Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]([Cl:1])=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNC1CCCCC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)C1CCCCC1
Yield: 295.9 %

Procedure:
To a solution of triphosgene (4.35 g) in toluene (70 ml) is added dropwise N-methylcyclohexylamine (5 g). To the mixture is added dropwise pyridine (3.5 g), and the mixture is refluxed for 4 hours. The mixture is allowed to cool, and the organic layer is separated, washed with 0.1 N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give N-methyl-N-cyclohexylaminocarbonyl chloride (7.62 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:14][CH2:13][CH2:11][OH:12]
Reactant: NCCO
Reactant: Fc1cccc(F)c1CBr
Solvent: CCO
Product: OCCNCc1c(F)cccc1F
Temperature: 75 °C
Yield: 97.5 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (3.7 g, 17.8 mmol) and ethanolamine (6.46 mL, 107 mmol) in ethanol (18 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (75 mL) and the aqueous layer extracted with dichloromethane (50 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellow solid (3.25 g). (m/z): [M+H]+ calcd for C9H11F2NO, 188.08; found, 188.1. 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H), 7.10-7.05 (m, 2H), 4.47 (t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J=5.5 Hz, 2H), 2.25 (t, J=5.7 Hz, 2H), 1.82 (br s, 1H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)[NH2:3].[C:11]([CH2:14][C:15](=O)[CH3:16])(=O)[CH3:12].[OH-].[Na+]>O>[CH3:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([N:2]2[C:15]([CH3:16])=[CH:14][C:11]([CH3:12])=[N:3]2)[CH:9]=1
Reactant: Cc1ccnc(NN)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccnc(-n2nc(C)cc2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
In a 50 mL recovery flask, 2-hydrazino-4-methylpyridine hydrochloride (0.5 g, 3.13 mmol), acetylacetone (0.376 g, 3.76 mmol), and water (7 mL) were added and stirred at room temperature for 16 hours. Upon completion of the reaction, a 10% aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH up to 14. The resulting mixture was extracted with ethyl acetate twice, and the organic phases were combined and washed with saturated brine once, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 0.47 g of the title compound (yield 80%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]([O:16]C)[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:2].B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([N+:18]([O-:20])=[O:19])=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:2]
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc(OC)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCc1c(NC(=O)C(F)(F)F)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-ethyl-2-nitro-4-trifluoroacetamidoanisole (19.3 mmol) in dry methylene chloride (250 mL) at -78° C. under nitrogen atmosphere is treated dropwise with a solution of boron tribromide (96.9 mmol) in dry methylene chloride (50 mL). After complete addition, the mixture is allowed to warm to room temperature and stirring is maintained for one hour. The mixture is cooled to -78° C. and methanol (100 mL) is added dropwise. After complete addition, the solution is allowed to warm to room temperature. The reaction mixture is distributed between water (100 mL) and methylene chloride (200 mL). The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to yield 3-ethyl-2-nitro-4-trifluoroacetamidophenol.
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[C:13]12([CH2:23][CH2:24][OH:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[Cl:26][C:27]1[C:28](F)=[CH:29][C:30](F)=[C:31]([CH:39]=1)[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33].ClC1C=C(C=CC=1F)C(NS(C)(=O)=O)=O>>[C:13]12([CH2:23][CH2:24][O:25][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[CH:39][C:27]=3[Cl:26])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1ccc(F)c(Cl)c1
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CS(=O)(=O)NC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with 2-(adamantan-1-yl)ethanol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.43 g, 71%): 1H NMR (300 MHz, DMSO-d6) 12.06 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.93 (dd, J=8.7 Hz, 2.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.93 (br s, 3H), 1.70-1.55 (m, 14H); MS (ES+) m/z 411.8, 413.8 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)O)[O:5][CH2:6][CH3:7])[CH3:2].C(Cl)Cl.C(N(S(F)(F)[F:26])CC)C>O>[CH2:1]([O:3][P:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[F:26])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(OCC)C(O)c1cccc(Br)c1
Solvent: ClCCl
Solvent: O
Product: CCOP(OCC)C(F)c1cccc(Br)c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
Into cold mixture of diethyl[(3-bromophenyl)(hydroxy)methyl]phosphonite (30 g) and CH2Cl2 (120 mL) was added diethylaminosulfur trifluoride (16.44 g, 101.53 mmol) and the mixture was stirred for 2 hours. The mixture was then poured into water and washed with NaHCO3 and brine. Purification by ISCO (hexane/EtOAc 1/1) gave diethyl[(3-bromophenyl)(fluoro)methyl]phosphonite (22.6 g); MS m/e (M+H)+ 325.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:47])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC(C)=CC=3)(=O)=O)[CH:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:22]2=[O:46])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.N12CCCCC1C=NCCC2>C1(C)C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([C@@H:16]2[N:21]3[C:22](=[O:46])[C@@H:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:47])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 670 mg (1 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxycrotonic acid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene is stirred for 25 minutes at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with toluene, washed successively with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue, after preparative thick layer chromatography on silica gel using toluene/ethyl acetate, 1:1, gives 7β-phenylacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethyl ester of melting point 166°-169° C. (from methylene chloride/hexane), UV spectrum (ethanol): λmax =258 mμ (ε=4,500), IR spectrum (methylene chloride) characteristic bands at 2.93, 5.62, 5.73, 5.93 and 6.66μ, Rf value~0.54 (silica gel; system toluene/ethyl acetate, 1:1), and amorphous 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, UV spectrum (ethanol): λmax =258 mμ (ε=6,350), 264 mμ (β=6,350), 282 mμ (ε=5,600) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.66μ, Rf value~0.37 (silica gel; system toluene/ethyl acetate, 1:1), in the ratio of 8:1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:11])=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)ccc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A stirred solution of 8.3 grams (0.063 mole) of 2-amino-6-methylbenzonitrile in 125 mL of N,N-dimethylformamide was cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide was added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, the reaction mixture was poured into 1 liter of aqueous 3N sodium hydroxide. The mixture was then diluted to a volume of about 1700 mL with distilled water. A solid precipitate was collected by filtration and dried under reduced pressure, yielding 12.3 grams of 2-amino-5-bromo-6-methylbenzonitrile, mp 111°-113° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:22]([O:21][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]=1[C:12]([NH:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 50; 120 mg, 0.30 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.11 ml, 0.61 mmol), 3-aminopyridine (42.8 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.40 mmol) and EDC (116 mg, 0.61 mmol). The solution was stirred for 2 hours, then the solvent was removed in vacuo. The yellow residue was purified by MDAP to give the title compound as a white solid. 106 mg.
Reaction SMILES: NC(COC1C=CC(CCOCC)=C(C)C=1C)CO.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[O:29][CH2:30][CH:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:37](C)[C:36]=2[CH3:49])[N:32]=1.FC1C=CC=C(F)C=1C1OCC(COC2C=CC(CCOCC)=CC=2C)N=1>>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=1[C:28]1[O:29][CH2:30][CH:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:37][C:36]=2[CH3:49])[N:32]=1
Reactant: Cc1c(Cc2ccccc2)ccc(OCC2COC(c3c(F)cccc3F)=N2)c1C
Agent: CCOCCc1ccc(OCC(N)CO)c(C)c1C
Agent: CCOCCc1ccc(OCC2COC(c3c(F)cccc3F)=N2)c(C)c1
Product: Cc1cc(Cc2ccccc2)ccc1OCC1COC(c2c(F)cccc2F)=N1

Procedure:
Following the same procedure with the same molar proportion of materials as in Production Example 1, 2-(2,6-difluorophenyl)-4-{[2,3-dimethyl-4-(2-ethoxyethyl)phenoxy]methyl}-2-oxazoline (Compound No. 2) is obtained by using 2-amino-3-[2,3-dimethyl-4-(2ethoxyethyl)phenoxy]propanol instead of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propanol. In the same way, 2-(2,6-difluorophenyl)-4-[(4-benzyl-2,3-dimethylphenoxy) methyl]-2-oxazoline (Compound No. 49), 2-(2,6-difluorophenyl)-4-{[4-(2-ethoxyethyl)-2-methylphenoxy]methyl}-2-oxazoline (Compound No. 50) or 2-(2,6-difluorophenyl)-4-{(4-benzyl-2-methylphenoxy)methyl}-2-oxazoline (Compound No. 51) is obtained by using 2-amino-3-(4-benzyl-2,3-dimethylphenoxy)propanol, 2-amino-3-[4-(2-ethoxyethyl)-2-methylphenoxy]propanol or 2-amino-3-[4-benzyl-2-methylphenoxy)propanol, respectively.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[N:29]=[C:23]4[CH:22]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N:24]3[CH:27]=[C:28]([CH2:30][NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[N:29]=[C:23]3[CH:22]=2)=[CH:17][CH:16]=1)[OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccn4cc(CNS(C)(=O)=O)nc4c3)cc2)OC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.2 %

Procedure:
To a stirred solution of (4S,5R)-4-Fluoromethyl-5-{4-[2-(methanesulfonylamino-methyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (75 mg, 0.14 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (0.3 mL) drop wise at 0° C. then stirred at room temperature for 2 hours. The reaction mixture is concentrated and stripped with CH2Cl2 to afford title compound (88 mg, crude) which is used as is in the next step. LC-MS (m/z): [M+H]=393.1.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.CCCCCC>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2[nH]1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2n1C
Yield: 96.2 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-naphth[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 96.2% yield of ethyl 1-methyl-1H-naphth[2,3-g]indole-2-carboxylate, mp 165°-165.5°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH:29]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:12]1[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=CCCCC1CC(C=Cc2ccccc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCNCC1CCCCC1CC(C=Cc2ccccc2)=NO1
Yield: 78.6 %

Procedure:
4-[3-(2-Phenylvinyl)-4,5-dihydroisoxazol-5-yl]butanal (23.4 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.7 mg (73.2%) of the target compound was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:32])=[O:31])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)C(F)(F)F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and trifluoromethanesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:35]>>[CH2:34]([N:36]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCNCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCc1ccccn1)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-[2-(ethylamino)ethyl]pyridine. ES-MS m/e (%): 519 (M+H+, 100).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[OH:7][C:4]1([C:11]#[C:10][C:9]2[CH:13]=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH:5]=[CH:6][C:1](=[O:8])[CH:2]=[CH:3]1
Reactant: C1CCOC1
Reactant: O=C1C=CC(=O)C=C1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
Benzoquinone (6.3 g, 0.006 mole) was dissolved in 25 mL of dry THF and placed under nitrogen. The reaction was cooled to -78° C. and the solution prepared above was added slowly. The reaction was stirred at -78° C. for 1.5 hr and quenched with ammonium chloride solution. The mixture was extracted with ether, the ether phase washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.91 g of a brown oil which crystallized while under vacuum. The crystals were further purified by flash column chromatography on silica using 1:4 EtOAc/hexane. The compound-bearing fractions were combined and concentrated in vacuo to yield 31% of the title 1,2-1,4 adduct.
Reaction SMILES: N1([CH:7]=[C:8]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[S:12])[C:9]#[N:10])CCOCC1.I[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CCN(C(C)C)C(C)C>C(#N)C>[C:9]([C:8]1[CH:7]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)#[N:10]
Reactant: CCOC(=O)CI
Reactant: N#CC(=CN1CCOCC1)C(=S)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc(C#N)c(N2CCOCC2)s1
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
A mixture of 3-morpholin-4-yl-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (0.07 g, 0.26 mmol), ethyl iodoacetate (0.034 mL, 0.29 mmol) and DIPEA (0.091 mL, 0.52 mmol) in ACN (0.55 mL) was subjected to MWI at 120° C. for 10 min. The crystals formed upon cooling were filtered, washed with cold MeOH and diethyl ether to give ethyl 4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.06 g, 87%). LCMS: (AA) ES+ 267.1. 1H NMR (400 MHz, CDCl3) δ: 7.62 s, 1H), 4.30 (q, 2H), 3.85-3.87 (m, 4H), 3.58-3.60 (m, 4H) and 1.34 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([N:13]([CH3:12])[C:2]2[C:3]3[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc2c(N(C)C3CCCCC3)ncnc2[nH]1
Yield: 57.7 %

Procedure:
The product from Method G (50 mg/0.298 mmol) was reacted with 100 mg (0.883 mmol) of N-methylcyclohexylamine as described in Method A. The reaction mixture was worked up as in Method A with the exception that ethyl acetate was used in place of ether. The title compound (42 mg, 58% yield) was obtained as a white solid. Mp 221° C. dec. 1H NMR (400 MHz, CDCl3) δ: 1.15-1.25 (m, 1H), 1.43-1.62 (m, 4H), 1.73 (br s, 1H, J=13.7 Hz), 1.82-1.90 (m, 4H), 2.41 (d, 3H, J=0.8 Hz), 3.21 (s, 3H) 4.63 (br s, 1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (br s, 1H). LRMS: 245 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH:38]([Si:41](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 95.7 %

Procedure:
Stir a mixture of (R)-4-{3,5-dichloro-4-[1-(4-hydroxy-piperidin-1-yl)-2-oxo-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.238 g, 0.5 mmol) and 15 mL dichloromethane in an ice bath. Add pyridine (0.205 g, 2.59 mmol) followed by triisopropylsilyltrifluoromethane sulfonate (0.19 g, 0.62 mmol). Remove the cold bath and stir the reaction 1 hour at room temperature. Dilute the reaction with dichloromethane and wash with water. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 0% to 50% ethyl acetate in hexanes gradient to afford 0.295 g of the title compound. MS (m/z): 615 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:14]12>>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[C:13]([C@H:14]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:23])[CH3:12]
Reactant: CCOc1ccccc1OCC
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Product: CCOc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OCC

Procedure:
Prepared from 1,2-diethoxybenzene and cis-hexahydrophthalic anhydride as described for compound A. M.p.: low melting solid.