Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[S:6][C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.O.O.[Sn](Cl)Cl>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Cc1ccc(Oc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2nc3cccc(N)c3s2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 114 %

Procedure:
A mixture of 2-(2,4-dimethylphenoxy)-7-nitro-1,3-benzothiazole (220 mg, 0.733 mmol) and tin(II) chloride dihydrate (694 mg, 3.66 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h and diluted with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over Magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:18][O:17][CH2:16][CH2:15][N:11]3[CH2:12][C:13]=2[CH:14]=1)([O-])=O.Cl.[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[CH2:18]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[C:5]([NH2:2])[CH:6]=[CH:7][C:8]=3[CH2:9]2)[CH2:15][CH2:16][O:17]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCOCC1C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCOCC1C2
Yield: 235.6 %

Procedure:
To 8-nitro-3,4,5,6,11,11a-hexahydro-1H-[1,4]oxazino[4,3-b]isoquinoline hydrochloride (0.4 g) in methanol (50 ml) was added 6N hydrochloric acid (0.3 ml) and 5% Pd-C (100 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 2.0 h. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (0.4824 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)ccc2c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
A mixture of the product of Example 11 (100 mg), potassium carbonate (174 mg) and (bromomethyl)cyclopropane (63 mg) in DMF (2 mL) was stirred at room temperature for 16 hours and at 70° C. for 24 hours. Further (bromomethyl)cyclopropane (300 mg) was added and the mixture heated at 70° C. for a further 24 hours. The reaction mixture was filtered and purified by HPLC to give the title compound (70 mg) as a solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:46]=O)=[C:28]([CH:45]=1)[O:29][CH:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH3:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:30]([O:29][C:28]1[CH:45]=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][C:27]=1/[CH:46]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1/C=C/C(=O)OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.272 g; 60% w/v dispersion in mineral oil; 6.8 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen is treated, dropwise, with methyl (diethylphosphono)acetate (1.43 g) and stirred for 15 minutes. It is then treated with a solution of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (1.96 g) in tetrahydrofuran (5 mL) in one portion, and the reaction mixture is stirred at ambient temperature for 15 minutes. The mixture is treated with water (100 mL) and extracted with ethyl acetate (3×100 mL), and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate, and filtered and the solvent is removed in vacuo, to give ethyl (E)-(RS)-4-(2-methylphenyl)-4-[2-(2-methoxycarbonylethenyl)-5-benzyloxyphenoxy]butanoate, in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl>CN1C(=O)CCC1>[CH2:10]([O:17][C:6]1[CH:5]=[C:4]([Cl:9])[CH:3]=[C:2]([Br:1])[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 120 °C

Procedure:
To 1-bromo-3-chloro-5-fluorobenzene (25 g, 112 mmol) and benzyl alcohol (25 mL, 239 mmol) in NMP (200 mL) at room temperature was added sodium hydride (60% in mineral oil; 10.5 g, 263 mmol), and the reaction was heated to 120° C. for 10 hours. The mixture was acidified with 10% aqueous HCl and extracted with EtOAc to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23]C)C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:20]3[CH:21]=[C:22]([OH:23])[C:14]([OH:13])=[CH:15][CH:16]=3)[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1OC
Product: Oc1ccc2nc(-c3ccc(O)c(O)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. 282–284° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>N1CCCCC1>[C:14]([C:13]1[C:12](=[O:17])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=2)(=[O:15])[CH3:16]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc2cc(C(C)=O)c(=O)oc2c1

Procedure:
A mixture of 15.2 g 2-hydroxy-4-methoxybenzaldehyde and 13.5 g ethyl acetoacetate was warmed on a hot plate until solution was attained. Thirty drops of piperidine were added and the reaction mixture continued to be heated gently. After several minutes the reaction mixture solidified. After cooling, the product was recrystallized from a mixture of alcohol and acetonitrile. Yield 20 g.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1
Reactant: OCC1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
A portion (0.7 g) of the 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 4 was dissolved in 50 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (1 g), water (3 ml) and concentrated sulfuric acid (1.4 g) was added dropwise over time, and the solution was stirred for 6 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized with acetone-water, yielding 0.4 g of 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 241.5°-243.5° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10]SC.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([S:10][CH3:9])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cnc(Cl)nc1
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A solution of 1.00 g (5.17 mmol) of 5-bromo-2-chloropyrimidine and 551 μl (6.20 mmol) of dimethyl disulfide in 26 ml of tetrahydrofuran was cooled to −78° C. and 1.89 ml (5.17 mmol) of 2.73 N n-butyl lithium/n-hexane solution was added thereto, and the reaction solution was stirred for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 149 mg of the title compound as a white solid (yield: 18%).
Reaction SMILES: O[CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.S(Cl)([Cl:16])=O>CCOCC>[Cl:16][CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1=NOC(c2ccccc2)C1
Solvent: CCOCC
Product: ClCC1=NOC(c2ccccc2)C1
Reaction time: 8 h

Procedure:
3-Hydroxymethyl-5-phenyl-4,5-dihydroisoxazole (3.2 g) is dissolved in 50 ml of anhydrous ether. To the solution cooled with ice is slowly added dropwise 2.6 g of thionyl chloride with stirring. The reaction mixture is allowed to stand overnight at room temperature and then the solvent is distilled off to give 3-chloromethyl-5-phenyl-4,5-dihydroisoxazole in the form of yellow brown oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:22]([NH:40][CH:41]([CH3:43])[CH3:42])[N:21]2[CH:44]=1>>[CH:41]([NH:40][C:22]1[N:21]2[CH:44]=[C:18]([CH3:17])[N:19]=[C:20]2[N:25]=[C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:28][CH:27]=2)[C:23]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([CH3:43])[CH3:42]
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6c(NC(C)C)c5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 64. 399.3 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 280 mg (0.76 mmol) 4-(2-methyl-5-isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde to yield finally after HPLC purification 10.4 mg (2.34%) of the desired compound.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.[BH3-]C#N.[Na+]>CO>[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][N:33]([CH:40]3[CH2:42][CH2:41]3)[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCN(C5CC5)CC4)cc3)c(Cl)sc2[nH]c1=O

Procedure:
A mixture of 2-chloro-4-hydroxy-3-{4-[(4-hydroxy-piperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (70 mg, 0.128 mmol),[(1-ethoxycyclopropyl)oxy]trimethylsilane (0.103 mL, 0.513 mmol), 3A molecular sieves (30 mg), and NaCNBH3 (32 mg, 0.513 mmol) in MeOH (1 mL) was heated to reflux for 12 h. The reaction was then quenched by the addition of H2O (1 mL) and EtOAc (1 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound. MS (ESI) m/e 472 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (m, 2H), 0.94 (m, 2H), 1.80 (d, J=12.0 Hz, 2H), 1.94 (m, 2H), 2.97, (m, 1H), 3.40 (m, 4H), 3.86 (s, 2H), 5.22 (s, 1H), 6.92 (d, J=8.82 Hz, 2H), 7.22 (d, J=8.82 Hz, 2H), 8.81 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[OH:24])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:31])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(O)c1
Reactant: FCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCCCCCF)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-methyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 141 in DMF (5 ml) were added 1-bromo-5-fluoropentane (0.11 g) and potassium carbonate (0.07 g), and the mixture was stirred at 50° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) to give the title compound as a pale-yellow amorphous substance (0.16 g, 77%).
Reaction SMILES: [C:1]1([C:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1)=[CH2:32]>CCOCC>[C:13]1([C:10]2[C:11]([C:36]3[CH:37]=[CH:38][C:33]([CH:31]=[CH2:32])=[CH:34][CH:35]=3)([OH:12])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Reactant: C=Cc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: C=Cc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
46.2 g (0.12 mol) of tetraphenylcyclopentadienone were reacted with 0.61 mol of p-vinylphenylmagnesium bromide in 400 ml of ether and then hydrolysis to yield 1,2,3,4-tetraphenyl-5-p-vinylphenylcyclopenta-1,3-dien-5-ol. (Elemental analysis for C37H28O: found: C, 90.91%, H, 5.75%. calculated: C, 90.85%, H, 5.78%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[F:7][C:8]([F:23])([F:22])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=O>>[F:7][C:8]([F:23])([F:22])[C:9]([Cl:2])=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1ccccc1C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C(Cl)=Nc1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
A mixture of 27.48 g of phosphorus pentachloride and 30.84 g of 2,2,2-trifluoro-N-(2-trifluoromethylphenyl)-acetamide was stirred at 80° C. for 4 hours and was then allowed to cool. The mixture was distilled under reduced pressure to obtain 15.2 g of 2,2,2-trifluoro-N-(2-trifluoromethylphenyl)ethanimidoyl chloride with a boiling point of 85° C. at 30 mm Hg and a refractive index of nD21 =1.4297.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Cl-].Br[CH2:17][CH2:18]Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17]2)=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(c2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
o a stirred solution of (4-bromo-2-trifluoromethyl-phenyl)-acetonitrile (3.33 g, 12.61 mmol) from step 2 of example A(141), benzyltriethylammoniym chloride (0.057 g, 0.25 mmol) and 1-bromo-2-chloroethane (1.57 g, 10.94 mmol), was added dropwise a solution of NaOH 40% ( 3 mL). The reaction mixture was stirred 6 hours at 50° C. After this time the reaction was quenched with 1 N HCl (30 mL) and extracted with EtOAC (3×30 mL). The organic phase was dried over Na2SO4 and evaporated. The crude organic product was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (3.1 g, 86%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.4–1.44 (m, 2H), 1.76–1.80 (m, 2H), 7.44 (d, J=8.3 Hz, 1 H), 7.69 (dd, J=8.3, 2 Hz, 1 H), 7.84 (d, J=2 Hz, 1 H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].C(Cl)Cl.[F:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](O)=[O:37])[CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[C:14]=2[NH:18][C:36](=[O:37])[CH2:35][C:27]2[CH:28]=[CH:29][C:30]([C:31]([F:32])([F:33])[F:34])=[C:25]([F:24])[CH:26]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A vial was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (160 mg, 0.00054 mol), methylene chloride (10 mL, 0.2 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (145 mg, 0.000651 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (413 mg, 0.00108 mol), and N,N-diisopropylethylamine (0.189 mL, 0.00108 mol), and was stirred at 40° C. for 2 days. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the product as colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](N5CCOCC5)=[O:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][Mg]Br>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](=[O:22])[CH3:31])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-[trans-4-(2-(morpholin-4-yl)-2-oxoethoxy)cyclohexyl]-1,3-benzoxazole (427 mg) in THF (5 mL) was added a solution (1.5 M, 1.37 mL) of methylmagnesium bromide in toluene/THF under ice-cooling. The reaction mixture was stirred at 0° C. for 1 hr, and extracted with ethyl acetate and 1M hydrochloric acid. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (260 mg).
Reaction SMILES: [S:1]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:5]3[CH2:4][CH2:3][CH2:2][S:1][CH2:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: O=C1CCCSCCC1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCSCCC3
Reaction time: 5 h

Procedure:
A mixture of 14.42g (0.1 mole) of 1-thiacyclooctane-5-one, 17.46g (0.1 mole) of p-methoxyphenylhydrazine hydrochloride and 8.21g (0.1 mole) of anhydrous sodium acetate in 170 ml of acetic acid is refluxed with stirring for five hours under nitrogen. The mixture is cooled and poured into 1 liter of water. On standing there is deposited a solid which after washing with water and recrystallization from methanol, gives 18.1g (74%) of an analytical sample, m.p. 122.5°-123.5° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[C:23]([C@@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
In 1 ml of acetic acid is dissolved 0.9 g of tert-butyl 3(R)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 30 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 3 ml of acetic acid, and purified by MCI-gel chromatography (water:methanol=1:2). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.43 g of 3(R)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.