Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N+:19]([O-])=O)=[CH:11]2)[C:4]=1[CH3:22]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11]2)[C:4]=1[CH3:22]
Reactant: COc1ncnc(Cn2cc([N+](=O)[O-])c3ncccc32)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1ncnc(Cn2cc(N)c3ncccc32)c1C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-3-nitro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.58 mmol) in ethanol (5 mL) was added Pd/C (0.03 g). The reaction mixture was hydrogenated under balloon pressure for 16 h at RT. The solvent was filtered and evaporated under the reduced pressure to yield 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-amine (25d) 0.1 g (74%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)Cl>[CH2:40]([O:39][C:37]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:26])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2cc(F)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccc(F)cc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an-ice cooled solution of (±)-[4-chloro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (900 mg, 2.25 mmol, 1.0 eq.) and DIPEA (1.16 mL, 6.75 mmol, 3.0 eq.) in DCM (30 mL), benzyl chloroformate (0.43 mL, 2.92 mmol, 1.3 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (25 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 50 g, flow: 40 mL/min, Heptane+10% EtOAc to Heptane+50% EtOAc) to yield the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and tributylphenylstannane: MS (m/z) 343.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([OH:20])=[O:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CCC[C@@H](C(O)=O)C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=[O:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC[C@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Agent: O=C(O)[C@@H]1CCCNC1
Product: COc1cc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]

Procedure:
(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid was prepared in a in an analogous fashion to (S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid of Example 460a replacing (S)-Piperidine-3-carboxylic acid with (R)-Piperidine-3-carboxylic acid. (R)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid was isolated as a yellow solid (955 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:23]3[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[CH:25]=[N:24]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:23]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[N:24]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)c1
Temperature: 60 °C
Yield: 34.9 %

Procedure:
To a solution of ethyl 1-[6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]-1H-pyrazole-4-carboxylate (0.022 g, 0.05 mmol) in a mixture of THF/ethanol 1:1 (1 mL), 2N sodium hydroxide aqueous solution (0.05 mL) was added. The mixture was heated at 60° C. for 2 hours and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture was purified by solid phase extraction, SCX, it was washed with water and eluted with methanol/ammonia (9:1) to give the title compound (0.007 g, 29% of yield).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[C:22]12([CH2:32][C:33](O)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:21])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: CC(C)c1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.75-7.78 (m, 1H), 7.50-7.53 (m, 2H), 7.43-7.46 (m, 2H), 2.96-3.06 (m, 1H), 2.05 (s, 2H), 1.94-1.97 (m, 3H), 1.65-1.72 (m, 9H), 1.58-1.64 (m, 3H), 1.28 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 457 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.O>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:10][C:9]1=2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a solution of 0.46 gram (2.85 mmole) 6-amino-3,4-dihydro-2H-naphthalen-1-one in 25 mL pyridine was added 0.605 grams (3.42 mmoles) benzenesulfonyl chloride. The reaction mixture was stirred at 23° C. for 24 hours. The mixture was diluted with 100 mL water and extracted with 200 mL ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 50% ethyl acetate in hexane. The title compound was obtained as a solid, 0.48 gram (56%), m.p. 164-165° C., M−H=300.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].[C:28](Cl)(=[O:30])[CH3:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:28]([N:20]1[CH2:21][C@H:22]([O:23][CH2:24][CH3:25])[C@H:18]([NH:17][C:12]2[C:11]([CH2:26][CH3:27])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:19]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (105 mg) in methylene chloride (5 ml) under N2 was added acetyl chloride (0.027 ml). The reaction mixture stirred for 30 min and was poured into saturated sodium bicarbonate (20 ml), extracted methylene chloride (2×20 ml), dried MgSO4, filtered and concentrated. MPLC chromatography was run on a biotage 25 S column with 60% ethyl acetate/heptane to provide the title compound as an oil (79 mg, 69%): 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34–7.26, 5.30, 5.12, 4.81, 4.19, 4.01, 3.87–3.67, 3.61–3.37, 2.72, 2.48, 1.33–1.26, 1.14; HRMS (FAB) calcd for C22H28Cl2N4O2+H 451.1667, found 451.1667.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:37]=[C:26]1[CH2:27][CH2:28][CH:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18])=[CH:14][C:9]=2[O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH2:24][CH2:25]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 15 h
Yield: 101.5 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (817 mg, 1.88 mmol). Anhydrous dichloromethane (50 ml) was added followed by benzylamine (0.82 ml, 7.52 mmol) and activated 4 Å molecular sieves (10.0 g). The reaction mixture was stirred vigorously for 15 hr, then dichloromethane (50 ml) was added and the reaction mixture filtered through celite, washing with dichloromethane (50 ml). The filtrate was concentrated in vacuo affording the desired product (1.00 g, 86%) as a yellow oil. δH(CDCl3) 0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.51 (1H, m), 1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60 (1H, m), 3.04 (1H, m), 3.22 (1H, m), 4.55 (1H, d), 4.60 (1H, d), 6.31 (1H, d), 6.41 (1H, dd), 6.93 (1H, d), 7.33 (5H, m).
Reaction SMILES: CS(C)=O.[Cl-].[OH:6][CH:7]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][N:9]1[C:14]2=[N:15][C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1.CCN(CC)CC>C(Cl)Cl>[O:6]=[C:7]([CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C:14]2=[N:15][C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c(-c2ccncc2)nc2n1CCCN2CC(O)CCc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)CN1CCCn2c1nc(-c1ccncc1)c(-c1cccc(C(F)(F)F)c1)c2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A solution of DMSO (0.25 mL, 3.5 mmol) in CH2Cl2 (10 mL) at −78 C was treated with a solution of oxallyl chloride (2N in CH2Cl2, 0.8 mL, 1.6 mmol) dropwise. After stirring for 15 min, a solution of 9-(2-hydroxy-4-phenyl-butyl)-2-pyridin-4-yl-3-(3-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (227 mg, 0.43 mmol) in CH2Cl2 (15 mL) was added. The mixture was stirred at −60 C for 15 min before a solution of Et3N (0.5 mL, 3.6 mmol) in CH2Cl2 (3 mL) was added. The reaction mixture was allowed to warm to room temperature overnight and was washed with NaHCO3 (aq). The organic layer was dired (Na2SO4), and concentrated. The residue was eluted on silica gel with 0-5% (2N NH3-MeOH in CH2Cl2) to afford the product as a light yellow solid (148 mg, 63%). M+1 519.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH:18][S:32]([C:30]3[C:29]([C:36]([F:39])([F:37])[F:38])=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)N)cc1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)cc1
Reaction time: 16 h
Yield: 25 %

Procedure:
The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel to give to give 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.82 mmol, 41%). To a solution of 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.8 mmol) in dioxan/methanol (1:1, 10 ml) was added hydrazine hydrate (0.83 g, 46.5 mmol). The reaction was stirred at room temperature for 24 h. The solvent was evaporated and dichloromethane added. The resultant white solid was filtered off and dried to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.21 g, 0.8 mmol, 100%) as a clear oil. To a solution of 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.1 g, 0.4 mmol) in dichloromethane (2 ml) was added triethylamine (123 mg, 1.2 mmol) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonylchloride (111 mg, 0.45 mmol). The reaction mixture was agitated for 16 h and quenched with saturated aqueuos sodium bicarbonate solution. The organic phase was washed with water, brine and dried over anhydrous magneium sulfate. The residue was chromatographed on silica gel to give the title compound (42 mg, 0.1 mmol, 25%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.45 (m, 3H), 7.35 (dd, 1H), 7.21 (d, 2H), 4.86 (d, 1H), 4.60 (q, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.50 (b, 3H) ppm; MS (ESI) m/z: 459.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 75.0 g (431 mmol) of 4-(trifluoromethyl)benzaldehyde in 750 ml of diethyl ether was slowly added dropwise to 517 ml (517 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at RT under argon. After heating under reflux for 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 9/1) to result in 87.0 g (100% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([OH:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:16][S:28]([CH3:27])(=[O:30])=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(OS(C)(=O)=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Hydroxy-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester (I101) (440 mg, 1.77 mmol) and DIPEA (0.43 mL, 2.48 mmol) are dissolved in dry DCM (17 mL) and cooled at 0° C. under N2. Methansulfonyl chloride (0.18 mL, 2.30 mmol) is added dropwise to the solution and the resulting mixture is allowed to warm to RT and stirred for 3 hours. The mixture is diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated to obtain intermediate I150 as a yellow oil (578 mg, quantitative yield), which is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 54 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 54% yield: mp 197-198° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 9H), 5.97 (t, J=5.4 Hz, 1H), 4.54 (d, J=5.4 Hz, 2H), 4.44 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.44 (t, J=8.1 Hz, 2H), 2.59 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 162.3, 157.2, 155.4, 152.9, 148.9, 137.9, 134.3, 129.7, 128.7, 127.8, 127.6, 121.4, 120.8, 117.4, 47.2, 44.0, 42.0, 41.7, 17.2: MS (ES+) m/z 491.3 (M+1).
Reaction SMILES: [CH2:1]([Si:5]([CH:18]1[S:23][CH2:22][CH2:21][CH2:20][S:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([Li])CCC.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH2:1]([Si:5]([C:18]1([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19][CH2:20][CH2:21][CH2:22][S:23]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Reactant: CC(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 32 (4.68 g, 13.1 mmol) in THF (100 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 M in hexanes, 18.4 mmol). After 3 h of stirring under argon, 1-bromo-2-methylpropane (2.14 mL, 19.7 mmol) was added dropwise over 5 min, and the mixture was stirred for 2 h at 78° C. and overnight at rt. The reaction mixture was quenched with water (10 mL) and the excess organic solvent was removed under reduced pressure. The crude mixture was extracted with three 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 26 as a colorless solid (5.0 g, 92%): Rf=0.75 (1/9 EtOAc:hexane); mp 67-69° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=6.0 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=10.1, 1.7 Hz, 1H), 3.04 (m, 2H), 2.49 (t, J=4.3 Hz, 1H), 2.44 (t, J=4.1 Hz, 1H), 2.08 (d, J=5.1 Hz, 2H), 1.98 (m, 4H), 1.79 (m, 1H), 1.54 (m, 2H), 0.82 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 141.5, 136.7, 132.9, 129.9, 127.7, 113.0, 45.7, 39.9, 28.3, 27.2, 24.6, 24.3, 24.2, 11.0; IR (film) 3068 (m), 3043 (m), 2951 (s), 2912 (s), 2863 (m), 1432 (s), 1274 (w), 1113 (s), 997 (m), 913 (m), 738 (s), 705 (s) cm−1; MS (EI) m/e (rel. intensity) 289 (M+−123, 3), 237 (8), 183 (72), 175 (100), 159 (32), 143 (17), 119 (16), 105 (35); HRMS (FAB) calcd for C24H32S2Si: 412.1715 (MH+−1), found: 412.1727. Anal. Calcd for C24H32S2Si: C, 69.84; H, 7.82. Found: C, 70.08; H, 8.07.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[K+]>CCO.CCOC(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Yield: 84.4 %

Procedure:
To a solution of 4-bromo-2-fluorobenzylbromide (44.5 g, 166 mmol) in EtOH (118 mL) was added KCN (13.13 g, 182 mmol) and the mixture was stirred at reflux under an argon atmosphere for 18 h. The mixture was allowed to cool and the solvent was concentrated. The residue thus obtained was dissolved in a mixture of EtOAc and H2O and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases dried and concentrated to a crude product. Purification by chromatography on silica gel (hexane-EtOAc, 10%) afforded the title compound as a reddish oil (30.0 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:10]=1
Reactant: [H][H]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(Oc2ccc(N)cc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
A solution of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (5.3 g, 18.5 mmol) in ethanol (200 ml) was placed in an autoclave, and 10% palladium carbon (2.0 g) was added. An atmosphere in the autoclave was fully replaced with hydrogen gas, and hydrogen gas was filled up to 5 kg/cm2. Then, the reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the catalyst was separated by filtration using Celite, and the solvent was distilled off from the filtrate under reduced pressure, to give a white solid of 3-(4-amino-2-trifluoromethylphenyloxy)-5-methylpyrazole (3.6 g, yield: 76.1%). mp: 143-145° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 2.17 (s, 3H), 5.33 (br s, 2H), 5.44 (s, 1H), 6.78 (dd, J=2.6 and 8.8 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 11.80-11.95 (br s, 1H).
Reaction SMILES: CC(C)=[CH:3][CH2:4][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[O:24]=[O+][O-]>C(Cl)Cl>[O:24]=[CH:3][CH2:4][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: O=[O+][O-]
Reactant: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-tert-Butyl 3-ethyl 3-(3-methylbut-2-en-1-yl)piperidine-1,3-dicarboxylate (2.75 g, 8.5 mmol) in CH2Cl2 (100 mL) was cooed to −78° C., and ozone was passed into the reaction mixture until a light blue color was observed (ca. 15 min). Nitrogen was then bubbled through the solution to remove the excess ozone. Dimethyl sulfide (10 mL) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was then washed with water and brine, dried and concentrated to give the product (2.5 g).