Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (S)-2-methylpropane-2-sulfinamide (3 g, 24.8 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered and the filtrate was extracted with DCM (2×150 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (6 g, yield: 84%); m/z (ES+): 346 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[N:44]([CH3:46])[N:43]=[C:42]3[N:47]([S:48]([CH3:51])(=[O:49])=[O:50])[C:52](=[O:54])[CH3:53])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:30])([F:31])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:33])[F:34])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1nn(C)c2c(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)cccc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 35 (20 mg, 0.027 mmol) in methylene chloride (2 mL) was added acetic anhydride (0.03 mL, 0.27 mmol), triethylamine (0.04 mL, 0.027 mmol), and the reaction mixture was stirred for one hour at room temperature. The solution was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title compound 38A: 1H NMR (400 MHz, methanol-d4) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.18 (m, 1H), 7.09 (d, 1H), 6.76 (tt, 1H), 6.46 (d, 1H), 6.42-6.21 (m, 2H), 4.85-4.52 (m, 3H), 3.50 (m, 6H), 3.12 (m, 1H), 3.00-2.80 (m, 1H), 2.59-2.31 (m, 2H), 1.86 (s, 3H), 1.41 (m, 1H), 1.04 (m, 1H). MS (m/z): 778.95 [M+H]+ and 11 mg of compound 38B. MS (m/z) 820.83 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[CH3:28][NH:29][CH3:30]>CN(C)C=O.CCOC(C)=O>[Cl:26][C:22]1[C:21]([CH3:27])=[C:20]([CH2:19][N:5]([C:6]2[N:7]=[C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:9][C:10]=2[C:11]#[N:12])[C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])[CH:25]=[CH:24][CH:23]=1
Reactant: CNC
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN(C)C)c1nc(N2CCOCC2)sc1C#N
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (100 mg, 0.235 mmol) (prepared according to the procedures of example 111) in N,N-Dimethylformamide (DMF) (2 mL) was added dimethyl amine (0.588 mL, 1.176 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The resultant mixture was diluted in EtOAc (100 mL) and washed with H2O (100 ml×2). The organic layer was concentrated to afford the crude product, which was use in next step without further purification. (88%)
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)O1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:6]3[C:5]4[C:24](=[CH:23][CH:27]=[CH:16][CH:4]=4)[CH2:25][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-carbonitrile (286 mg), indanone-2 (132 mg) and NaH (41 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 148-150° C.; FAB MS 357 (M++1); IR (KBr) 2215 cm−1 (CN), 1H NMR (200 MHz, CDCl3) δ 1.60-1.64 (m, 2H, CH2), 1.79-1.82 (m, 4H, 2CH2), 3.20-3.25 (m, 4H, 2CH2), 4.10 (s, 2H, CH2), 6.92 (s, 1H, ArH), 7.10-7.24 (m, 5H, ArH & CH), 7.49-7.54 (m, 2H, ArH & CH); HRMS calcd. for C23H20N2S 356.13472. Found 356,13580.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccc(C=CCCl)cn1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cn1
Yield: 30 %

Procedure:
Prepared from 3-(6-methyl-3-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 30% of theory, Melting point: 180°-184° C. (ether).
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:15]([F:17])[F:16].[C:27]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]([F:17])[F:16])=[C:7]([CH:12]=1)[CH2:6][NH:5][C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 50.9 %

Procedure:
EDC (0.171 g, 1.25 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g, 0.96 mmol), N-BOC-L-proline (0.207 g, 0.96 mmol) and HOAT (0.171, 1.25 mmol) in DMF (2.0 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and reduced in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g) as a foam; LC-MS m/z=524.3.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6](I)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: CCn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-ethyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 69) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow solid. MS: 499.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[N:10]=[C:11]([CH3:24])[N:12]=[C:13]([NH:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[N:7]=[N:6]1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.O>[CH2:27]([N:14]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]=2[N:10]=[C:11]([CH3:24])[N:12]=1)[CH3:28]
Reactant: COCCn1nnc2c(Nc3c(C)cc(C)cc3C)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1c(C)cc(C)cc1C)c1nc(C)nc2c1nnn2CCOC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from Example 38, Part B (150 mg, 0.46 mmol) was treated with sodium hydride (17 mg, 0.55 mmol, 80%) and ethyl iodide (55 ml, 0.69 mmol) in dry dimethylformamide (3 ml) and stirred at room temperature for 48 h. The reaction was diluted with 50 ml water, and extracted with 4-30 ml methylene chloride. The combined organic extracts were dried over anydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, 1/1 hexanes/ethyl acetate) afforded the desired product, 144 mg (88%) as a clear viscous oil. CI-HRMS calcd. for C19H27N6O1 (M+H): 355.2246. Found: 355.2240.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=[O:16].OO>>[Cl:1][C:2]1[N+:11]([O-:16])=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: OO
Product: COC(=O)c1cc(Cl)c[n+]([O-])c1Cl
Temperature: 70 °C
Yield: 99 %

Procedure:
A solution of methyl 2,5-dichloronicotinate (15 g, 73 mmol), trifluoroacetic acid (91 mL) and 30% aqueous hydrogen peroxide solution (15 mL) were stirred and heated at 70° C. for 1 hour. Evaporation and purification by flash column chromatography using ethyl acetate in hexanes (0-100%) gave the desired product (16 g, 99%). LCMS calculated for C7H6Cl2NO3 (M+H)+: m/z=222.0. found: 221.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:15][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C(=O)N(O)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CN(C)C(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3,3-dimethylurea (12.5 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) are charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (7.8 grams; 0.05 mol) is added to the flask, with stirring, at a temperature of about 10° to 15°C. After the addition is completed, the reaction mixture is stirred for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture is poured onto ice and the precipitate is recovered by filtration and is dried. The dried precipitate is recrystallized to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3,3-dimethylurea.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][N:11]([C:16](=[O:27])[CH2:17][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[F:31][C:32]1[C:37](O)=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42]>CN(C=O)C>[F:31][C:32]1[C:37]([O:14][C:13](=[O:15])[CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16](=[O:27])[CH2:17][N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1cn(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cn(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(N-Boc-2-aminoethyl)-N-[(1-thyminyl)acetyl]glycine (5) (2.00 g; 5.20 mmol) was dissolved in DMF (5 ml) and methylene chloride (15 ml) was added. Pentafluorophenol (1.05 g; 5.72 mmol) was added and the solution was cooled to 0° C. in an ice bath. DDC then was added (1.29 g; 6.24 mmol) and the ice bath was removed after 2 min. After 3 h with stirring at ambient temperature, the precipitated DCU was removed by filtration and washed with methylene chloride. The combined filtrate was washed twice with aqueous sodium hydrogen carbonate and once with saturated sodium chloride, dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was dissolved in dioxane (150 ml) and poured into water (200 ml) at 0° C. The title compound was isolated by filtration, washed with water, and dried over an appropriate drying agent, in vacuo. Yield: 2.20 g (77%). An analytical sample was obtained by recrystallisation from 2-propanol. M.p. 174–175.5° C. Analysis for C22H23N4O7F5, found(calc.): C, 48.22(48.01); H: 4.64(4.21); N: 9.67(10.18). 1H-NMR (250 MHz, CDCl3):Due to the limited rotation around the secondary amide bond several of the signals were doubled in the ratio 6:1 (indicated in the list by mj. for major and mi. for minor). 7.01 ppm (s, mi., ArH); 6.99 ppm (s, mj., ArH); 5.27 ppm (unres. t, BocNH); 4.67 ppm (s, mj., T-CH2—CO—); 4.60 ppm (s, mi., T-CH2—CO—); 4.45 ppm (s, mj., CONRCH2CO2Pfp); 4.42 ppm (s, mi., CONRCH2CO2Pfp); 3.64 ppm (t,2H,BocNHCH2CH2-); 3.87 ppm (“q”,2H,BocNHCH2CH2—); 1.44(s,9H,t-Bu). FAB-MS: 551 (10; M+1); 495 (10; M+1-tBu); 451 (80; -Boc).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1[C:16](=C)C[C@H:14]2[C@@H:10]1[CH2:11][C@@H:12]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:5]([O:4][CH:1]1[C:9](=[CH2:16])[CH2:10][C@H:14]2[C@@H:2]1[CH2:11][C@@H:12]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2C1O
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2C1OC(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
Acetic anhydride (5.0 ml) and pyrdine (5.0 g) were added to the (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane (928 mg, 2.00 mmoles) obtained in Example 65, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and subjected to column chromatography (silica gel 200 g; hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-acetoxy-3-methylene-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane (982 mg, 1.94 mmoles, 97%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH2:15][CH3:16])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=1.[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:2]2[C:7]([CH2:8][N:9]([C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[CH2:15][CH3:16])=[CH:6][C:5]([CH3:17])=[CH:4][N:3]=2)[CH:24]=1)[CH3:19]
Reactant: CCN(Cc1cc(C)cnc1Cl)C(=O)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarboxylic acid (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amide (0.120 g, 0.48 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.183 g, 0.57 mmol), and potassium carbonate (0.198 g, 1.43 mmol) were combined in DME and H2O. The mixture was purged with N2 for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol) was added, and the reaction was stirred at 80° C. for 2 hours. Once no starting material was seen by analytical tlc, the mixture was diluted with H2O and extracted three times with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(O[C:24](OCC)(OCC)[CH2:25][CH3:26])C>C(O)(=O)C.CO>[CH2:25]([C:26]1[N:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]#[N:20])[CH2:16][CH2:17]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:24]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (20.1 mg, 0.0702 mmol) and 1,1,1-triethoxypropane (0.0428 mL, 0.213 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (13 mg, 57%). LCMS calculated for C18H21N4S (M+H)+: m/z=325.1. Found: 325.1.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:59](N1C=CN=C1)([N:61]1[CH:65]=[CH:64][N:63]=[CH:62]1)=O.CN(C)CCN>C1COCC1>[CH3:59][N:61]([CH3:62])[CH2:65][CH2:64][NH:63][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Yield: 85.1 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give an orange/brown oil. The oil was purified by silica gel flash chromatography using 10% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl 2-carboxylic acid (2-dimethylamino-ethyl)-amide (0.81 g, 85% yield) as a faint yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:23]3[N:24]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[N:25]=[C:26]4[C:31]=3[CH:30]=[C:29]([F:32])[C:28]([F:33])=[CH:27]4)[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:24]2[C:23]([CH:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:10][CH:11]=3)=[C:31]3[C:26]([CH:27]=[C:28]([F:33])[C:29]([F:32])=[CH:30]3)=[N:25]2)=[CH:35][CH:36]=1
Reactant: COC(=O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless liquid. MS: m/e=553.3 [M+H+].
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[N:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: Cc1c(Cl)nn2ncnc2c1C
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ncnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In 30 ml of dimethylformamide was suspended 1.38 g of 60% sodium hydride in oil, followed by addition of 2.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 1 hour. To this was added 2.56 g of 6-chloro-7,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was stirred at room temperature for 3 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3 portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (30:1). The fractions containing the desired product were pooled and concentrated to provide 0.63 g of the title compound. m.p. 175°-177° C.