Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(OC1C=C(C)C=CC=1C)C1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])(=O)C.O1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:12]([C:11]1[C:16]([CH3:17])=[CH:28][C:29]([O:30][CH2:31][C:32]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:8])[CH:6]=1)([OH:14])=[O:13]
Reactant: C/C=C(/C(=O)OC)c1ccccc1C(Oc1cc(C)ccc1C)C(C)=O
Reactant: C1COCCO1
Product: C/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)O)cc1C

Procedure:
In a similar manner to the process for precursor δ), 9.6 g of methyl 2-[2-(acetyl-2,5-dimethylphenoxymethyl)phenyl]-E-but-2-enoate in 60 ml of dioxane were reacted to give the carboxylic acid. After concentrating on a rotary evaporator a yellow oil remained which in addition to 70% of the title compound contained a further 30% of the diacid formed by hydrolysis of the methyl butanoate.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[NH2:13][C@H:14]([C:16]1[CH:17]=[C:18]([C:22]2[C:23]([NH2:28])=[N:24][O:25][C:26]=2[CH3:27])[CH:19]=[CH:20][CH:21]=1)[CH3:15]>>[NH2:28][C:23]1[C:22]([C:18]2[CH:17]=[C:16]([C@@H:14]([NH:13][C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[CH3:15])[CH:21]=[CH:20][CH:19]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: Cc1onc(N)c1-c1cccc([C@H](C)N)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: Cc1onc(N)c1-c1cccc([C@H](C)NC(=O)C=Cc2ccccc2F)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-4-[3-(1-amino-ethyl)-phenyl]-5-methyl-isoxazol-3-ylamine following the general procedures as described for Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C[O-].[Na+].O.[C:18](OCC)(=[O:20])C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH3:18]
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
A mixture of 2-bromo-4-ethylsulfonyl-1-fluorobenzene (0.6 g, 2.25 mmol) and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 mL) was stirred at room temperature for 18 h. Water (30 mL) was added and extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=10:1 to 1:1) gave the title compound (0.5 g, 79.4%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, J=2.4 Hz, 1H), 7.87-7.84 (dd, J1=8.6 Hz, J2=2.4 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H).
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][C:6]1[C:5]([CH:4]=[O:20])=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:14])[F:13])[N:7]=1
Reactant: COCCCc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCc1nc(C(F)(F)F)ccc1C=O

Procedure:
N-Methoxy-2-(3-methoxy-propyl)-N-methyl-6-trifluoromethyl-nicotinamide (156 mg, 0.509 mmol) was reacted with 1M-LAH in THF solution to give 2-(3-methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively as oil. The crude product was used directly in the following reaction. 2-(3-Methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde was reacted with methyl(triphenylphosphoranylidene)acetate (204 mg, 0.61 mmol) to give 3-[2-(3-methoxy-propyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid methyl ester (124 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:15]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccc(C)cc3)c2c1
Reactant: BrCc1ccccc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
800 mg of 6-[[2-mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 8 ml of N,N-dimethylformamide, mixed with 0.3 ml of benzylbromide, 438 mg of potassium hydrogen carbonate and 75 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 976 mg was obtained.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.[OH-].[Na+]>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([O:42][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Oc3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 4 h

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl-8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (16.5 mg, 0.376 mmol) prepared as described in Example 359, in 0.3 mL of DMF at RT, potassium carbonate (19.4 mg, 0.14 mmol) was added followed by phenol (13.2 mg, 0.14 mmol). The mixture was stirred for 4 h. After this time, the reaction mixture was diluted with 5 mL of 1N aqueous sodium hydroxide. The precipitate was collected by filtration and washed with 1N aqueous NaOH, and water. The solid was dried to the title compound, 2-(4-(trifluoromethyl)benzyl-7-(4-chlorophenyl)-8-phenoxy-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (15.8 mg) as light yellow solid. HPLC RT: 4.02 min; MS, M+H=497; 1H NMR (CDCl3): δ 8.21 (s, 1H), 7.52-6.97 (m, 13H), 5.12 (s, 2H).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32]C(N)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[CH:17]1([C:16]#[C:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:32]=[CH:33][C:28]([N:24]5[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]5)=[CH:29][CH:30]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Product: CN1CCCN(c2ccc(-n3cnc4cc(C#CC5CC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopropylethynyl-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(4-methyl[1,4]diazepan-1-yl)phenylamine by method A1. The product with the molecular weight of 404.53 (C23H24N4OS) was obtained in this way; MS (ESI): 405 (M+H+).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)[CH2:28][CH2:29]2)=[O:16])=[CH:15][CH:14]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Product: O=C(Nc1ccncc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyridin-4-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. 1H NMR (400 MHz, CDCl3): 8.33 (d, J=5.3 Hz, 2H), 7.35-7.34 (m, 2H), 6.79 (s, 1H), 6.68-6.67 (m, 2H), 5.89 (s, 2H), 3.48-3.45 (m, 4H), 3.39 (s, 2H), 2.43-2.40 (m, 4H).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (170 mg, 0.521 mmol) in chloroform (10 mL) was added triethylamine (0.145 mL, 1.042 mmol) followed by ethyl chloroformate (0.055 mL, 0.573 mmol). The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated to dryness. The oil was partitioned between 3 mL of ethanol and 3 M of 1 M NaOH. After 1 hour, the reaction mixture was concentrated, and 10 mL of ethyl acetate followed by 4 mL of brine were added. The organic layer was separated, dried over MgSO4, filtered and evaporated. The resulting oil was dissolved in 5 mL of 10% AcCN:Et2O and 0.5 mL of 4 M HCl/dioxane was added. The suspension was stirred for 30 min, and then it was filtered. Ethyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (120 mg, 0.336 mmol, 64.6% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.30-7.39 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 4.19 (dd, J=1.26, 13.64 Hz, 2H), 4.13 (q, J=7.16 Hz, 3H), 3.15 (d, J=7.07 Hz, 2H), 3.02 (dt, J=4.14, 7.64 Hz, 1H), 2.86 (d, J=3.28 Hz, 2H), 2.54 (ddd, J=3.66, 6.69, 10.36 Hz, 1H), 1.99 (ddd, J=4.04, 7.52, 11.18 Hz, 1H), 1.82 (d, J=12.13 Hz, 2H), 1.56 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.42 (q, J=6.82 Hz, 1H), 1.27 (t, J=7.07 Hz, 3H), 1.17-1.33 (m, 1H); LC-MS Rt=0.76 min; MS (ESI): 303.3 [M++H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:19].[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:20][C:3]1[C:2]([CH3:1])=[C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]2[C:4]=1[C:5]([NH2:19])=[N:6][CH:7]=[N:8]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc2c(N)ncnn2c1CN1CCCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c2c(N)ncnn2c1CN1CCCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.5 %

Procedure:
To a stirring solution of chloroform (20 mL) and 6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (650 mg, 2.49 mmol), at −40° C., was added 1,3-dibromo-5,5-dimethylhydantoin (356 mg, 1.24 mmol). The mixture was allowed to stir for 10 minutes while warming to rt. The mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous Na2CO3 solution (150 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. Trituration with acetonitrile afforded 500 mg (59%) of the desired product. 1H-NMR (DMSO-d6) δ 7.82 (s, 1H), 3.91 (s, 2H), 3.62 (t, J=5.4 Hz, 2H), 3.55-3.53 (m, 2H), 2.61-2.56 (m, 4H), 2.15 (s, 3H), 1.77-1.72 (m, 2H); MS [M+H]+=339.9, 341.9; LCMS RT=1.09.
Reaction SMILES: [C:1]([S:8]([O:11][K])(=[O:10])=[O:9])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].[F-].[K+]>>[C:1]([S:8]([OH:11])(=[O:9])=[O:10])([C:4]([F:5])([F:7])[F:6])([F:3])[F:2]
Reactant: O=S(=O)(O[K])C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)(O)C(F)(F)C(F)(F)F

Procedure:
The obtained solution was heated to its boiling point until evaporation of 402 g of water, and the remaining liquid was cooled to 30° C. to cause precipitation of crystals 0.5 to 1 mm in size. The precipitate was separated by suction filtration and was dried to obtain 230 g of a crystalline powder, which consisted of 223.1 g (97.0 wt%) of C2F5SO3K, 5.5 g (2.4 wt%) of KOH and 1.4 g (0.6 wt%) of KF. Acid decomposition of this sulfonate powder and distillation of the reaction product were performed in the same manner as in Example 3. As the result C2F5SO3H of more than 99% purity was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>N1C=CC=CC=1.ClCCl>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a stirred suspension of 3-bromophenol (50 g, 0.29 mol) in pyridine (200 mL) and dichloromethane (100 mL) was added dropwise acetyl chloride (25 mL, 0.35 mol) at 0° C. and the mixture was stirred 18 h at room temperature. LC-MS showed that the reaction was complete. Pyridine and dichloromethane was evaporated in vacuo. Water (600 mL) was added and acidified with hydrochloric acid at pH 2. The reaction mixture was extracted with ethyl acetate (500 mL×3) and the organic phase was dried over anhydrous sodium sulfate, filtrated, concentrated and purified by column chromatography (PE:EA=60:1) to afford compound E-1 as a colorless liquid (46 g, 74%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 1-bromomethyl-4-methanesulfonyl-benzene are processed according to the method described in Example 11 to give 5-chloro-1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 2.29 (s, 3H), 3.09 (s, 3H), 5.46 (s, 2H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.53-7.57 (m, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.79-7.84 (m, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 8.52 (dd, J=2.3, 1.0 Hz, 1H), 8.61 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 411.0927 [(M+H)+ Calcd for C22H20N2O2SCl: 411.0934].
Reaction SMILES: [C:1]1(=[O:14])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl.[Br:21]Br>C(Cl)(Cl)Cl.II>[Br:21][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:1](=[O:14])[CH2:2]1
Reactant: BrBr
Reactant: O=C1CCCCCCCCCCCN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1CC(Br)CCCCCCCCCN1
Yield: 45.9 %

Procedure:
19.7 g of laurolactam in 100 ml of chloroform were cooled to 0° C. 20.8 g of phosphorus pentachloride were added portionwise over a period of 40 minutes while keeping the temperature below 5° C. There was then added 0.2 g of iodine, followed by 16.0 g (0.2 mol) of bromine over a period of 20 minutes. The mixture was heated under reflux for 4 hours, cooled, evaporated and poured on to ice. The product was taken up in chloroform, washed with sodium hydrogen sulfate solution, dried over anhydrous magnesium sulfate and evaporated. Crystallization from chloroform/ n-hexane yielded 12.65 g (46%) of 3-bromolaurolactam of melting point 155°-157° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.C(O)C.C(O)(=O)C.[N+:32]([CH3:35])([O-:34])=[O:33]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH:15]=[CH:35][N+:32]([O-:34])=[O:33])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C=O)c1OCCCCCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1OCCCCCc1ccccc1
Yield: 49 %

Procedure:
Operating analogously to example 2 using 2-(5-phenylpentyloxy)-3-methoxy-benzaldehyde (1 g, 3.35 mmoles), obtained as described in example 12, 8.03M methylamine in ethanol (0.088 ml, 0.7035 mmoles), acetic acid (0.04 ml, 0.7035 mmoles) and nitromethane (0.198 ml, 3.685 mmoles) in methanol (5 ml), 0.56 g of the title product was obtained (yield: 49%).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:21])[C@@H:10]([CH:11](Br)[C:12](=O)CBr)[C@H:9]1[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[CH3:7][C:8]1([CH3:21])[C@@H:10](/[CH:11]=[CH:12]\[C:1]([OH:3])=[O:4])[C@H:9]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@@H]1[C@H](C(Br)C(=O)CBr)C1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reaction time: 1.5 h

Procedure:
1 ml of a 1N solution of potassium carbonate was placed under an inert gas atmosphere and then a solution of 0.342 g of methyl (1R,cis) 2,2-dimethyl-3-(1,3-dibromo-2-oxopropyl)-cyclopropane-1-carboxylate in 1.5 ml of tetrahydrofuran was added at about +5° C. The mixture was stirred for 90 minutes and then the temperature was allowed to rise to 20° C. and stirring was continued for 4 hours. Water was added and extraction was carried out with methylene chloride. The organic phase was dried and the solvent was evaporated. The residue was chromatographed on silica, eluting with a methylene chloride - ethanol mixture (97-3) to obtain 0.046 g of the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1OCC(C)C)[C:6]([O:8]CC)=[O:7])#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:1][CH:3]([CH3:4])[CH3:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)c1ccc(OCC(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Temperature: 30 °C
Reaction time: 4 h
Yield: 212.9 %

Procedure:
Ethyl 3-cyano-4-isobutyloxybenzoate (20.0 g, 80.9 mmol) was dissolved in a mixture of ethanol (100 mL) and THF (100 mL). Aqueous 2M sodium hydroxide (45 mL, 90.0 mmol) was added to the resulting solution, and the mixture was stirred at 30° C. for 4 hours. The solvent was distilled off under reduced pressure. Water (100 mL) was added to the residue and further aqueous 2M hydrochloric acid to obtain an aqueous mixture of pH 1. The precipitated crystalline product was collected by filtration, washed with water (200 mL×2), and dried in air, to give 17.5 g (yield 99%) of the desired compound in the form of a white crystalline product.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:39](N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(C)C(C)=CC1=2)(=O)C>>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([F:37])[C:34]([CH3:39])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(Br)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(C)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-fluoro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7,8-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 549 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[H-].[Na+]>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
A solution of 3,4-difluorobenzonitrile (28 g, 201 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (40.5 g, 201 mmol) in THF (500 mL) was treated with sodium hydride (4 g, 100 mmoL) and stirred at 25° C. for 16 h. The reaction mixture was washed with water, extracted with EtOAc, and the crude product purified by flash silica gel chromatography gave tert-butyl 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (25 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc(Cl)n1
Yield: 63.5 %

Procedure:
A solution of 2,6-dichloro-4-methyl-pyridine (250 mg, 1.5 mmol) in methanol (2 mL) was added to a solution of sodium methoxide (prepared from sodium (71 mg, 3.0 mmol) and anhydrous methanol (20 mL)) and heated at reflux for 48 h. The solvent was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 2-chloro-6-methoxy-4-methyl-pyridine (150 mg, 61%) as a pale orange oily liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8][N:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[CH:11]([N:9]1[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8]1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)n1cc(CO)c(C(F)(F)F)n1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 111, 10.2 g, 40.76 mmol) in toluene (200 mL) at −78° C. was added DIBALH (85 mL, 101.91 mmol) dropwise and the reaction allowed to stir at this temperature for 2 hours. 2N HCl was added to quench the reaction followed by extraction into EtOAc. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound (8.3 g) that was taken directly on to the next step.