Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:14][C:15]([F:27])([F:26])[S:16]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[H-].[Na+]>>[F:26][C:15]([F:14])([F:27])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: OCc1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: O=S(=O)(c1ccc(OCc2ccc(SC(F)(F)F)cc2)cc1)C(F)(F)F
Yield: 66.7 %

Procedure:
4-(Trifluoromethylthio)benzyl alcohol (300 mg, 1.44 mmol) was coupled with 4-(trifluoromethylsulfonyl)chlorobenzene (370 mg, 1.51 mmol) using sodium hydride (65 mg, 60% dispersion in oil, 1.58 mmol) to give 400 mg of 4-trifluoromethylthiobenzyl 4-trifluoromethylsulfonylphenyl ether as a white solid. 1HNMR (360 MHz, DMSO-d6) δ 8.06 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.39 (s, 2H, OCH2).
Reaction SMILES: CC1C=C(CC(C2C=CC=CC=2)=O)ON=1.CN(CN(C)C)C.FC(F)(F)C(O)=O.NN.[CH3:32][C:33]1[CH:37]=[C:36]([CH:38]2[CH2:42][NH:41][N:40]=[C:39]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:35][N:34]=1.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[O:60])=[CH:54][CH:53]=1>ClCCl.C(O)(=O)C>[CH3:32][C:33]1[CH:37]=[C:36]([CH:38]2[CH2:42][N:41]([C:59]([NH:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][C:50]([F:49])([F:61])[F:62])=[CH:53][CH:54]=3)=[O:60])[N:40]=[C:39]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:35][N:34]=1
Reactant: Cc1cc(C2CNN=C2c2ccccc2)on1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: CN(C)CN(C)C
Agent: Cc1cc(CC(=O)c2ccccc2)on1
Agent: NN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C2CN(C(=O)Nc3ccc(OC(F)(F)F)cc3)N=C2c2ccccc2)on1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
A mixture of 20 mL of dichloromethane, 2.01 g (10 mmol) of 2-(3-methyl-5-isoxazolyl)-1-phenylethanone and 1.12 g (11 mmol) of N,N,N',N'-tetramethydiaminomethane was prepared and cooled to -15° C. and 1.25 g (11 mmol) of trifluoroacetic acid in 5 mL of dichloromethane was added with cooling and stirring. Stirring was continued for 5 min at about 0° C. and then the mixture was allowed to warm to ambient temperature and stir for another 1.75 hr. A proton NMR spectrum of the mixture was taken which indicated complete disappearance of the starting material. Anhydrous hydrazine (0.96 g, 30 mmol) was added and the mixture was allowed to react with stirring for 2 hr. A proton NMR spectrum of the mixture indicated complete conversion to 4,5-dihydro-4-(3-methyl-5-isoxazolyl)-3-phenyl-1H-pyrazole. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and filtered. 4-(Trifluoromethoxy)phenyl isocyanate (2.19 g, 10.8 mmol ) was then added with stirring. The mixture was allowed to react for 1 hr and then 1 mL of acetic acid was added and the mixture was allowed to react for 5 min. It was then washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure. The resulting solid was extracted with boiling ether and air dried to obtain 3.1 g (72 percent of theory) of the title compound as a white solid melting at 195°-197° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cccc(F)n2)cc1
Temperature: 50 °C

Procedure:
To a solution of 2,6-di-fluoro-pyridine (2.2 g, 1 equiv.) in DMF (20 mL) is added 4-methoxy-benzylamine (5.6 g, 2.2 equiv.) and potassium carbonate (12 g, 4.4 equiv.). After heating at 50° C. for 16 hours, the solution is cooled to rt and filtered through Celite. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using a gradient of hexane:EtOAc (19:1→4:1) to give the title compound.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:30]1[C:34]2[CH:35]=[C:36]([C:39]([N:41]3[CH2:48][CH2:47][C:46]4([CH3:50])[CH2:49][CH:42]3[CH2:43][C:44]3[CH:54]=[CH:53][C:52](OS(C(F)(F)F)(=O)=O)=[CH:51][C:45]=34)=[O:40])[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1>CN(C)C=O.[Cl-].[Na+].O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[S:30]1[C:34]2[CH:35]=[C:36]([C:39]([N:41]3[CH2:48][CH2:47][C:46]4([CH3:50])[CH2:49][CH:42]3[CH2:43][C:44]3[CH:54]=[CH:53][CH:52]=[CH:51][C:45]=34)=[O:40])[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc31)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccccc31)C2
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Palladiumdiacetate (10 mg), triethylamine (0.25 mL), formic acid (93 μL), and triphenylphosphine (16 mg) are added in turn to a solution of trifluoro-methanesulfonic acid 3-(benzothiazole-6-carbonyl)-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester (0.30 g) in dimethylformamide (1 mL) under argon atmosphere. The resulting mixture is stirred at 60° C. for 20 h. After cooling to room temperature, brine is added and the resulting mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine and dried (Na2SO4). The solvent is evaporated under reduced pressure and the residue is purified by HPLC on reversed phase (H2O/MeCN).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B.C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][NH2:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCC1(c2ccc(Br)cc2)CC1
Yield: 93.4 %

Procedure:
Following the procedure outlined for Example 666, 1-(4-bromophenyl)cyclopropane carbonitrile (2.0 g, 9.0 mmol) was reacted with BH3.THF (1.0 M in THF, 50 mL, 50 mmol) to afford the desired product (1.9 g, 94%) as a yellow oil: ESI MS m/z 226 [C10H12BrN+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc(N)c3)ncnc12
Reactant: Clc1ccccn1
Product: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc(Nc4ccccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 549 starting with 4-[1-(3-Amino-phenyl)-3-pyrrolidin-1-yl-propylamino]-quinazoline-8-carboxylic acid amide and 2-chloro-pyridine. LCMS [468.1 (M+1)].
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(COC)[O:14]C>O.C(=O)([O-])[O-].[Ag+2]>[OH:14][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1
Reactant: O=C1CC(Br)c2ccc(F)cc21
Reactant: COCCOC
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C1CC(O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-6-fluoro-1-indanone (2.50 g, 10.0 mmoles) and silver carbonate (4.19 g, 15.2 mmoles, Aldrich) in dimethoxyethane (85 mL) and water (65 mL) was stirred overnight at ambient temperature. The mixture was filtered through a pad of celite, and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (4×100 mL). The combined extracts were washed with water (100 mL) and brine (75 mL), dried over sodium sulfate, filtered, and evaporated in vacuo to give 2.80 g (quantitative) of crude 3-hydroxy-6-fluoro-1-indanone which was used without further purification. Chromatography of 0.41 g on silica gel, eluting with hexane: ethyl acetate (3:4) gave 0.050 g of analytically pure 3-hydroxy-6-fluoro-1-indanone as a tan solid, mp 73°-76° C.;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([CH2:28][CH2:29][N:30]4C(=O)C)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1>Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([CH2:28][CH2:29][NH:30]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CC(=O)N1CCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc21
Agent: Cl
Solvent: CO
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc4c(c3)NCC4)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 156, but using 1-(6-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)ethanone, obtained in Step 1, (101 mg; 0.22 mmol). The solvent was removed in vacuo to afford a purple oil which was dissolved in HCl (1 M, 1 mL) and MeOH (1 mL). The solution was passed through an SCX column eluting with MeOH (50 mL) followed by NH3 (1 M in MeOH, 50 mL). The solvent was removed in vacuo from the fractions containing product to afford Example 157 as a yellow solid. 1H NMR: (DMSO-d5, 400 MHz) δ 8.74 (2H, d, J=5.2 Hz), 7.90 (1H, t, J=7.7 Hz), 7.77-7.68 (1H, m), 7.60 (2H, d, J=5.2 Hz), 7.55-7.41 (2H, m), 7.24-7.15 (2H, m), 7.10-6.95 (1H, m), 5.89 (1H, s), 3.56-3.44 (2H, m), 3.01 (2H, t, J=8.6 Hz). LC/MS (Method C): 426 (M+H)+. HPLC (Method I) Rt 14.83 min (Purity: 95.2%).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[S:22]1[CH:23]=[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]1=2
Reactant: Brc1csc2ccccc12
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1csc3ccccc13)O2
Reaction time: 96 h
Yield: 45.5 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 6.4 g (30 mmol) of 3-bromobenzo[b]thiophene, 0.4 g of triphenylphosphine, 95 mg of cuprous iodide, 6 ml of triethylamine and 150 ml of acetonitrile was degassed with argon for 15 minutes. Palladium acetate, 110 mg, was then added and stirring at room-temperature was continued for 4 days. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was chromatographed over 200 g of silica gel using methylene chloride/hexane 1:1(v/v) for elution. Crystallization of the combined clean fractions from ether/hexane yielded 3.3 g (45.5%) of colorless crystals with m.p. 123°-124° C. A lower melting modification with m.p. 88°-91° C. was also observed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:15]1([C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccc(NC(=O)C3CC3)cc2)=NN1
Yield: 61.3 %

Procedure:
6.0 g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone and 4.0 g (38.3 millimoles) of cyclopropanecarboxylic acid chloride in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 5.0 g (61% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 272°-273° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-])=[CH:4][N:3]=[CH:2]1.C[Si]([C:17]#[N:18])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[O:1]1[C:5]([C:6]2[N:7]=[C:8]([C:17]#[N:18])[CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: [O-][n+]1ccccc1-c1cnco1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1cccc(-c2cnco2)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 74.4 %

Procedure:
2-(1,3-Oxazol-5-yl)pyridine N-oxide (1.0 g, 6.6 mmol) was dissolved in nitroethane (15 ml), and trimethylsilyl cyanide (2.7 g, 27.2 mmol) and N,N-dimethylcarbamoyl chloride (3.0 g, 27.8 mmol) were added thereto. The mixture was stirred at room temperature for 5 days. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.84 g, 75%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:3]1[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:3]1[CH:4]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1cc(-c2cccs2)ccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1cc(-c2cccs2)ccc1=O
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(2-oxo-5-(thiophen-2-yl)pyridin-1(2H)-yl)ethylcarbamate (125 mg, 390 μmol) in CH2Cl2 (1 mL) was added TFA (5 mL) and stirred for 30 min at 23° C. Solvents removed under reduced pressure and residue partioned between CH2Cl2 (10 mL) and 1M NaOH (5 mL). The organic layer was dried over MgSO4 and reduced to a brown oil under reduced pressure. MS (ESI pos. ion) m/z (MH+): 221 (MH+). Calc'd exact mass for C11H12N2OS: 220.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:16]([CH3:19])=[N:17][CH:18]=3)[CH2:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[N:12]([C:16]([CH3:19])=[N:17][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C2=CCCn3c2cnc3C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1ccc(-c2cccn3c(C)ncc23)cc1

Procedure:
Combine 15 g (59 mmol) of the product of Example IV with 150 g of manganese dioxide in 500 ml of methylene chloride and heat at reflux for 24 hr. Filter off the solids and remove the solvents under vacuum. Crystallize the residue from ethyl acetate to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:46][C@H:47]([OH:48])[CH3:49])[CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:37])=[O:38])[C:17]3=[N:18][CH:19]=2)[CH:3]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 79 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 179) (170 mg, 0.272 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.544 mmol), DIPEA (105 mg, 0.812 mmol) and ethanol (5 mL) to get 147 mg (79% yield) of the titled compound. MS: m/z=684.2 (M+1).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCCCCCCCC(O)/C=C/C(O)CCCCCC(O)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCC(O)/C=C/C(O)CCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
Microbial conversions of unsaturated fatty acids have been widely exploited to produce new, value-added products. Hou, (C. T Hou, “Microbial Oxidation of Unsaturated Fatty Acids”, Advances in Applied Microbiology Vol. 41, pp. 1-23, 1995) recently reviewed the work on some biological oxidation systems. Wallen et al., (L. L. Wallen et al., “The Microbiological Production of 10-Hydroxystearic Acid from Oleic acid”, Arch. Biochem. Biophys. 99:249-253, 1962) reported the first bioconversion of oleic acid to 10-hydroxystearic acid by a Pseudomonad. The bioconversion of fatty acids to produce mono-, di-, and tri-hydroxy unsaturated fatty acids has also been found (A. C. Lanser et al., “Production of 15-, 16- and 17-Hydroxy-9-Octadecenoic Acid from Oleic Acid with Bacillus pumilus”, J. Am. Oil Chem. Soc. 69:363-366, 1992), (C. T. Hou et al., “A Novel Compound, 7,10-Dihydroxy-8(E)-Octadecenoic Acid from Oleic Acid by Bioconversion”, J. Am. Oil Chem. Soc. 68:99-101, 1991), (C. T. Hou et al., “Production of a New Compound, 7,10-Dihydroxy-8(E)-Octadecenoic Acid from Oleic Acid by Pseudomonas sp. PR3”, J. Indust. Microbial. 7:123-130, 1991) and (C. T. Hou et al., “A Novel Compound, 12,13,17-Trihydroxy-9(Z)-Octadecenoic Acid, from Linoleic Acid by a New Microbial Isolate Clavibacter sp. ALA2”, J. Am. Oil Chem. Soc. 73:1359-1362, 1996). The production of a novel compound, 7,10-dihydroxy-8(E)-octadecenoic acid (DOD) from oleic acid by strain PR3 has been described most extensively. Under optimal conditions, the yield of bioconversion is greater than 60%, (C. T. Hou et al., “Production of a New Compound, 7,10-Dihydroxy-8(E)-Octadecenoic Acid from Oleic Acid by Pseudomonas sp. PR3”, J. Indust. Microbiol. 7:123-130, 1991). PR3 is a strain of Pseudomonas aeruginosa, and its DOD production is inversely correlated with the accumulation of phenazine 1-carboxylic acid (PCA), (C. T. Hou et al., “Identification of NRRL Strain B-18602 (PR3) as Pseudomonas Aeruginosa and Effect of Phenazine-1-Carboxylic Acid Formation on 7,10-Dihydroxy-8(E)-Octadecenoic Acid Accumulation”, World J. Microbiol. Biotechnol. 9:570-573, 1993). The production of DOD and PCA by strain PR3, however, was not consistent, and studies were conducted to stabilize and maximize cultures for the bioconversion of oleic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([OH:3])=O.O>S1(CCCC1)(=O)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[C:17]=2[CH:16]=1
Reactant: Cc1ccc(C=Cc2ccccc2C(=O)O)cc1
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Cc1ccc2c(c1)C(=O)c1ccccc1CC2
Yield: 87.2 %

Procedure:
The acid from Step A (37.5 g) in sulfolane (200 ml) was heated to 110° C. and polyphosphoric acid (150 ml) added. After 1.5 hr at 110° C. the mixture was poured into water (500ml). extracted with hexane (3×200 ml) and the extract washed, dried, diluted with an equal volume of ether and percolated through silica (200 g). The eluate Was evaporated to afford 3-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (30.5 g) as an oil. 60MHz NMR in deuterochloroform 2.35 (CH3), 3.20 ppm [(CH2)2 ].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:33]1[N:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:39])[NH:21][C:9]4[CH:10]=[C:11]([C:14]5[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:36]=[C:35]([CH3:37])[N:34]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K59) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (54 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][C@H:45]([CH3:47])[O:44][C@H:43]([CH3:48])[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][C@H:45]1[O:44][C@@H:43]([CH3:48])[CH2:42][N:41]([CH2:40][CH2:39][NH:38][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:37])[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]2)=[O:36])[CH2:46]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: C[C@@H]1CN(CCN)C[C@H](C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2F)C[C@H](C)O1
Yield: 94.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.20 g, 0.36 mmol) was reacted with 4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood) (0.20 g, 1.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.60 g, 4.6 mmol) in CH2Cl2 (20 mL) at room temperature for 20 hrs to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-ethyl]-amide as a white solid (0.20 g, 94%). HRMS (ES+) m/z Calcd for C31H39Cl2FN4O2+H [(M+H)+]: 589.2507. found: 589.2507.