Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([NH:25][C:26]3[S:27][C:28]([C:38](=[O:40])[NH2:39])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[N:30]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41](OCC)(OCC)OCC>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]3[N:22]=[CH:41][N:25]([C:26]4[S:27][C:28]([C:38](=[O:40])[NH2:39])=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=5)[N:30]=4)[C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1

Procedure:
The crude 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (VII.23) was dissolved in 4 mL of acetic acid and 0.14 mL (0.84 mmole) of triethyl orthoformate. The mixture was heated at 70 degrees for 2 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium carbonate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-dichloromethane (gradient 50:50-100:0) to give 0.13 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (I.23a).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)=[O:6])#[N:2].Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+].N#N>C1(C)C=CC=CC=1>[N:2]1[NH:44][N:45]=[N:46][C:1]=1[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:10][CH:11]=1)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(SC(c2ccc(C(=O)NCC#N)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(SC(c2ccc(C(=O)NCc3nn[nH]n3)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
A solution of 5-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]-thiophene-2-carboxylic acid cyanomethyl-amide (Isomer 1) (220 mg, 0.436 mmol) in toluene (8.7 mL) is treated with triethylamine hydrochloride (300 mg, 2.18 mmol) and sodium azide (142 mg, 2.18 mmol), then heated at reflux overnight (thermal conditions) or alternatively, placed in a CEM microwave reactor for 20 min (300 W, 180° C., N2 cooling) (microwave conditions). After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated to give the title compound (105 mg). MS (ES): 548.3 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([NH:10][C@@H:11]([C:26](O)=[O:27])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1)=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][C:26](=[O:27])[C@@H:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[NH:10][C:8](=[O:9])[CH:7]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: NCc1ccc(CC(N)=O)cc1
Reactant: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 89 %

Procedure:
Prepared analogously to Example 6d) from (R)-N2 -diphenylacetyl-N5 -(phenylmethoxycarbonyl)-ornithine, 4-(aminocarbonylmethyl)-benzenemethanamine and TBTU in a yield of 89% of theory. Colourless crystals, Mp. 203-205° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4].[NH:28]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[N:29]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCOCC1.ClCCCl>[NH:28]1[CH:32]=[CH:31][C:30]([CH2:33][NH:1][C@@H:2]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=3)[CH:7]=2)=[O:4])=[N:29]1
Reactant: O=Cc1cc[nH]n1
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3cc[nH]n3)n(C)n2)ccn1
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-(methylamino)pyridin-4-yl)-1H-pyrazol-5-yl)propanamide (79 mg, 214 μmol) was added 1H-pyrazole-3-carbaldehyde (29 mg, 300 μmol), then DCE and dioxane were added as solvents, followed by acetic acid (13 μl, 225 μmol) and NaBH(OAc)3 (136 mg, 643 μmol). Heating was continued for 1 hr. 40 min. The reaction was concentrated and purified by reverse phase HPLC purification to afford 23.2 (27 mg, 28%) as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 7.77-8.01 (m, 1H) 7.55 (br. s., 1H) 7.25 (dd, J=8.61, 5.48 Hz, 2H) 7.03 (t, J=8.80 Hz, 2H) 6.91 (dd, J=5.67, 1.37 Hz, 1H) 6.51-6.65 (m, 1H) 6.23 (d, J=1.96 Hz, 1H) 3.74-3.91 (m, 2H) 3.60-3.63 (m, 1H) 3.59 (s, 3H) 2.97-3.11 (m, 2H) 2.89 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C@@H:10]([NH:12][S@@](C(C)(C)C)=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[ClH:19]>CO.O1CCOCC1>[ClH:19].[NH:1]1[C:9]2[C:4](=[N:5][C:6]([C@@H:10]([NH2:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]ccc2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc2[nH]ccc2n1
Temperature: 40 °C
Reaction time: 7 h
Yield: 99.5 %

Procedure:
To a solution of (R)—N—((S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (597.0 mg, 2.25 mmol) in anhydrous MeOH (9 mL) was added HCl (4.0 mol/L) in dioxane (11 mL). The reaction mixture was stirred at 40° C. under N2 for 7 h. Volatile solvent was removed under reduced pressure. The crude product was triturated with MeOH/ether until solid is seen. The light yellow solid was filtered and dried under high vacuum to afford 524.0 mg (99.5%) of the desired product as HCl salt: 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.00 (s, 3H), 8.42 (d, J=6.8 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 6.79 (s, 1H), 4.88 (s, 1H), 1.67 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 162.1 [M+1]+.
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1.[CH:24]([C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1)=[CH2:25].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[CH3:33][O:32][C:28]1[CH:27]=[C:26](/[CH:24]=[CH:25]/[C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C=Cc1cccc(OC)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 5 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 0.50 g were added 3-vinylanisole 0.37 mL, triethylamine 0.47 mL and palladium acetate 0.11 g at room temperature, and it was stirred under nitrogen atmosphere at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-((E)-2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate 0.20 g of pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.O=O>>[C:1]([C:5]1[CH:14]=[C:13]([C:15](=[O:16])[CH3:17])[CH:12]=[C:7]([CH2:8][O:10][CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Reactant: CI
Agent: O=O
Product: COCc1cc(C(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate was reacted with methyl iodide analogously to O5.043, and converted to the title compound analogously to the sequence O4.008 to O2.008. 1.54 g were obtained.
Reaction SMILES: COC(=O)COC1C=C(OC)C(SCCC=O)=CC=1C.C(NCC)C1C=CC=CC=1.C[O:32][C:33](=[O:64])[CH2:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([S:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:61][CH3:62])[C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59]C=CC=3)=CN=2)=[CH:38][C:37]=1[CH3:63]>>[CH2:49]([N:48]([CH2:61][CH3:62])[CH2:47][CH2:46][CH2:45][S:44][C:39]1[C:40]([O:42][CH3:43])=[CH:41][C:36]([O:35][CH2:34][C:33]([OH:32])=[O:64])=[C:37]([CH3:63])[CH:38]=1)[C:54]1[CH:53]=[CH:52][CH:55]=[CH:60][CH:59]=1
Reactant: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Agent: CCNCc1ccccc1
Agent: COC(=O)COc1cc(OC)c(SCCC=O)cc1C
Product: CCN(CCCSc1cc(C)c(OCC(=O)O)cc1OC)Cc1ccccc1

Procedure:
Compound 64A and benzyl-ethyl-amine were reacted in a manner analogous to Compound 64C to give the title product. MS m/z 418 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)([O-])=O.C(OCC)(=O)C.O>[Fe].C(O)(=O)C>[O:15]1[C:14]2[CH:18]=[CH:19][C:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:12][C:13]=2[O:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCO2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
13.6 g (244 mmol) of iron powder and 10.5 g (40 mmol) of N-(2-nitrophenyl)benzo[d][1,3]dioxol-5-ylamine were added to a solvent mixture of ethyl acetate (130 ml), water (65 mL) and acetic acid (15 mL), and the mixture was stirred for 1 hour at 70° C. The reaction solution was cooled to room temperature, and the waste was separated by filtration using a filter aid. The organic layer of the filtrate was batched off, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 9.2 g (yield: 99%) of N-(benzo[d][1,3]dioxol-5-yl)benzene-1,2-diamine as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17][CH2:16]2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:25]1([NH:24][C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:4]3[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]4[C:5]=3[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]4)[CH2:16][CH2:17]2)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1
Reaction time: 0.5 h

Procedure:
382 mg (1 mmol) of N-(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-piperidine-4-carboxylic acid (Example 6), 186 mg (2 equiv.) of aniline, 480 mg (2.5 equiv.) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 384 mg (2.5 equiv.) of 1-hydroxy-benzotriazole are stirred at 20° C. in dried dimethylformamide for 48 hours. The mixture is poured into water and extracted three times with 100 ml of dichloromethane. The organic phases are combined and concentrated by evaporation. The residue is dissolved in 30 ml of dichloromethane and the solution is stirred for 30 minutes. The white solid is filtered off, washed with dichloromethane and dried.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=[O:14].[Li].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.CCCCCC.O>[C:7]1([C:4]2[C:3]([C:13]([OH:15])=[O:14])=[C:2]([CH2:1][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)noc1CCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 1.5 g of 5-methyl-3-phenyl-4-isoxazolecarboxylic acid in 50 mL of anhydrous tetrahydrofuran stirred at −78° C. under N2 atmosphere, 5.9 mL of a 2.5M solution of n-buthyl lithium in n-hexane was added and the solution was stirred at −78° C. for 2 hours. Afterwards, 0.89 mL of benzyl bromide was added at −78° C. and the solution stirred at room temperature for 2 hours. After overnight resting, the solution was poured into water (300 mL), acidified with hydrochloric acid and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvents were evaporated to dryness. The solid residue was washed with petroleum ether to give 1.82 g (84%) of the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: OC1CCCNC1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCCN(c2ccc(Br)cc2)C1

Procedure:
A solution of 1-bromo-4-iodobenzene (Aldrich, 4 g, 14.14 mmol), piperidin-3-ol (Aldrich, 1.14 g, 11.31 mmol), copper (I) iodide (0.269 g, 1.41 mmol) and K3PO4 (6.00 g, 28.3 mmol) in N,N-dimethylformamide (50 mL) under N2 were stirred at 100° C. for 48 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed successively with water and brine then dried over anhydrous Na2SO4, filtered through celite and concentrated under reduced pressure. The sample was purified on silica gel column chromatography using a cyclohexane to cyclohexane/ethyl acetate 70:30 as eluant. The appropriate fractions were combined and concentrated in vacuo and the residue was triturated with pentane. The resulting solid was filtered, washed with pentane and dried to give the title compound 1-(4-bromophenyl) piperidin-3-ol as a beige powder. LCMS: (M+H)+=256-258; Rt=2.90 min.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([Cl:37])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:9]=1>CCO>[Cl:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([Cl:37])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@@H:15]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1

Procedure:
Racemic trans-1-tert-butyl 3-ethyl 4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}-piperidine-1,3-dicarboxylate was resolved by a Chiral Pak AD preparative column (15% EtOH in Hex) to afford two enantiomers. 1-tert-Butyl 3-ethyl (3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1,3-dicarboxylate was eluted as the slower enantiomer (retention time=26.5 min)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][N:28]=1)[CH3:26])(=O)=O>O1CCCC1.CS(C)=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=3)[CH3:26])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (263 mg, 1.1 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (44.2 mg, 60 wt % in mineral oil, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. A solution of the crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate prepared above in DMSO (6 mL) was added. The mixture was heated to 60° C. for 48 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1-(4′-(trifluoromethyl) biphenyl-4-yloxy)ethyl)nicotinic acid (60 mg). 1H NMR (400 MHz, CD3OD, δ): 8.98 (m, 1H), 8.19-8.21 (m, 1H), 7.54-7.61 (m, 4H), 7.42-7.44 (m, 3H), 6.86-6.89 (m, 1H), 5.42-4.43 (q, 1H), 1.58 (d, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:3](=[O:31])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][S:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:40])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2c(OCCSc3ccccc3Cl)n[nH]c(=O)c2Br)cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2c(OCCS(=O)c3ccccc3Cl)n[nH]c(=O)c2Br)cc1OC
Yield: 82.5 %

Procedure:
To a solution of 0.4 g of 4-bromo-6-[2-(2-chlorophenylthio)ethyloxy]-5-(3,4-dimethoxyphenylmethylamino)-3(2H)-pyridazinone in 30 ml of dichloromethane was added dropwise a solution of 0.15 g of metachloroperbenzoic acid in 5 ml of dichloromethane at 0° C. The excess peracid was decomposed by the addition of saturated aqueous sodium thiosulfate. The mixture was diluted with dichloromethane, washed with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel to give 0.34 g of the objective compound. Yield, 83%, Melting point, 183°-185° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[CH3:27]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[C@H:28]([CH2:26][CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)nn1
Yield: 6.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and (R)-4-ethyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (8 mg) was obtained.
Reaction SMILES: C([C:8]1([CH2:18][C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)(OC(C)(C)C)=O.Cl.[CH3:23]O>>[CH3:23][O:21][C:19](=[O:20])[CH2:18][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)C1(CC(=O)O)NCCc2ccccc21
Agent: Cl
Product: COC(=O)CC1NCCc2ccccc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To Boc-tetrahydoisoquinoline-1-acetic acid (100.4 g, 520.0 mmol) in MeOH (200 mL) is added 400 mL of 2.3 M HCl in methanol. The mixture is stirred overnight and then concentrated to dryness. The resulting residue is dissolved in EtOAc and washed with saturated sodium bicarbonate and brine, which is then dried (Na2SO4) and concentrated to dryness to afford about 109.5 g (100%) of the ester. EIS-MS 206 [M+1]
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][P:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21]
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(NC(=O)C(F)(F)F)cc1C(F)(F)F)OCC
Temperature: 120 °C

Procedure:
A mixture of 1.75 g (5 mMol) N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (WO 2005/051366; Step 14.2) and 1.05 ml (6 mMol) triethylphosphite in 10 ml toluene is heated at 120° C. for 6 h. After cooling, the suspension is filtered and the crystalline solid washed with hexane to give the title compound as a colourless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: Cn1cc(C=O)c2cccnc21
Reactant: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.