Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29]Cl)=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C-:31]#[N:32].[Na+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][C:31]#[N:32])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(CCl)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(CC#N)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (0.83 g) and sodium cyanide (0.12 g) in DMF (10 ml) was stirred for 22 hours at room temperature. To the reaction mixture was added water and this mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was crystallized from ethyl acetate to givecolorless prisms (0.76 g, 94%), m.p. 180°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][CH:21]([F:25])[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:20][CH:21]([F:25])[C:22]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:23]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C(F)F)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol), 2,2-difluoroacetic acid (171 mg, 1.78 mmol), 4-(Dimethylamino)pyridine (18 mg, 0.15 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (676 mg, 1.78 mmol) were dissolved in pyridine (20 mL). After the reaction mixture was stirred at room temperature overnight, water (1 mL) was added and it was extracted with ethyl acetate. It was concentrated and purified by prep-HPLC to give the desired product (59.6 mg). LCMS (ESI): RT (Min)=1.161, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.22 (s, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.44 (t, J=54.0 Hz, 1H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1C#N>C(#N)C1C=CC=CC=1>[CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[C:4][C:16]1[O:15][CH:19]=[CH:18][CH:17]=1
Reactant: C#CC(C)(C)C
Reactant: N#Cc1ccco1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CC(C)(C)C#Cc1ccco1
Reaction time: 16 h
Yield: 91 %

Procedure:
The procedure was identical to Example 1, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 16 h at 65° C. showed the presence of 1.82 mmol (91% yield) of 2-(3,3-dimethyl-1-butynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[CH3:26][CH2:27][C:28](=O)[CH2:29][CH3:30].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(CC)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(C)cn2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 39.2 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess 3-pentanone (1.32 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol furnished 0.21 g (39%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH:10]([O:13][CH3:14])OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)[Cl:36]>C(Cl)(=O)C.II>[Cl-:36].[CH2:1]([O:8][C:9]([CH:10]([P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:13][CH3:14])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(=O)OCc1ccccc1
Reactant: ClCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: II
Solvent: CC(=O)Cl
Product: COC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
Methyl dimethoxyacetate (1.094 g, 8.15 mmol) and LiOH (420 mg, 10 mmol) were dissolved in 5 ml dioxane and 5 ml water at 0° C. and the reaction mixture stirred 30 minutes at 0° C. and 0.75 hours at r.t. It was then diluted with tBuOMe and washed with NaOH 1M/ice. The aqueous layer was acidified to pH 2 and extracted three times with AcOEt, the combined organic phases dried over Na2SO4 and evaporated to give the dimethoxy-acetic acid as a yellow oil (600 mg). Dimethoxy-acetic acid (8.86 g, 73.8 mmol), obtained from an analogous preparation, was dissolved in 100 ml acetonitrile at 0° C., benzylalcohol (7.3 ml, 70 mmol), EDCI (15 g, 80 mmol) and DMAP (855 mg, 7 mmol) were added and the reaction mixture kept at r.t. during 18 hours. It was then diluted with AcOEt, washed with water, HCl 1M, brine, Na2CO3 (10%) and brine again and the combined organic phases were dried over Na2SO4 and evaporated to give dimethoxy-acetic acid benzyl ester (10.4 g). To crude dimethoxy-acetic acid benzyl ester (4.86 g), were added acetylchloride (2 ml) and iodine (100 mg) as catalyst and the mixture was heated during 4 hours at 65° C., evaporated after addition of 100 ml of ether, diluted with 10 ml CH2Cl2 and added to a solution of triphenylphosphine (25 mmol, 6.63 g) in 50 ml CH2Cl2 and stirred 24 hours at r.t. A chromatography (silicagel; 0.6 kg; elution AcOEt and 1/1 AcOEt/ethanol) provided (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride as a white foam (6.87 g, 62%).
Reaction SMILES: [N:1]#[C:2][SH:3].[C:4]1([CH:10]([OH:15])[CH2:11][N:12]2[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CC1.[ClH:19]>C(O)C>[ClH:19].[OH:15][CH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][N:12]1[CH2:14][CH2:13][S:3][C:2]1=[NH:1]
Reactant: N#CS
Reactant: OC(CN1CC1)c1ccccc1
Agent: C1CN1
Agent: Cl
Solvent: CCO
Product: N=C1SCCN1CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the stirred solution of thiocyanic acid is added a solution of the crude dl-α-phenyl-1-aziridineethanol in 250 ml. of ethanol at a rate sufficient to keep the reaction temperature at 30°-35° C. After the aziridine addition is complete, 72 g. of a methanolic solution of hydrogen chloride (0.35 mole) is added and the solution stirred for 1.5 hours at room temperature. An additional 0.05 mole of hydrogen chloride in 10 g. of ethanol is added, and the reaction heated at 35°-40° C. for 0.5 hour. It is then allowed to proceed at room temperature for 2.5 days. The mixture is concentrated under reduced pressure to about 100 ml., filtered, washed with ethanol and dried to give 27.1 g. of white crystals, melting point 198°-200° C. The yield is 42% (based on styrene oxide) or 71% (based on dl-α-phenyl-1-aziridineethanol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]2=[O:31])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O-])([O-])=O.[Na+].[Na+].[CH3:40][C:41]#N>>[CH2:1]([O:8][C:9](=[O:33])[NH:10][C@H:11]1[CH2:16][CH2:15][N:14]([CH:41]([CH3:40])[CH3:34])[CH2:13][C@H:12]1[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]2=[O:31])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: O=C(N[C@H]1CCNC[C@H]1NC(=O)c1ccc(-n2ccccc2=O)cc1)OCc1ccccc1
Agent: [Na+]
Product: CC(C)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Cis-{3-[4-(2-Oxo-2H-pyridin-1-yl)-benzoylamino]-piperidin-4-yl}-carbamic acid benzyl ester (0.26 mmol) was dissolved in CH3CN (1.5 ml). Iodoisopropane (0.04 mL) was added, followed by the addition of Na2CO3 (70 mg). The resulting mixture was stirred at 80° C. overnight. After cooling, it was extracted with EtOAc (3×), dried over MgSO4, filtered, and concentrated to dryness to give crude cis-{1-isopropyl-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidin-4-yl}-carbamic acid benzyl ester (115 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=3)=[CH:11][CH:10]=2)[C:5](=[O:23])[CH2:4][O:3]1.[CH3:24][NH2:25]>CO.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][C:2](=[O:1])[O:3][CH2:4][C:5]([NH:25][CH3:24])=[O:23])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: N#Cc1cccc(-c2ccc(CCN3C(=O)COC3=O)cc2)c1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(-c2cccc(C#N)c2)cc1
Yield: 48.6 %

Procedure:
2.0 g (6.53 mmol) of 4′-[2-(2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]-3-biphenylcarbonitrile, prepared in step 11.2., are dissolved in a mixture of 13 ml of methanol and 9.8 ml of a 2N solution of methylamine (19.6 mmol) in tetrahydrofuran. The solution is left to react overnight and then evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 96/4 then 95/5 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.07 g of product in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:11]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=2[C:13]#[N:14])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:20].CCOC(C)=O>CO>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:10])[C:12]=1[C:13]#[N:14]
Reactant: Cc1cc(C)cc(S(=O)c2cccc(F)c2C#N)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(S(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Yield: 59.2 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfinyl]-6-fluorobenzonitrile (Example 19) (0.4 g, 1.5 mmol) was dissolved in 40 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to 150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.24 g (61%) of 2-amino-6-[(3,5-dimethylphenyl)sulfinyl]benzonitrile: mp 190°-191° C.; NMR (Me2SO-d6, 200 MHz) δ 2.32 (s, 6H), 6.48 (br s, 2H), 6.90 (apparent d, 1H), 7.11 (apparent d, 1H), 7.20 (m, 1H), 7.32 (m, 2H), 7.52 (apparent t, 1H); mass spec (CI) M+ +1=271. Anal. Calc. for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S, 11.86. Found: C, 66.71; H, 5.27; N, 10.32; S, 11.84.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2O)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])[CH3:3].[ClH:23]>>[Cl:23][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[S:11][C:9]1[CH:10]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1
Reactant: Cl
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(SC2CCCC2Cl)cc(C(C)(C)C)c1O

Procedure:
The product of Example 7 (0.40 g, 0.0012 mole) was stirred with concentrated hydrochloric acid (5 ml) at room temperature for 20 hours. The solid was removed by filtration, washed with water and air dried to give the product as a white powder. The product was purified by silica gel chromatography to give a white solid. The structure was supported by NMR.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]([CH2:21][NH2:22])O>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH2:2]([C:1]1[O:18][CH2:19][CH2:21][N:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure described in Example 2, palmitic acid was reacted with ethanolamine in the presence of titanium tetrabutylate to form 2-pentadecyl-2-oxazoline. The quantities used were as follows:
Reaction SMILES: [C:1]1(C)[CH:6]=CC=C[CH:2]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.CC(C)=O>[Pt].O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:1]([CH3:6])[CH3:2])=[CH:11][CH:10]=1
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pt]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
520 parts of toluene, 423 parts (3 mol) of 4-fluoronitrobenzene, 192 parts (3.3 mol) of acetone and 8 parts of catalyst (5% Pt on charcoal, water-moist, water content 50%) are placed in a hydrogenation autoclave. After the gas space has been flushed three times with each of nitrogen and hydrogen, the mixture is heated to from 80°=0 to 85° C. with stirring and reduced at a hydrogen pressure of from 0.2 to 1.0 MPa. When after about 2 hours the uptake of hydrogen falls sharply, the pressure is raised to 2.0 MPa and stirring is continued at 85° C for 30 minutes until there is no longer any drop in pressure. The batch is cooled to 60° C., the autoclave is let down and flushed with nitrogen, and the catalyst is filtered off on a pressure filter at from 50° to 60° C. The aqueous phase is separated off from the filtrate and toluene is distilled off until the water content of the solution is <0.02%. The solution is processed further in accordance with Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([C:15]([CH3:17])=[CH2:16])[CH:5]=1)([O-])=O.O>C1(C)C=CC=CC=1.Cl.[Fe]>[CH2:16]=[C:15]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:11]([F:12])([F:14])[F:13])[NH2:1])[CH3:17]
Reactant: C=C(C)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc(N)ccc1OC(F)(F)F
Yield: 95.4 %

Procedure:
To a solution of 4-nitro-2-(prop-1-en-2-yl)-1-(trifluoromethoxy)benzene (275 mg, 1.11 mmol) in toluene (9.85 mL) was added iron (1.24 g, 22.25 mmol) and concentrated HCl (3.38 μL, 0.11 mmol) (3 drops). The mixture was stirred vigorously under reflux and water (0.20 mL, 11.13 mmol) was added and the r×n was stirred at reflux for 2 hr. The crude mixture was filtered through celite and concentrated under reduced pressure. The crude was diluted with EtOAc and dried with Na2SO4, filtered and concentrated under reduced pressure to give 3-(prop-1-en-2-yl)-4-(trifluoromethoxy)aniline (230 mg). LCMS retention time=1.46 minutes (LC method 5); MS (m+1)=218.2.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[C:8]([O:26][C@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[O:33][CH3:34])[CH:7]=1.O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42]>CN(C=O)C.CCOC(C)=O>[O:42]=[C:37]1[CH2:38][CH2:39][C:40](=[O:41])[N:36]1[O:24][C:23]([C:20]1[S:19][C:15]2[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=3[O:26][C@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[O:33][CH3:34])[C:14]=2[C:21]=1[CH3:22])=[O:25]
Reactant: O=C1CCC(=O)N1O
Reactant: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)ON3C(=O)CCC3=O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (53 mg, 0.28 mmol) was added to a mixture of 0.100 g 4-[4-fluoro-2-((1S,2S)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd.42.2) and 0.040 g N-hydroxysuccinimide in 1 ml DMF. And stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was passed through a hydrophobic frit and concentrated.
Reaction SMILES: C(OC(C)C)(C)C.[F:8][C:9]([F:25])([F:24])[C:10]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])([OH:15])[C:11]([F:14])([F:13])[F:12].[H][H]>[Ru].O>[F:8][C:9]([F:24])([F:25])[C:10]([CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH:17]1[OH:23])([OH:15])[C:11]([F:12])([F:14])[F:13]
Reactant: Oc1ccc(C(O)(C(F)(F)F)C(F)(F)F)c(O)c1
Reactant: [H][H]
Agent: [Ru]
Solvent: CC(C)OC(C)C
Solvent: O
Product: OC1CCC(C(O)(C(F)(F)F)C(F)(F)F)C(O)C1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A 2,000 ml inner capacity of pressure-resistant reactor having a stirrer and a thermometer and formed of SUS316 was charged with 800 ml of diisopropyl ether, 350 g (1.27 mol) of Compound 6 and 17.5 g of 5% Ru/C (a substance containing 50% of water, produced by N.E. CHEMCAT), and then closed. Thereafter, stirring was started and then the interior of the reactor was substituted with hydrogen, followed by setting hydrogen pressure at 3.0 MPa. The temperature of the reactor was increased up to 130° C., upon which stirring was continued for 20 hours.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)([CH3:13])[CH2:11][CH:10]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9][CH:8]=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][OH:55].C(N(CC)CC)C.CN([CH:66]=[O:67])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:25][CH:10]1[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:23])([F:22])[F:24])[CH:15]=2)([CH3:13])[C:7]([C:54]([O:67][CH3:66])=[O:55])=[CH:8][CH2:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)C=O
Reactant: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(OCc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCC(OCc2ccccc2)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 23 h
Yield: 78 %

Procedure:
A solution of (4RS,6RS)-4-(benzyloxy)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enyl trifluoromethanesulfonate (91 mg, 0.172 mmol) in DMF (1 mL) was treated with triphenylphosphine (9 mg, 34 μmol), methanol (279 μl, 6.88 mmol) and triethylamine (48 μl, 344 μmol). The resulting mixture was bubbled with nitrogen for 5 min and then palladium (II) acetate (4 mg, 17 μmol) was added. Upon completion of addition, the resulting solution was bubbled with carbon monoxide for 5 min and then stirred under a carbon monoxide balloon at 70° C. for 23 h. After this time, the mixture was cooled to rt and diluted with ether. The resulting mixture was washed twice with water and once with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 5-50% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-4-(benzyloxy)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enecarboxylate as a yellow gum (59 mg, 78%). Mass spectrum m/z 456 (M+NH4+), 492 (M+OAc−). 1H NMR (400 MHz, CDCl3) δ 1.68 (s, 3 H) 1.80 (dd, J=12.7, 11.2 Hz, 1 H) 1.98-2.06 (dm, J=12.7 Hz, 1 H) 2.28 (ddd, J=19.0, 9.0, 3.1 Hz, 1 H) 2.65-2.74 (dtd, J=18.8, 5.1, 1.5 Hz, 1 H) 3.28-3.37 (m, 1 H) 3.63 (s, 3 H) 4.32-4.41 (ab, J=11.7 Hz, 2 H) 7.11-7.14 (m, 2 H) 7.16 (dd, J=5.3, 2.8 Hz, 1 H) 7.21-7.28 (m, 3H) 7.32-7.40 (m, 2 H) 7.49 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8 ml of tetrahydrofuran:methanol (1:1, and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR-MS: m/z Calculated for C23H25NO8S2 509.1094; Found 508.1073.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([OH:33])=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:33])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)N1CCOCC1
Reaction time: 0.25 h
Yield: 35.2 %

Procedure:
To a solution of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid (0.05 g, 0.1 mmol, obtained in example 44) in DMF (1 mL), N,N′-dicyclohexylcarbodiimide (0.02 g, 0.1 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.1 mmol) were added under argon atmosphere. The mixture was stirred for 15 min and morpholine (0.01 g, 0.1 mmol) was added. This was stirred at room temperature for 2 days. EtOAc was added and the mixture was filtered. The filtrate was washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 18 mg of title compound (yield: 35%).