Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:21])[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35]([NH:34][C:25]4[CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=[CH:29][C:24]=4[F:23])=[O:36])=[C:3]([F:22])[CH:4]=3)=[CH:9][N:10]=2)([OH:21])[CH2:14][CH2:15]1)[CH3:20]
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)s2)CC1
Reaction time: 1 h

Procedure:
To an ambient solution of Example 8B (0.02 g, 0.062 mmol) in tetrahydrofuran (1 mL) was added 2-fluoro-5-trifluoromethylphenylisocyanate (0.010 g, 0.065 mmol). After 1 h, the mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min). The fractions containing the desired product were diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01 (t, J=7.1 Hz, 3H), 1.73 (br d, J=11.9 Hz, 2H), 2.08 (dt, J=11.9 and 3.7 Hz, 2H), 2.25-2.37 (m, 4H), 2.64-2.73 (m, 2H), 6.15 (s, 1H), 7.33-7.52 (m, 3H), 7.61 (m, 1H), 8.05 (s, 1H), 8.24 (m, 1H), 8.64 (m, 1H), 8.90 (s, 1H), 9.34 (s, 1H); MS (ESI) m/z 527 [M+H]+.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH3:8]COCC.[NH2:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:22]=[C:23]([C:43](=[O:45])[CH3:44])[CH:24]=[N:25][C:26]=2[NH:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:33]=2)[N:15]=1>C1COCC1.CCOC(C)=O>[NH2:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:22]=[C:23]([C:43]([OH:45])([CH3:8])[CH3:44])[CH:24]=[N:25][C:26]=2[NH:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:33]=2)[N:15]=1
Reactant: CC(=O)c1cnc(Nc2cncc(S(=O)(=O)c3ccccc3)c2)c(-c2nc(C)nc(N)n2)c1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)(C)O)cnc2Nc2cncc(S(=O)(=O)c3ccccc3)c2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To cerium(III) chloride (304 mg, 1.235 mmol) was added THF (4.1 mL) and the resulting mixture was heated to 40° C. for 1 h. The reaction mixture was then cooled to −78° C. and methylmagnesium bromide in ether (3.0 M, Aldrich; 1372 μL, 4.12 mmol) was added. The resulting mixture was stirred at −78° C. for 15 min. 1-(5-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-(phenylsulfonyl)pyridin-3-ylamino)pyridin-3-yl)ethanone (190 mg, 0.412 mmol) in THF (4.1 mL) was then added, and the resulting mixture was stirred at −78° C. for 4 h. The reaction mixture was subsequently diluted with 100 mL of EtOAc, added to a separatory funnel, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was separated, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2 M ammonia in MeOH)/DCM) provided the title compound (36% yield) as a light yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.38 (s, 1H) 9.18-9.23 (m, 1H) 9.06 (d, J=2.35 Hz, 1H) 9.00 (d, J=2.35 Hz, 1H) 8.67 (d, J=2.15 Hz, 1H) 8.53 (d, J=2.54 Hz, 1H) 8.02-8.08 (m, 2H) 7.98 (br. s., 1H) 7.79 (br. s., 1H) 7.71-7.77 (m, 1H) 7.64-7.71 (m, 2H) 5.22-5.26 (m, 1H) 2.46 (s, 3H) 1.51 (s, 6H). m/z (ESI, +ve ion) 478.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:1]1([N:7]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-n2cccn2)cc1
Product: CC(=O)c1cnn(-c2ccccc2)c1

Procedure:
1-Phenyl-4-acetyl-pyrazole was prepared by acetylation of 1-phenyl-pyrazole with acetic anhydride according to the procedure described in Chemical Abstracts Vol. 63, 16332.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:46][C:47]([F:54])([F:53])[CH:48]([CH3:52])[CH2:49][CH2:50]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:50][CH2:49][CH:48]([C:47]([F:54])([F:53])[F:46])[CH3:52])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(CCO)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (189 mg, 0.5 mmol), Ph3P (262 mg, 1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF (25 mL) was added dropwise a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, (yield: 180 mg 71%). mp 126-128° C. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m, 1H), 3.29 (s, 3H), 4.46 (m, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 503 (M+H)+; (APCI−) m/z 537 (M+Cl)−. Anal. calc. for C22H19F5N2O4S: C, 52.59; H, 3.81; N, 5.57. Found: C, 52.70; H, 3.73; N, 5.63.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:15])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:15][C:5]1[N:4]=[N:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][C:22]=2[O:27][CH3:28])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1nnc(Cl)c(Nc2ccccc2)n1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine (1 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (1 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 h in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])=[CH:10][C:4]=2[O:3]1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:15]=[C:13]([CH:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:16])[O:3][C:4]=3[CH:10]=2)[O:14][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Solvent: Cc1ccccc1
Product: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1

Procedure:
6.90 g (30.4 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide, 4.76 g (37.5 mmol) 1,3-dichloro acetone and 50 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 60 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 4-Chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole.
Reaction SMILES: [CH2:1]([OH:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:21]=1>C(Cl)Cl>[CH:1](=[O:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:21]
Reactant: c1cc[nH+]cc1
Reactant: CCCCCCCCCC/C=C/CO
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C=O

Procedure:
To dodecyl aldehyde (5.0 g) dissolved in methylene chloride was added (carbomethoxymethylene)triphenylphosphorane (9.1 g), and the mixture was stirred for 2 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans-2-tetradecenoic acid (5.2 g). To the methyl ester dissolved in tetrahydrofuran was added lithium aluminium hydride (0.9 g) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give trans-2-tetradecenol (3.2 g). To the solution of the trans-2-tridecenol in methylene chloride were added pyridinium chlorochromate (3.5 g) and Celite (5.0 g), and the mixture was stirred. The reaction mixture was filtered and concentrated to give trans-2-tetradecenal (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)[nH]n2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccc4)CC3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]piperidine (INTERMEDIATE 7, 4 g, 15.28 mmol) in 60 mL DMF was added K2CO3 (63 g, 45.8 mmol), and 2-(bromoethyl)benzene (2.3 mL, 16.8 mmol). The reaction mixture was stirred at ambient temperature overnight, diluted with EtOAc, and washed three times with water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. LC-MS m/z=366.17 [M+1]+.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C(N(CC)CC)C>[CH:8]([NH:21][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)(C)Br
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C(C)(C)NC(c1ccccc1)c1ccccc1

Procedure:
To the above-obtained 3-bromo-3-methylbutan-2-one (5.88 g) in methanol (30 mL), benzhydrylamine (5.0 mL) and triethylamine (7.5 mL) were added. The resultant mixture was stirred at 70° C. for 24 hours, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and to the solid, diethyl ether was added, and then insoluble matter was removed by filtration. The mother liquid was brought to the dryness under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 3-(benzhydrylamino)-3-methylbutan-2-one as an oily product (3.3 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.927 g, 2.42 mmol) (from example 130, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.097 g, 2.42 mmol) dissolved in water (0.800 mL) was added over 7 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.148 mL, 2.42 mmol) was added over 4.5 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (12.45 mL, 74.71 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.648 g, 76%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.45-2.12 (m, 4H), 2.80-3.35 (m, 4H), 3.35-3.70 (m, 3H), 4.12 (s, br., 1H), 4.62 (s, br., 1H), 5.71 (s, 1H), 6.77 (t, 1H), 6.87 (s, br., 2H). MS m/z 353 (M+H)+
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Methyl iodide (55.2 g, 389.2 mmol) was added dropwise to a stirred mixture of 3-hydroxy-4-nitrobenzaldehyde (50 g, 288.4 mmol) and potassium carbonate (53.8 g, 389.2 mmol) in DMF (250 ml). The reaction mixture was stirred overnight, poured into ice-cold water, and the precipitated solid was collected by filtration. The resulting solid was dried on a high vacuum overnight to obtain 53.4 g of 3-methoxy-4-nitrobenzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[S:38]([CH3:37])(=[O:40])=[O:39])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3S(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-((E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 92, step A) and methanesulfonyl chloride analogous to Example 192, step B.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([O:16]C)=[CH:8][CH:7]=1.O.[OH-].[Na+]>ClCCl>[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([OH:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(Cl)c(C(=O)O)c1F
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1c(Cl)ccc(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
Boron tribromide (1.5 ml, 15.3 mmol) was added dropwise to a solution of 6-chloro-2-fluoro-3-(methyloxy)benzoic acid (intermediate 33, 1.04 g, 5.1 mmol) in dichloromethane (100 ml) at 0° C. under an atmosphere of Argon. The reaction was stirred at room temperature for 18 hrs. Water (5 ml) was added and the solid formed stirred for 5 mins. Sodium hydroxide (2M, 4 ml) was added and the remaining solid dissolved. The layers were separated and the aqueous layer evaporated to afford a colourless solid. This was extracted with ethyl acetate (3×) and the combined organics evaporated to afford the title compound as a yellow solid (831 mg). 1H-NMR δ 7.02 (1H, t, J 10), 7.16 (1H, dd, J 10, 3), 10.48 (1H, s), 13.96 (1H, br s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.ClCCl>C(O)C>[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C2OCCO2)c(C)cc1NC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a 500 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (17.0 g, 58 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (13.1 g, 52.9 mmol). Ethanol (150 mL) and dichloromethane (150 mL) were added to form a slurry. The reaction mixture was heated at 50° C. to 55° C. for about 24 hours and then cooled to room temperature. Most of the solvent was removed on a rotary evaporator, resulting in a thick slurry. Ethanol (reagent grade) was added to form a total volume of about 200 mL and the resulting mixture was heated to 80° C. and then cooled slowly to room temperature. The resulting thick white slurry was filtered, washed with ethanol (20 mL) and dried in vacuum to provide biphenyl-2-ylcarbamic acid 1-[2-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (23.8 g, about 98% purity) as a white solid.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3OC)[CH2:17][CH2:16]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]1(O)C2CCCCC=2C=CC=1.ClCCCN1CCN(C2C=CC=CC=2OC)CC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:29][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:17]1
Reactant: COc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1
Reactant: Oc1cccc2c1CCCC2
Agent: COc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3)CC1

Procedure:
1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-propyl]-4-(2-methoxyphenyl)-piperazine from 5,6,7,8-tetrahydro-1-naphthol and 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine; yield 48% of theory; m.p. of the dihydrochloride 202°-203°C. (decomp.).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylamine (1.3 mL, 20.0 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) were combined in CH2Cl2 (200 mL) and cooled to 0° C. Benzyl chloroformate (2.86 mL, 20.0 mmol) was added dropwise, and the reaction was stirred at 0° C. for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was warmed to room temperature and washed with H2O, 0.1N aqueous HCl, and H2O, and then dried and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1.CC#N>CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[CH2:3][C:4]1[N:5]([CH2:28][C:29]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[O:31][N:30]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.080 g, 0.27 mmol), K2CO3 (0.042 g, 0.30 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.143 g, 0.54 mmol) and CH3CN (5 mL) was stirred at 60° C. for 6 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.031 g, 22%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.69-7.63 (m, 2H), 6.94 (s, 1H), 5.56 (s, 2H), 3.96 (q, 2H); MS m/z 517 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(Cl)Cl>[C:2]1([NH:1][C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Aniline (2.03 g, 25.0 mmol) was dissolved in CH2Cl2 (30 mL). To the solution were added pyridine (2.22 mL, 27.5 mmol) and decanoyl chloride (5.25 g, 27.5 mmol) in an ice bath. After stirring for 3 h at room temperature, the reaction mixture was poured into 1M HCl (30 mL) and the mixture extracted with CH2Cl2 (3×100 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated to give 5.62 g (22.8 mmol, 91%) of N-phenyldecanamide as a white solid, mp 65-66° C. (lit5 mp 65-66° C.); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=6.9 Hz), 1.26 (m, 12H), 1.72 (m, 2H), 2.35 (t, 2H, J=7.8 Hz), 7.10 (t, 2H, J=7.8 Hz), 7.31 (t, 1H, J=7.8 Hz) 7.50 (t, 2H, J=7.9 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.5, 25.7, 29.2, 29.2, 29.3, 29.3, 31.7, 37.5, 120.1, 124.0, 128.7, 138.1, 172.3.