Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3](O)([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]([F:40])([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: OC(CCCc1cccc(Oc2ccccc2)c1)(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)Oc1ccc(C(F)(CCCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane (0.18 g) in dichloromethane (6 cm3) was cooled to -78° C. and diethylaminosulphur trifluoride (0.1 g) was added. The mixture was allowed to warm to room temperature, stirred for a further 20 minutes and poured into water. The products were extracted into dichloromethane. The combined organic extracts were dried and the solvent evaporated under reduced pressure to leave an oil. The oil was purified by chromatography to give 1,1,1,2-tetrafluoro-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:52])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:51])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:50])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:49])[CH2:22][CH2:23][C:24](=[O:48])[CH:25]([CH3:47])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:46])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:45])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:44])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])=[CH:3][CH2:4][OH:5].[C:53](OC(=O)C)(=[O:55])[CH3:54]>N1C=CC=CC=1>[C:53]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:52])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:51])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:50])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:49])[CH2:22][CH2:23][C:24](=[O:48])[CH:25]([CH3:47])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:46])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:45])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:44])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])(=[O:55])[CH3:54]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
To a solution of 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-on-1-ol (6.8 g) in pyridine (1 g), acetic anhydride (3.5 g) is added, and the resultant mixture is allowed to stand at room temperature for 6 hours. The reaction mixture is treated as in Example 7 (5) (a) to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-one (6.2 g), which is then similarly reduced. The resultant product (4.7 g) is treated as in Example 1 (5) (a) to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22ol (1.9 g) as a fraction (1) and 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaene-1,22-diol (0.8 g) as a fraction (2). The latter is treated with acetic anhydride as above to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-ol (0.73 g).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(Br)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Br)C(=O)NCC(=O)OCc1ccccc1

Procedure:
65.96 g (355.7 mmol) of α-bromobutyric acid chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[C@H:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][C@H:10]1[C@@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(F)c(F)c2ccoc12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCC[C@@H]1c1cc(F)c(F)c2ccoc12

Procedure:
The title compound was prepared by treating cis-1-(tert-butoxycarbonyl)-3-methyl-4-(4,5-difluorobenzofur-7-yl)piperidine with 4N hydrochloric acid in dioxane essentially as described in EXAMPLE 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:20][C:21]([C:23]1([CH3:26])[CH2:25][O:24]1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:26][C:23]([OH:24])([CH3:25])[C:21]([NH:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:10])=[O:22]
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)c(Cl)c1
Product: Cc1c(NC(=O)C(C)(O)COc2ccc(F)c(Cl)c2)cccc1[N+](=O)[O-]

Procedure:
3-(3-Chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 starting from 3-chloro-4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.27 (3H, s), 3.99 (1H, d, J=9.8 Hz), 4.23 (1H, d, J=9.8 Hz), 6.15 (1H, s), 6.92-6.97 (1H, m), 7.17-7.20 (1H, m), 7.29-7.35 (1H, m), 7.41-7.46 (1H, m), 7.66-7.69 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:9]1[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:12]3)=[N:14]2
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCBr)cc4c3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCN5CCCC5)cc4c3)nc2c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one (6.10 g, 14.2 mmol) in anhydrous DMF (45 mL) was added pyrrolidine (6.07 g, 85.4 mmol) and the reaction mixture was stirred at 45° C. for 15 hours. DMF was removed under reduced pressure, the residue was taken in water (150 mL), and stirred for 30 minutes. Separated solid was filtered, washed with water, and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh, eluting with 5% 7.0 M ammonia in methanol solution in dichloromethane) to give the title compound as a white solid. Yield: 3.4 g (57%). MP 215-217° C. 1H NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1H), 11.21 (s, 1H), 8.31 (s, 1H), 7.88 (dd, J=8.8 and 1.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.28 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.89 (t, J=8.0 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.48 (m, 4H), 1.67 (m, 4H).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[C:15]([SiH2:19][O:20][C:21]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[C:29][CH3:30])[CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:15]([SiH2:19][O:20][C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:22]1[CH:27]=[CH:26][N:25]2[N:13]=[C:29]([CH3:30])[CH:28]=[C:24]2[CH:23]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC#Cc1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine (18.6 g, 77.8 mmol, 5.0 equiv) in chloroform (50 ml) is added at 0-10° C. to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-2-prop-1-ynyl-pyridine in chloroform (50 ml). The resulting mixture is stirred at room temperature overnight. The solvent is removed in vacuo, and N,N-dimethylformamide (50 ml) is added to the residue. Potassium carbonate (4.30 g, 31.1 mmol, 2.0 equiv) is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient from hexane/EtOAc 100:0 to 30:70) affords the title compound (2.6 g, 42%). 1H NMR (400 MHz, d6-DMSO): δ=8.42 (d, J=7.1 Hz, 1H), 7.60-7.58 (m, 4H), 7.43-7.35 (m, 7H), 6.64 (dd, J=7.3/1.9 Hz, 1H), 6.27 (s, 1H), 4.71 (s, 2H), 2.30 (s, 3H), 0.99 (s, 9H). MS (ES+): 401 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[S:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+].Cl>CO.O>[F:21][C:2]([F:1])([C:7]1[S:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:15])[F:13])[N:11]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)c1sc(C(F)(F)C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(C(F)(F)C(F)(F)F)nc1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 540 mg (1.57 mmol) of ethyl 2-(pentafluoroethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate in 3 ml of methanol and 1 ml of water is admixed with 94.4 mg (2.36 mmol) of sodium hydroxide solution and heated at 60° C. for two hours. The reaction mixture is acidified with conc. hydrochloric acid and extracted four times with dichloromethane, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and, after filtration, is concentrated by evaporation. This gives 417 mg (min. 50% strength, max. 82%) of 2-(pentafluoroethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([N+:7]#[N:12])[CH:8]=1
Reactant: Cc1c(F)c(N)cc(Br)c1F
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)c(Br)cc([N+]#N)c1F

Procedure:
To a suspension of 5-bromo-2,4-difluoro-3-methylaniline (24.60 g) in 42% fluoroboric acid (150 ml) with stirring vigorously at -3° to 0° C. was added sodium nitrite (11.47 g) in water (20 ml) dropwise during 40 minutes. After stirring for 1.5 hours at 0° to 5° C., the reacting mixture was cooled with ice bath sufficiently and the resulting precipitate was collected by filtration. This precipitate was washed with small portion of water and ether and dried under reduced pressure to give the title compound (28.83 g) as pale brown prisms, mp 147°-150° C. (decompd.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ncn(Cc2ccc(Cl)cc2)n1
Product: COc1cc(Nc2ncn(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(4-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine from example 3a). The title compound was obtained as a colorless solid (Yield=42%). MS ISP (m/e): 395.1 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)C1
Yield: 130.4 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.187 g, 1 mmol), triethylamine (0.14 mL, 1 mmol), and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.25 g of the title compound as a solid.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.C1C(O)=CC=C(C)C=1.C(C(Cl)C1C=CC=CC=1)=C.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[OH-].[K+].C(Br)CC>CN1CCCC1=O.CO.C1(C)C=CC=CC=1>[CH2:2]1[CH:1]2[CH:8]3[CH:7]=[CH:6][CH:10]([CH:5]2[CH:4]=[CH:3]1)[CH2:9]3
Reactant: C1=CCC=C1
Agent: C=CC(Cl)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cc1ccc(O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 60 °C

Procedure:
318.5 grams of the para-cresol icyclopentadiene (PCDP) from above was dissolved in 1100 mL of N-methylpyrrolidinone (NMP) in a 2000 mL 3-neck round bottom flask equipped with mechanical stirrer, addition funnel, condenser, thermometer, nitrogen purge and Therm-O-Watch. To this reaction mixture was added 195.0 g (1.278 moles) of vinylbenzylchloride (60/40 para/meta isomer ratio) and 0.30 g of 2,6-di-tert-butyl-p-cresol (BHT). The reaction mixture was heated to 60° C. and 84.05 g (1.498 moles) of potassium hydroxide in 200 mL of methanol was added dropwise over a 3 hour interval. The reaction was maintained at 60° C. for 16 hrs with stirring under a nitrogen purge. To this reaction mixture was added 49.88 g (0.406 moles) of n-propylbromide, and then 24.43 g (0.435 moles) of potassium hydroxide in 125 mL of methanol added over a 2 hour interval. The reaction was maintained at 60° C. for 4 hours and then allowed to cool to room temperature. The reaction mixture was then transferred to a separatory funnel, and 1.5 Liters of toluene added and then washed once with 4 Liters of water and twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum, yielding a red resinous product; Mn=700, Mw=1600, dispersity of 2.3.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:13][CH:14]([CH3:19])[CH2:15][C:16]([N:9]1[CH2:10][CH2:11][O:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:17]
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-methyl-butyryl chloride (301.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 3-methyl-1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])#[N:2].[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoate (1.40 g, 3.50 mmol) in ethanol (10 ml) and THF (10 ml) was added a 1 N aqueous sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material. The resultant material was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][CH2:10][CH2:9]2.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.[H-].[Na+].[I-].[K+]>CN(C=O)C.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:11]3[CH2:10][CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:17][CH3:18])[CH:7]=4)[C:12]3=[O:16])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: COC(COc1ccc2c(c1)CCNC2=O)OC
Reactant: Fc1ccc(-c2ccc(CBr)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline (5.79 g, 23.05 mmol) and 4'-fluoro-4-biphenylylmethyl bromide (9.16 g, 34.57 mmol), in DMF (100 ml) is added sodium hydride (1.1 g, 27.5 mmol) and a catalytic amount of potassium iodide. The reaction mixture is stirred for 2 hours at room temperature and is subsequently diluted with H2O (500 ml). The mixture is then extracted with EtOAc (2×300 ml). The combined EtOAc portions are washed with saturated NaCl solution (600 ml), dried over MgSO4, and concentrated in vacuo and washed with hexanes to yield the acetal, 2-(4'-fluoro-4-biphenylylmethyl)-6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@H:38]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[N:39]1[CH2:45][CH2:46][CH2:47][C:48]1[S:52][C:51]([C:53]([O:55][CH3:56])=[O:54])=[CH:50][CH:49]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:36][CH2:37][C@H:38]1[CH2:42][CH2:41][S:40](=[O:43])(=[O:44])[N:39]1[CH2:45][CH2:46][CH2:47][C:48]1[S:52][C:51]([C:53]([O:55][CH3:56])=[O:54])=[CH:50][CH:49]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCS2(=O)=O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCN2[C@@H](CO)CCS2(=O)=O)s1
Reaction time: 16 h
Yield: 73.7 %

Procedure:
Tetrabutylammonium fluoride (1.95 mL of a 1.0M solution in THF, 1.95 mmol) was added to a solution of the silyl ether 9 (751 mg, 1.29 mmol) in THF (3.0 mL). After stirring for 16 h the reaction was diluted with EtOAc and washed with water followed by brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 20% EtOAc/hex followed by 40% EtOAc/hex) afforded 317 mg (73%) of alcohol 10.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][NH:21][CH2:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH3:13]
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1nc2ccccc2n1C

Procedure:
Experimental condition analogous to Example 5, from 1-methyl-1H-benzoimidazol-2-carbaldehyde 0.2 g (1.25 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.18 g (1.38 mmol), and sodium triacethoxyborohydride 0.39 g (1.87 mmol), in 10 mL dichloromethane. After work-up the material was used as a crude.
Reaction SMILES: [Br:1][C:2](=[CH:5][CH3:6])[CH:3]=[O:4].C(N(CC)CC)C.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16].[I-].[Na+]>C(#N)C.C(OCC)C>[Br:1][C:2]([CH:5]=[CH2:6])=[CH:3][O:4][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CC=C(Br)C=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: C=CC(Br)=CO[Si](C)(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Furthermore, 2.98 g (20 mmoles) of 2-bromobut-2-enal and 3 g (30 mmoles) of triethylamine are introduced into a 250 ml container. At room temperature, in a nitrogen atmosphere with agitation, there is added 1.63 g (30 mmoles) of chlorotrimethylsilane followed, drop by drop, by the solution of sodium iodide in acetonitrile which was previously prepared. After reaction for 90 minutes, 60 cc of anhydrous petroleum ether (petroleum ether 40-60) are added and agitation is effected for 30 minutes. The precipitate which forms is filtered off under a nitrogen atmosphere and then washed twice with 30 ml of anhydrous petroleum ether. The upper phase of the filtrate (petroleum ether) is collected and the lower phase (acetonitrile) extracted 3 times with, in each case, 30 ml of petroleum ether. The petroleum ether fractions are collected and 5 g of anhydrous magnesium sulfate added thereto. Filtration is effected over fritted glass and the solvent eliminated by vacuum distillation (rotary evaporator) in an inert atmosphere. The residue obtained is diluted in 80 cc of anhydrous ethyl ether; the precipitate is filtered and the solvent evaporated under an atmosphere of nitrogen. 3.76 g of product are obtained, representing a yield of 85%. Purity (GC) of the product obtained is 98% and its structure is confirmed by nuclear magnetic resonance and mass spectrometry.
Reaction SMILES: O.[NH2:2][NH2:3].C(O[CH:7]=[C:8]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])C>C(O)C>[F:16][C:15]([F:18])([F:17])[C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:3][N:2]=1
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of hydrazine hydrate (459 mg, 9.16 mol) in ethanol (5 mL) was added to a solution of ethyl 3-ethoxy-2-(trifluoroacetyl)acrylate (2.00 g, 8.33 mmol) in ethanol (15 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 24 hrs. The reaction was concentrated in vacuo, dissolved in ethyl acetate (30 mL), washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo to afford ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.365 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.24 (t, 3 H), 4.22 (q, 2 H), 8.56 (s, 1 H); MS (ESI) m/z: 209.0 (M+H+).