Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:39]1([CH2:45][S:46](Cl)(=[O:48])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:46]([CH2:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)(=[O:48])=[O:47])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(CN2CCN(S(=O)(=O)Cc3ccccc3)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 28.6 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (26 mg, 0.05 mmol), DIEA (26 μL, 0.15 mmol) and alpha-toluenesulfonyl chloride (20 mg. 0.10 mmol) to afford 8 mg (29%) of the desired product after purification.
Reaction SMILES: [CH:1]1[C:9]2[C:4]3=[C:5]([CH2:10][CH2:11][N:3]3[C:2]=1C(O)=O)[CH:6]=[CH:7][CH:8]=2.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH2:1]1[C:9]2[C:4]3=[C:5]([CH:10]=[CH:11][N:3]3[CH2:2]1)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C(O)c1cc2cccc3c2n1CC3
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: c1cc2c3c(c1)ccn3CC2
Temperature: 200 °C
Yield: 61.1 %

Procedure:
A mixture of 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid (120 mg, 0.64 mmol) and copper chromite (50 mg) in quinoline (5 ml) in a sealed vessel was heated to 200° C. in a microwave for 20 minutes. After cooling to room temperature the mixture was poured into ethyl acetate (100 ml) and washed with 1M hydrochloric acid (3×100 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (SiO2, 20% EtOAc in hexanes) to yield 1,2-dihydro-pyrrolo[3,2,1-hi]indole as a pale yellow crystalline solid (56 mg). 400 MHz 1H NMR (CDCl3) δ: 7.33 (d, J=8.0 Hz, 1H), 7.14 (d, J=2.8 Hz, 1H), 7.04-6.97 (m, 1H), 6.91 (d, J=6.8 Hz, 1H), 6.44 (d, J=2.8 Hz, 1H), 4.51 (t, J=7.2 Hz, 2H), 3.80 (t, J=7.2 Hz, 2H); LCMS: 144 [M+H].
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH2:9].[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16](O)=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH:9][C:16]([CH:12]1[C:13]([CH3:15])([CH3:14])[C:11]1([CH3:19])[CH3:10])=[O:17]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2c(s1)CCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)Nc2nc3c(s2)CCC3)C1(C)C

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine (177 mg, 1.26 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (244 mg, 1.52 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine (351 μL, 2.52 mmol) in 20 mL of THF was processed according to the method of Example 118A to provide the title compound: MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:31][Si:32]([C:35]#[C:36][C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC=C(C#C[Si](C)(C)C)C1C2
Yield: 58.9 %

Procedure:
To a solution of t-butyl 4-trifluoromethanesulfonyloxy-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (1.8 g, 5.0 mmol) in 10 mL of toluene was added 20 mL of triethylamine, followed by trimethylsilylacetylene (0.49 g, 5.0 mmol). The mixture was degassed, placed under a nitrogen atmosphere, and copper iodide (50 mg) and bis(triphenylphosphine)palladium dichloride (100 mg) were added. The reaction mixture was heated under reflux for 16 h, then cooled and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, using 0-50% ethyl acetate in hexane as eluent, to give tert-butyl 4-trimethylsilylethynyl-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (900 mg, 58.9%). This was dissolved in 25 mL of methanol and treated with solid potassium carbonate (˜1 g) with vigorous stirring. After 4 h, the mixture was concentrated to dryness in vacuo, and the residue was column chromatographed on silica gel, eluting with 2:1 hexane/ethyl acetate, to give a yellow oil (300 mg, 25.8% for two steps).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:47]2[C:48]([CH:53]=O)=[N:49][CH:50]=[CH:51][CH:52]=2)([CH3:46])[CH3:45])=[CH:40][CH:39]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1)[CH2:53][C:48]1[C:47]([C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)([CH3:46])[CH3:45])=[CH:52][CH:51]=[CH:50][N:49]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1CNCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncccc1C(C)(C)c1ccc(F)cc1

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester in CH2Cl2 and 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde with NaBH(OAc)3 gave [4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-butyl]-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.26 (m, 4H), 1.44 (s, 9H), 1.64 (s, 6H), 2.13 (s, 3H), 2.31 (t, 2H, J=7.5 Hz), 2.94 (d, 2H, J=6.0 Hz), 3.28 (s, 2H), 3.51 (s, 2H), 5.12 (br s, 1H), 6.90-6.98 (m, 4H), 7.23 (dd, 1H, J=7.5, 3.0 Hz), 7.36 (s, 1H), 7.86 (d, 1H, J=9.0 Hz), 8.25 (d, 1H, J=3.0 Hz), 8.53 (d, 1H, J=3.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24](OC1C=CC=CC=1)=[O:25].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][O:20][C:21](=[O:38])[C@H:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[NH:23][C:24]([N:14]([CH2:13][C:10]1[S:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:11]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:25]
Reactant: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C[C@H](NC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound (1.1 g, 4.1 mmol) obtained in step 1 and the compound (1.2 g, 4.1 mmol) obtained in step 2 were dissolved in acetonitrile (40 ml), N,N-diisopropylethylamine (0.71 mL, 4.1 mmol) was added, and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][NH:19][O:20][CH3:21])#[N:14]>>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][N:19]([O:20][CH3:21])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)#[N:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)c(C#N)c1
Product: CON(Cc1ccc(F)c(C#N)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-cyano-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (97% yield): mp 119–120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.75 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.36 (1H, s, CH), 7.17 (1H, t, aromatic), 7.58–7.64 (2H, m, aromatics). Anal. calcd for C16H15F2NO5: C, 57.48; H, 4.52; N, 8.38. Found: C, 57.39; H, 4.61; N, 8.32.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[H][H].[CH2:26]=[C:27]([CH3:29])[CH3:28]>C(Cl)Cl.S(=O)(=O)(O)O.C(O)(C)(C)C.[C].[Pd]>[C:27]([O:20][C:18](=[O:19])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH2:11])([CH3:29])([CH3:28])[CH3:26]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Reactant: C=C(C)C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 85.5 %

Procedure:
Benzyloxycarbonyl-L-alanyl-L-proline (16.02 g, 50 mmole) was dissolved in methylene chloride (100 ml) solution of 98% sulfuric acid (0.5 ml), and isobutene gas was blown into the solution under cooling until the volume of the solution was increased by 50 ml. After standing it for 64 hours at room temperature, the solution was washed with 0.15M sodium carbonate. The methylene chloride layer was further washed with 10% aqueous citric acid, water, 5% aqueous sodium bicarbonate and water in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the oily residue thus obtained was dissolved in t-butanol (90 ml). Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon (6.5 g) as a catalyst for 2 hours at room temperature. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure to give colourless oily L-alanyl-L-proline t-butylester (yield: 10.36 g, 85.5%).
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[NH:14][C:13]([C:17]([C:20](OCC2C=CC=CC=2)=O)([CH3:19])C)=[N:12][C:11]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][N:37](C(C)C)C(C)C.ClCC(Cl)=[O:47].C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C.[Pd]>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:35][C:36](=[O:47])[NH:37][C:17]([CH3:20])([CH3:19])[C:13]2=[N:12][C:11]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1nc(C(C)(C)C(=O)OCc2ccccc2)[nH]c(=O)c1OC(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC(=O)NC2(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Intermediate 29, ethyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonyl)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (479 mg, 1 mmol) was dissolved in methanol and treated with H2 (1 atm) over 10% Pd/C (106 mg) for 1 hour. The reaction mixture was filtered through Celite and the solvent removed in vacuo. The remaining residue was dissolved in 2 mL of CH2Cl2 to which was added iPr2NEt (0.174 mL, 1 mmol) and chloroacetyl chloride (0.080 mL, 1 mmol). The resulting mixture was allowed to stir for 1 hour, then transferred to a seperatory funnel and washed with 1 N HCl. The organic layer was dried (Na2SO4) and the solvent removed to provide a solid. The solid (1 mmol) was dissolved in 4 mL of DMF. To this was added K2CO3 (140 mg, 1 mmol) and the resulting solution heated to 70° C. After stirring for 2 hours the reaction was quenched with 1 N HCl and transferred to a seperatory funnel. The mixture was washed with ethyl acetate which was then dried over Na2SO4. The solvent was removed in vacuo to provide the title compound as an oil.
Reaction SMILES: BrC1C=CC(O)=CC=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1>>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=2[CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=3)[CH2:35]2)=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(I)c1
Agent: Oc1ccc(Br)cc1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2)c(C#Cc2ccc(OCc3ccccc3)cc2)c1
Yield: 67.3 %

Procedure:
Synthesized from 4-bromophenol according to an analogous synthetic method to Preparation Example 117 described below, 1-benzyloxy-4-ethynylbenzene (470 mg) and 2-(2-iodo-4-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene (690 mg) were used according to an analogous synthetic method to Preparation Example 45 to provide 2-[2-(4-benzyloxyphenylethynyl)-4-methoxyphenyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene (559 mg). This compound (557 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (482 mg).
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[S:3][CH:2]=1.C([Li:14])CCC.[C:15](=[O:17])=[O:16]>CCOCC>[N:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[S:3][C:2]=1[C:15]([O-:17])=[O:16].[Li+:14]
Reactant: [Li]CCCC
Reactant: c1nc2c(s1)COCC2
Reactant: O=C=O
Solvent: CCOCC
Product: O=C([O-])c1nc2c(s1)COCC2
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 200-mL three-necked flask, 4,5-dihydro-7H-pyrano[4,3-d]thiazole (1.14 g) was added and dissolved in ether (30 mL). After cooling to −78° C., 1.6M butyl lithium (6.6 mL) was added and the resulting mixture was stirred. After 20 minutes, a carbon dioxide gas was introduced. After about 15 minutes, the introduction was terminated. The reaction mixture was allowed to rise back to room temperature and concentrated under reduced pressure, whereby the title compound (1.65 g) was obtained as a colorless amorphous substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:10][C:6]([CH2:4][OH:3])=[C:7]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]3)[N:8]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 220 g of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carboxylic acid ethyl ester in 2.2 L of tetrahydrofuran at 0° C. was dropwise added 250 mL of a 2M solution of lithium aluminum hydride in tetrahydrofuran. The resulting mixture was stirred for 1 h allowing it to warm up to room temperature then slowly poured into 1 L of cold water and extracted twice with 1.5 L of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was washed with 500 mL of hot diisopropyl ether then purified by column chromatography on silica gel (gradient of dichloromethane/ethanol from 100/0 to 90/10) to give 163 g of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol as a white solid.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]1([F:60])[CH:55]2[CH2:56][C:51]3([CH2:58][OH:59])[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:51]23[CH2:56][CH:55]4[CH2:54][CH:53]([CH2:57][CH:49]([C:48]4([F:47])[F:60])[CH2:50]2)[CH2:52]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(C1)C(F)(F)C(C3)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4,4-difluoro-1-(hydroxymethyl)adamantane, the title compound was obtained as a colorless solid (0.21 g, 44%): 1H NMR (300 MHz, CDCl3) δ 8.64 (br s, 1H), 8.16-8.03 (m, 1H), 6.73-6.60 (m, 1H), 3.63 (s, 2H), 3.03 (s, 6H), 2.37-2.25 (m, 2H), 2.11-1.84 (m, 5H), 1.81-1.66 (m, 6H); MS (ES−) m/z 479.2 (M−1), 481.1 (M−1);
Reaction SMILES: CC1C=CC=C(C)C=1[CH:9]([NH2:18])C(C1C=CC=CC=1)C.Br[CH:20]([CH3:31])[CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[N:22]1[CH2:21][CH:20]([CH3:31])[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]1=[NH:18]
Reactant: Nc1ccccc1
Reactant: Cc1cccc(C)c1NCC(C)Br
Reactant: Cc1cccc(C)c1C(N)C(C)c1ccccc1
Product: Cc1cccc(C)c1N1CC(C)N(c2ccccc2)C1=N

Procedure:
1-(2',6'-Dimethylphenyl)-2-phenyl-amino-propane, applied as starting substance, is prepared with a yield of 41.0% by reacting N-(β-bromopropyl)-2,6-dimethyl-aniline, a compound obtained as described in Example 3, Method (c), point (a), with aniline according to the process given in Example 3, Method (c), point (b). The boiling point of the product is 116°-120° C./1.5 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1[O:11][C@@H:10]1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:11])[CH2:12][OH:13])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Temperature: 120 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 205 mg, 1.81 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) was treated with (R)-glycidol (148 mg, 2.00 mmol) and potassium carbonate (770 mg, 5.58 mmol). The mixture was heated in a sealed vial at 120° C. for 1 h. After this time, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (6×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Teledyne Isco RediSep Flash Column 40 g, 15-100% ethyl acetate/hexanes) afforded (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (118 mg, 34%) as a thick yellow oil. 1H-NMR (400 MHz, CD3OD) δ 3.55 (2H, d, J=5.2 Hz), 4.02-4.05 (1H, m), 4.20 (1H, dd, J=13.6 Hz, 7.6 Hz), 4.39 (1H, dd, J=14.0 Hz, 3.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=2.0 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cccc(C(=O)CCCCCBr)c1
Agent: Cl
Product: COc1cccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-methoxyphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-methoxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([N:8]([S:16]([CH2:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24]([CH3:28])[CH2:25][CH2:26][NH2:27].[C:29]([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([N:8]([S:16]([CH2:19][CH2:20][CH2:21][N:27]([CH3:29])[CH2:26][CH2:25][NH:24][CH3:28])(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)CCCCl
Reactant: CN(C)CCN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCN(C)CCCS(=O)(=O)N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tert-butyl benzyl[(3-chloropropyl)sulfonyl]carbamate was dissolved in MeCN (0.2 M) and N,N-dimethylethane-1,2-diamine (5 eq.) was added followed by K2CO3 (5 eq.). The mixture was stirred at 65° C. overnight. The solvent was removed under reduced pressure and the residual material was dissolved in EtOAc and washed with water. After drying over Na2SO4, all volatiles were evaporated in vacuo and the residual material used in the next step without purification. MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: C[C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[S:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1.CC1C=NNC=1.N1C=CC=N1>>[N:5]1([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27](=[O:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[S:25])=[CH:21][CH:22]=3)[CH:8]=2)[CH:6]=[CH:2][CH:3]=[N:4]1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Agent: Cc1cn[nH]c1
Agent: c1cn[nH]c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-n4cccn4)sc23)cc1

Procedure:
Following the procedures described above for the synthesis of compound 258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in the step 1 with 1H-pyrazole, title compound 258b was obtained. Characterization of 258b is provided in the table 23.