Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:16]2[S:15][C:14]3[CH:17]=[C:18]([C:21](O)=O)[CH:19]=[CH:20][C:13]=3CC[C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:32]O.[C:34](OCC)(=[O:36])[CH3:35]>ClCCCl>[O:36]=[C:34]1[C:17]2[C:14]3[S:15][C:16]4=[CH:10][CH2:9][CH2:8][CH:7]=[C:6]4[CH:5]=[C:4]([C:1]([O:3][CH3:32])=[O:2])[C:13]=3[CH:20]=[CH:19][C:18]=2[CH2:21][CH2:35]1
Reactant: CCOC(C)=O
Reactant: CO
Reactant: O=C(O)CCc1cccc2c1Sc1cc(C(=O)O)ccc1CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
6-(2-Carboxyethyl)-10,11-dihydrodibenz-[b,f]thiepin-3-carboxylic acid (328 mg; 1 mmole) was treated with thionyl chloride (6 ml) and after heating the mixture under reflux for 2 hours excess thionyl chloride was removed under vacuum. The residue was dissolved in 1,2-dichloroethane and the solvent was evaporated off to remove the last traces of thionyl chloride. The crude acid chloride dissolved in 1,2-dichloroethane (5 ml) was treated at 0°-5° C. with anhydrous aluminum chloride (100 mg; 0.75 mmole) in 1,2-dichloroethane (2 ml). The mixture was stirred in the ice-bath for 2 hours and then it was treated with methanol (4 ml). The mixture was stirred in the ice-bath for 5 minutes, then at room temperature for 30 minutes and finally at 50° C. for 30 minutes. Ethyl acetate (20 ml) was added and the solution was washed in succession with 2N hydrochloric acid (2×6 ml), water (6 ml), N sodium (2×6 ml) and finally with water (6 ml). Evaporation of the dried (MgSO4) ethyl acetate solution gives 291 mg of crude product which on purification by column chromatography (10 g Merck silica gel eluted with 3% ethyl acetate in methylene chloride) gave 228 mg (70%) of solid m.p. 156°-158° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][CH2:32][O:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:40]=[CH:41][C:34]([O:33][CH2:32][CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:35][CH:36]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3.0 ml) was added 4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (0.031 g, 0.13 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 10%) in ethyl acetate/dichloromethane (v:v; 1:1). afforded a pale yellow solid. This material was triturated with diethyl ether, and the resulting white precipitate was collected by filtration, and successively washed with diethyl ether, water, and diethyl ether, then dried in vacuo (0.014 g, 24%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 2.72 (t, J=5.7 Hz, 2H, OCH2CH2N), 3.59 (t, J=4.7 Hz, 4H, morpholine O(CH2)2), 3.62, (s, 2H, NCH2-pyridyl), 3.68 (br t, 4H, piperazine N(CH2)2), 4.18 (t, J=5.8 Hz, 2H, OCH2CH2N), 7.11 (d, J=8.9 Hz, 2H) and 8.12 (d, J=8.9 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.39 (d, J=5.9 Hz, 2H, pyridine 3-H, 5-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O[CH2:34][CH3:35])(=O)C>COCCOC>[NH2:3][C:2]1[CH:10]=[C:9]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:8]=[CH:34][CH:35]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1

Procedure:
The title compound was prepared as described in example 161 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.7 g, 5.55 mmol), in ethylene glycol dimethyl ether (60 mL), 3-amino boronic acid (1.72 g, 11.10 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.641 g, 0.555 mmol), and potassium phosphate (5.89 g, 27.75 mmol). A second batch was prepared using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.0 g, 6.53 mmol), in ethylene glycol dimethyl ether (70 mL), 3-amino boronic acid (2.025 g, 13.06 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.755 g, 0.653 mmol), and potassium phosphate (6.92 g, 32.65 mmol). The crude compounds were combined and purified by column chromatography using 30% ethyl acetate in hexanes (3.2 g, 82% yield): ES-MS (m/z) 319 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 4-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours whereupon 0.3 g (2.0 mmol) of 4-formylbenzeneboronic acid and 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and heating continued for 16 hours. To this solution was added 5 mL of water and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (50% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane/ethyl acetate, filtered and dried in vacuo at 60° C. to afford 0.5 g (32%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[H][H]>C1COCC1.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:34][S:35]([N:38]([CH3:39])[CH3:40])(=[O:36])=[O:37])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)[CH2:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (45 mg, 0.08 mMol) was dissolved in 3.8 mL of THF and 0.9 mL of methanol added. 10% palladium on carbon (13 mg) was added and the reaction placed under 1 atm (balloon) of hydrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was filtered through a plug of celite and the celite rinsed using dichloromethane. Removal of volatiles from the filtrate in vacuuo yield 47 mg of material which was purified by prep. HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=20 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=10.09 min to 10.88 min. Obtained 33.7 mg (75%) of the title compound as a colorless solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20-1.31 (m, 1.1 H) 1.31-1.52 (m, 2.1 H) 1.66 (d, J=13.12 Hz, 1.1 H) 1.78 (d, J=9.16 Hz, 2.0 H) 1.93 (d, J=13.12 Hz, 1.1 H) 1.96-2.09 (m, 2.9 H) 2.82-2.98 (m, 2.2 H) 3.03-3.08 (m, 6.0 H) 3.11-3.19 (m, 1.0 H) 3.73-3.81 (m, 1.0 H) 3.84 (s, 1.3 H) 3.90 (s, 1.8 H) 3.97-4.02 (m, 0.9 H) 4.05 (dd, J=14.95, 5.80 Hz, 0.7 H) 4.75-4.85 (m, 0.4 H) 4.90 (d, J=14.95 Hz, 0.6 H) 6.84 (d, J=2.44 Hz, 0.4 H) 6.94 (dd, J=8.55, 2.44 Hz, 0.5 H) 6.97-7.01 (m, 1.2 H) 7.09-7.17 (m, 1.0 H) 7.32-7.49 (m, 2.0 H) 7.64 (s, 0.6 H) 7.69 (s, 0.4 H) 7.78-7.87 (m, 1.2 H) 7.90 (d, J=8.55 Hz, 0.4 H) 8.02 (s, 0.4 H) 8.42 (s, 0.5 H) 8.59 (s, 0.4H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.02 min, purity 99%; Flow injection Mass Spectrometry: MS m/z 563(MH+), m/z 561(M-H)−.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]([C@@H:25]([CH:33]3[CH2:35][CH2:34]3)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:19]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH:15]=[CH:16][CH:17]=1.[CH2:43](Br)[CH:44]=[CH2:45]>C1COCC1>[CH2:45]([C@H:22]1[CH2:23][C@H:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)[C@@H:19]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[N:20]([C@@H:25]([CH:33]2[CH2:35][CH2:34]2)[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C:21]1=[O:24])[CH:44]=[CH2:43]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)[C@H](C1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C(=O)OC(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in THF, 0.165 mL, 0.165 mmol) was added dropwise at −78° C. to a solution of (S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate (Example 249, Step C, 71 mg, 0.15 mmol) and allyl bromide (15.54 uL, 0.165 mmol) in 0.5 mL of THF. The reaction was allowed to warm to ambient temperature. After stirring for 2 h, the reaction was quenched with sat. aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution and dried over sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with ethyl acetate/hexane provided the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:22]=[CH:21][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]O)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33][NH2:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:22]=[CH:21][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:34][CH2:33][C:32]4[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=4)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(c1)ncn2-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)ncn2-c1cccc(CNCc2ccc(F)c(F)c2)c1

Procedure:
Compound 27 was prepared from compound 7 by the method described in Example 2. To a solution of compound 27 (3 g, 1.01 mmol) in DMF (30 ml) was added potassium carbonate (2 g; 1.45 mmol) and 3,4-difluorobenzylamine (1.43 ml; 1.2 mmol) and the resultant mixture was stirred at ambient conditions over night. Aqueous work-up followed by column chromatography afforded compound 28a (0.9 g). LC-ESI-HRMS of [M+H]+ shows 422.1697 Da. Calc. 422.167925 Da, dev. 4.2 ppm
Reaction SMILES: [N:1]([O-])=O.[Na+].C(O)(=O)C.[CH3:9][O:10][CH:11]([O:30][CH3:31])[CH:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[NH2:29])[CH3:13]>O.C(COC)OC>[CH3:9][O:10][CH:11]([O:30][CH3:31])[CH:12]([CH3:13])[N:14]1[C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[N:29]=[N:1]1
Reactant: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Solvent: O
Product: COC(OC)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A solution of NaNO2 (34 g, 0.492 mole) in water is added to a cold (3° C.) solution of acetic acid and water. A cold (4° C.) solution of 2-[2-amino-5-(benzyloxy)anilino]-propionaldehyde dimethyl acetal in dimethoxyethane is then added in one portion to the vigorously-stirred NaNO2 acetic acid solution. The reaction temperature rises to 22° C. The reaction mixture is stirred at 18°-22° C. for 20 minutes, cooled to 5° C., and filtered. The solid filter cake is washed with water and dried at 50° C., to give the title product as a white solid, 75.7 g (65.7%). A sample is recrystallized twice from 1:1 toluene-heptane solution to a white solid, mp 101°-103° C. (sinter 100° C.), identified by elemental and NMR analyses.
Reaction SMILES: C[Si](C)(C)CC[O:5][NH:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[C:11](=[O:28])[NH:10]1)=[O:8].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[C:11](=[O:28])[NH:10]1)=[O:8]
Reactant: C[Si](C)(C)CCONC(=O)[C@H]1C[C@@H](c2ccc(OCc3ccccc3)cc2)C(=O)N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1N[C@@H](C(=O)NO)C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension of (2R, 4S)-4-(4-benzyloxyphenyl)-5-oxo-pyrrolidine-2-carboxylic acid (2-trimethylsilanylethoxy)amide (95 mg, 0.22 mmol) in methylene chloride was added boron trifluoride etherate (0.86 μL, 0.68 mmol). The mixture was stirred at room temperature for 75 minutes. During this period the suspended solid dissolved completely and the product precipitated. The mixture was quenched by addition of saturated aqueous NH4Cl solution. The title compound was collected by filtration, washing well with ethyl acetate and water, and dried. The yield was 56 mg (78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC=CC=1C(Cl)=O.COC(=O)CN.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[F:20][C:21]([F:33])([F:32])[O:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Agent: COC(=O)CN
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above. 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid was prepared from 2-trifluoromethoxy-benzoyl chloride, amino-acetic acid methyl ester and trifluoroacetic anhydride. LCMS calcd for C12H5F6NO4 (m/e) 341, obsd 342 (M+H).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1>O.Cl.C(OCC)C>[N:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=1)=[N+:14]=[N-:1]
Reactant: NNc1cccc(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Sodium nitrite (262 mg) dissolved in 1.0 ml of water was dropped, under cooling with ice, into a solution of 500 mg of 3-fluorophenylhydrazine hydrochloride in 2.5 ml of concentrated hydrochloric acid and 3.0 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 3 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 252 mg of the title compound as a brown oily crude product.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCn1ccc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90.5 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.0 g of 2-(indol-1-yl)-ethanol (prepared as described in Preparation 13), 4.81 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.20 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of anhydrous benzene were used, to give 5.69 g of the title compound, melting at 63.5°-65.9° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24]NC(OC(C)(C)C)=O)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C([C:54](OC)=[O:55])=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.COCCBr>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH2:23][CH2:24][O:55][CH3:54])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: COCCBr
Product: COCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 2-bromoethyl methyl ether.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14](Br)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22]([Cu])#[N:23]>CN(C)C=O.O>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:22]#[N:23])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: N#C[Cu]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20 mg, 0.24 mmol) and the mixture was microwaved at 200 C. for 0.5 hours. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (35% EtOAc in hexane, silica) resulted in 10 mg of a clear oil. MS calculated for C15H15F3N2O2+H: 313, observed: 313.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][N:24]2[C:32]3[CH2:31][CH2:30][N:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][C:27]=3[C:26]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[N:25]2)[CH2:17][CH2:16]1)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]([CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][N:24]4[C:32]5[CH2:31][CH2:30][N:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][C:27]=5[C:26]([C:37]5[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][CH:38]=5)=[N:25]4)[CH2:19][CH2:20]3)=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1sc2cc(F)ccc2c1C1CCN(CCCn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirred solution of 635 mg (0.94 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid methyl ester in 10 mL of THF was treated a solution of 53 mg (0.94 mmol) of KOH in 0.5 mL of water. This was stirred overnight, after the hydrolysis was deemed complete 1 mL of 1 N HCl solution was added. This was then extracted with EtOAc (3×30 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated to yield 622 mg (100%) of a white solid. MS (electrospray): exact mass calculated for C31H32F4N4O4S2: 664.18; m/z found, 665.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 8.12 (dd, J=8.81, 5.28 Hz, 1H), 7.83 and 7.76 (A and B of AB quartet, J=8.41 Hz, 4H), 7.17 (br t, J=8.61 Hz, 1H), 4.47 (s, 2H), 4.29 (br s, 1H), 4.16 (t, J=7.04 Hz, 2H), 3.53 (t, J=5.67 Hz, 2H), 3.28 (br m, 4H), 3.00 (s, 3H), 2.96 (m, 2H), 2.73 (br s, 2H), 2.52 (br m, 2H), 2.13 (br m, 2H), 1.76 (br m, 2H).