M+1) 551.2; 1H NMR (400 MHz, CD3OD) δ 7.50-7.34 (m, 4H), 7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 4.60 (br s, 1H), 2.46 (s, 3H), 2.10-1.99 (br m, 2H), 1.50-1.40 (m, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:54]=[CH:55][CH:56]=[CH:57][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:50])([F:49])[F:51])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:54]=[CH:55][CH:56]=[CH:57][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CCCC(=O)O)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 27.1 from 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propyl) -piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.40 mg (0.10 mmol) LiOH.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]1([C@H:26]([NH:28][C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A solution of 252A (22 g, 81 mmol) and toluene (400 mL) was treated with (R)-1-phenylethanamine (12.5 mL, 97 mmol) and p-TsOH (1.5 g). The reaction mixture was heated to reflux with a Dean-Stark trap for 23 hours. The mixture was cooled to room temperature, washed with saturated aqueous NaHCO3 (2×200 mL) and brine (2×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was filtered through a pad of silica (100% CH2Cl2) and concentrated to provide 14.7 g (yield: 49%) of Compound 252B as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH:23]=[CH:24][CH:25]=[C:26]3[CH2:31][CH2:30][N:29](C(O)=O)[CH2:28][CH2:27]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.O1CCOCC1>CO>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH:23]=[CH:24][CH:25]=[C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCN(C(=O)O)CC3)cc2)c2ccccc2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCNCC3)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.37 mmol) of tert-butyl ester of 4-{3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]allylidene}piperidine-1-carboxylic acid (II-24a) obtained in Example 12 (12-2) in methanol (2.0 mL) was added 4N hydrochloric acid-dioxane solution (2.0 mL) at 0° C. and stirred for 2 hours at room temperature. The reaction mixture was then concentrated under a reduced pressure, treated with saturated aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous magnesium sulfate. After drying, the solution was filtered, and the filtrate was concentrated under a reduced pressure to give crude 2-methyl-4-[4-(3-piperidin-4-ylidene-1-propene-1-sulfonyl)phenoxymethyl]quinoline. This was dissolved in dichloromethane (10 mL), treated with triethylamine (0.077 mL, 0.56 mmol) and pivaloyl chloride (0.058 g, 0.48 mmol) at 0° C., and stirred for 2 hours. The reaction mixture was then concentrated under a reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The filtrate was concentrated under a reduced pressure to obtain 0.18 g (yield 94.7%) of 2,2-dimethyl-1-(4-{3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]allylidene}piperidin-1-yl)propan-1-one (X-25). Its physical property is shown below.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=[C:3]1[CH:23]=O.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(O)(=O)C.CO>[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29]/[N:30]=[CH:23]/[C:3]1[N:2]([CH3:1])[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cn1c(C=O)nc2c(-c3ccccc3)ccc(-c3ccccc3)c21
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C/N=C/c2nc3c(-c4ccccc4)ccc(-c4ccccc4)c3n2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.1 g (0.32 mmol) 1-methyl-4,7-diphenyl-1H-benzimidazole-2-carbaldehyde, 55 mg (0.32 mmol) 2,4-dimethoxybenzylamine and 1 drop glacial acetic acid in 8 ml methanol were stirred for 12 hour at room temperature. The reaction mixture was cooled to −20° C. and filtered while cold. The solid was washed with cold (−20° C.) methanol (2×1 ml) and dried at reduced pressure. Yield—0.12g (81.1%). %). 1H NMR (250 MHz, CDCl3), δ, ppm: 3.76 (s, 3H), 3.80 (s, 6H), 4.81 (s, 2H), 6.46 (m, 2H), 7.14 (d, JHH=8.8 Hz, 1H), 7.25 (d, JHH=7.6 Hz, 1H), 7.46 (m, 9H), 8.02 (d, JHH=7.0 Hz, 2H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:40])[CH2:17][CH:16]([CH2:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[CH2:13]2.[Br-:41].[Li+]>CC(C)=O>[Br:41][CH2:18][CH:16]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:29](=[O:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:13]2)[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:40])[CH2:17]1
Reactant: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: COc1ccccc1CC(=O)N1CC2CC(CBr)CC(O)(c3ccccc3OC)C2C1
Yield: 65.7 %

Procedure:
A solution of 1.16 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol and 0.345 g of anhydrous lithium bromide in 60 cm3 of acetone is heated at reflux for 18 hours and then concentrated to reduced volume (10 cm3). Following the addition of 20 cm3 of water, the mixture is subjected to extraction with 40 cm3 of ethyl acetate, washed with 20 cm3 of water and then dried over magnesium sulphate. After concentration to dryness under reduced pressure (2.7 kPa), the residue is washed with 20 cm3 of ethyl ether, drained and dried under reduced pressure (2.7 kPa). 0.66 g of (3aRS,4RS,6SR,7aSR)-6-bromomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of a white solid. M.p.K =191° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=1.[OH-].[K+]>C(O)C.O>[O:5]1[CH2:4][CH:3]1[CH2:1][O:16][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(F)ccc1OCC1CO1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Epichlorohydrin (38 g) was added to a stirred solution of 5'-fluoro-2'-hydroxyacetophenone (20.9 g) in ethanol (20 ml). A solution of potassium hydroxide (9.5 g) in a mixture of ethanol (30 ml) and water (5 ml) was then added and stirring continued for one hour. The solvent was removed in vacuo and the residue poured into water then extracted with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography on silica, eluting with a 9:1 mixture, then a 3:2 mixture, of petroleum ether (b.p. 40-60° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give 2'-(2,3-epoxypropoxy)-5'-fluoroacetophenone (4.68 g) as an oil.
Reaction SMILES: O([CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)CC.B(Br)(Br)[Br:23]>C(Cl)(Cl)Cl>[Br:23][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Reactant: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: Nc1nc(-c2ccccc2)c(CCBr)c2ncnn12
Temperature: 0 °C

Procedure:
To 2.8 g of 8-(2-ethoxylethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine dissolved in 30 ml of chloroform was added 5 ml of boron tribromide (1 M solution in dichloromethane) at room temperature with stirring. After 8 hours the complex was decomposed by the addition of ice water. The phases were separated and the aqueous layer was adjusted to pH 8 with potassium carbonate, then extracted three times with chloroform. The chloroform extract was added to the original chloroform layer, and the resultant solution was washed with water and dried over sodium sulfate. Removal of chloroform followed by chromatography on Porosil afforded, in order of elution, title compound (m.p. 163°-164°), and title compound Example 1, (m.p. 193°-194°)
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH3:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:27][CH:28]([NH:38][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCC(C)N
Reactant: O=C(O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Product: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 51 %

Procedure:
The title compound was prepared from 3-phenyl-3-(4-nitrophenyl)propenoic acid via mixed anhydride formation using ethyl chloroformate, followed by reaction with 1-methyldecylamine, substantially according to the procedure of Preparation 21. The product was induced to solidify by trituration under hexane. The solid was recrystallized from hexane, giving a small amount of material which was discarded. The mother liquors were evaporated in vacuo to give an oil which solidified when stirred under acetonitrile. The solid was filtered off, giving a 51% yield of the title compound, m.p. 69°-71° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:8][CH:7]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].N1C=CC=CC=1>>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH:13][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(OC(C)CN)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCC(C)Oc1ccc(OCC=C(C)C)cc1

Procedure:
Following the procedure of Example 8, the above propylamine (2.0 g, 8.5 mmol) and ethyl chloroformate (1.01 g, 9.35 mmol) are reacted together, in the presence of pyridine (0.74 g, 9.35 mmol), to give ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]propyl}carbamate, MS m/e 307 (M+).
Reaction SMILES: [CH3:1][C:2]#[N:3].[CH2:4]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[N:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5]>C(OCC)(=O)C>[C:2]([CH2:1][C:23]([C:21]1[N:22]=[C:17]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]([O:6][CH2:4][CH3:5])=[O:8])[CH2:10][CH2:11]2)[CH:18]=[CH:19][CH:20]=1)=[O:24])#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)N1CCC(COc2cccc(C(=O)OC)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(COc2cccc(C(=O)CC#N)n2)CC1

Procedure:
CH3CN addition to methyl 6-((1-(ethoxycarbonyl)piperidin-4-yl)methoxy)picolinate following the method described in Example 6 gave ethyl 4-(((6-(2-cyanoacetyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate in ethyl acetate solution which was used in the next step without further purification.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:34])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.94 ml of DBU and then 1.54 ml of benzyl bromide are added at RT to a solution of 3 g of 6-(tert-butoxycarbonylamino)hexanoic acid in 60 ml of DCM and the mixture is stirred for 24 hours at RT. It is concentrated under vacuum, the residue is taken up with 100 ml of water and extracted with AcOEt, the organic phase is washed with a 5% solution of potassium carbonate, with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 2.8 g of the expected product, which is used as such.