Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[C:17]([CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([NH:31][C:32]([C:34]2[NH:38][C:37]3[S:39][C:40]([Cl:42])=[CH:41][C:36]=3[CH:35]=2)=[O:33])[C:22]1=[O:43])(O)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.C(Cl)Cl>[Cl:42][C:40]1[S:39][C:37]2[NH:38][C:34]([C:32]([NH:31][CH:23]3[CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH2:20][C:17]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:18])[C:22]3=[O:43])=[O:33])=[CH:35][C:36]=2[CH:41]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 48 h

Procedure:
Methanesulphonamide (90 mg, 0.94 mmol), 4-(dimethylamino)pyridine (287 mg, 2.35 mmol) and EDCI (225 mg, 1.17 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 315 mg, 0.78 mmol) in DCM (50 mL) and stirred for 2 days. The reaction was diluted with MeOH:DCM (1:19) (50 mL) and washed with 1M HCl(aq). (50 mL), the organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by applying the material to a 10 g Isolute NH2 column in MeOH:DCM (1:9) (10 mL) and eluted with MeOH:DCM (1:9) (6×10 mL) then MeOH: 2M HCl in Et2O:DCM (5:4:45) (6×10 mL) and the relevant fractions evaporated to give a pink gum which was triturated with refluxing Et2O (25 mL) and after cooling the title product (206 mg, 55%) was collected by filtration as pale pink powder.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]([Cl:28])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[N:20]2)=[CH:15][CH:14]=1.O.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:27]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:14][CH:15]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: COC(=O)CCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
A mixture of the product of step 1 (0.37 g, 0.89 mmol), water (1 mL) and HCl (4 M in dioxane, 2.3 mL, 9.1 mmol) in dioxane (5 mL) was stirred at room temperature for 16 h. After the solvent was removed, the residue was triturated with ether to provide the title compound (200 mg, 44%) as a hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.72-7.66 (m, 4H), 7.41 (m, 1H), 7.23 (m, 3H), 4.44 (br, 2H), 4.03 (br, 1H), 3.71 (br, 2H), 3.35 (br, 1H), 3.20 (br, 1H), 2.87 (t, J=8 Hz, 2H), 2.27 (m, 1H), 2.09-1.98 (br, 3H), LC/MS (APCI) m/z: 85%.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]3[C:12]4[C:17]([CH:18]=[CH:19][C:9]=3[CH:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:3][CH:2]=1.N([CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)C1C=CC=CC=1>>[C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=1[CH:28]=[CH:20][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:11][C:10]3[C:12]4[C:17]([CH:18]=[CH:19][C:9]=3[CH:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:5][CH:6]=1)([OH:31])=[O:29]
Reactant: O=C1OC(Nc2ccccc2)c2ccccc21
Reactant: Cc1ccc(-c2cc3ccc4ccccc4c3o2)cc1
Product: O=C(O)c1ccccc1C=Cc1ccc(-c2cc3ccc4ccccc4c3o2)cc1

Procedure:
Following the procedure as in Example 8, 2-(p-tolyl)naphtho[1,2-b]furan was interacted with an equimolar quantity of 3-anilinophthalide to produce 2-[4-(2-carboxystyryl)phenyl]naphtho[1,2-b]furan which, when crystallized from chlorobenzene, melted at 210°-211°C. The measured wavelength of maximum excitation was 374 nm and wavelength of maximum emission was 438 nm.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][NH:8][CH:9]=[C:5]2[CH2:4][CH2:3]1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][N:8]([CH2:11][OH:12])[CH:9]=[C:5]2[CH2:4][CH2:3]1
Reactant: C=O
Reactant: CC1(C)CCc2c[nH]nc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CCc2cn(CO)nc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 15.1 %

Procedure:
The mixture of 1.68 g of 6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta [c] pyrazole, 0.41 g of paraformaldehyde and 0.2 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 0.31 g of {6,6-dimethyl-5,6-dihydrocyclopenta [c] pyrazole-2 (4H)-yl} methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:22])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:25][CH:24]=2)=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cccc(C2=C(C(=O)c3ccc(O)cc3)c3ccc(OC)cc3CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2=C(C(=O)c3ccc(OCCN4CCCCC4)cc3)c3ccc(OC)cc3CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone, (3.5 g, 9.0 mmol), anhydrous K2CO3 (6.25 g, 45 mmol), N-2-chloroethylpiperidine hydrochloride (1.75 g, 9.5 mmol, Aldrich Chem. Co.) 10 mg of KI, and anhydrous DMF (150 mL) were combined under a nitrogen atmosphere and the resulting mixture was stirred at room temperature for 16 hr. The DMF was removed under reduced pressure and the residue was distributed into water and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. After concentration to an oil, the product was purified by column chromatography over silica gel using a gradient from chloroform to 95:5 chloroform:methanol. The appropriate fractions gave, on evaporation of the solvent and vacuum drying of the residue at 80° C. overnight, an oil which weighed 3.1 g. (69%). 1H NMR (CDCl3) δ 7.80 (d, J=9.0 Hz, 2H), 7.10-7.00 (m, 1H), 6.90-6.70 (m, 6H), 6.70-6.68 (m, 2H), 4.09 (t, J=5.9 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.02 (t, J=8.1 Hz, 2H), 2.90-2.70 (m, 4H), 2.60-2.40 (m, 3H), 1.70-1.50 (m, 5H), 1.50-1.01 (m, 2H); MS (FD) m/e 497 (M+); Anal. Calc′d. for C32H35NO4: C, 77.24; H, 7.09; N, 2.82. Found: C, 77.05; H, 7.19; N, 3.05.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][OH:19].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:17]1[CH2:18][O:19][C:12]2([CH2:13][CH2:14][CH2:15][CH:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)[O:16]1
Reactant: O=C1CCCC(S(=O)(=O)c2ccccc2)C1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)C1CCCC2(C1)OCCO2
Yield: 97 %

Procedure:
To a solution of 5.3 g of 3-(phenylsulfonyl)-cyclohexan-1-one in 60 ml of benzene, were added 0.3 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid. The reaction mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and then, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 6.1 g of 1,1-(ethylenedioxy)-3-(phenylsulfonyl)-cyclohexane (m.p.: 93–95° C.) were obtained in the form of white crystals. Yield: 97%
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:3]=1[OH:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][CH:14]=1>B(F)(F)F.CCOCC.C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:8]2[C:7](=[O:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:3](=[O:4])[C:2]=2[CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][CH:14]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C(O)CCCCCC(O)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccc(Cl)cc2)=C(C)C1=O
Temperature: 60 °C
Yield: 78.2 %

Procedure:
Toluene (15 ml) was added to 0.76 g (5.0 mmole) of 2,5,6-trimethylhydroquinone and 1.28 g (5.0 mmole) of 7-(4-chlorophenyl)-7-hydroxyheptanoic acid, and the mixture was warmed at 60° C. and stirred. 0.19 ml (5.0×0.3 mmole) of boron trifluoride ethyl etherate was added to the mixture, followed by stirring at 60° C. for 15 hours. After the conclusion of the reaction, a large amount of the toluene was distilled off, and the residue was dissolved in tetrahydrofuran (20 ml). An aqueous solution (10 ml) of ferric chloride (2.7 g, 10.0 mmole was added to the solution, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and ethyl acetate was added to the residue to extract the reaction product. The organic layer was separated out, washed with aqueous sodium chloride solution and dried (magnesium sulfate). The ethyl acetate solution was chromatographed on a short silica gel (10 g) column, and elution was performed with ethyl acetate. The fractions containing the object compound were collected and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/isopropyl ether to give 1.52 g (78%) of 7-(4-chlorophenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=1[C:23]#[N:24])(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:23]#[N:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCCCCCCCOc1cccc(N)c1C#N
Yield: 100 %

Procedure:
A solution of 8-(2-cyano-3-nitrophenoxy)octyl acetate (802 μmol, 268 mg) (Example 274c) in EtOH (15 mL) was hydrogenated in an H-cube apparatus's using 10% Pd/C as catalyst. The solution was evaporated to give 8-(3-amino-2-cyanophenoxy)octyl acetate (244 mg, 244 mg). MS 305 (MH+)
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:15](=O)[CH3:16])([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.[NH2:19][OH:20].Cl.[OH-].[Na+]>CCO.O>[F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5](/[C:15](=[N:19]\[OH:20])/[CH3:16])([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=N/O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A mixture of 1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, 1.38 mmol), NH2OH.HCl (143.7 mg, 2.07 mmol) and NaOH (165.6 mg, 4.14 mmol) in EtOH/H2O (16 mL, 1:1) was heated to 80° C. overnight. The EtOH was removed. The residue was extracted with EtOAc (2×20 mL). The organic layer was dried over Na2SO4 and concentrated to give (Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime (320 mg), which was used for the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:20][C:21]1[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccn1)N(C)C(=O)N2

Procedure:
To a solution of crude 6-Bromo-3-methyl-4-pyridin-2-yl-3,4-dihydro-1H-quinazolin-2-one (600 mg, 0.002 mol) in DME/H2O (12 mL/4 mL) is added 3,5-dimethylisoxazole-4-boronic acid (265 mg, 0.002 mol), Pd(PPh3)4 (77 mg, 0.08 mmol) and Na2CO3 (332 mg, 3.14 mmol). After addition, the mixture is refluxed for 3 h. The mixture is concentrated in vacuum and the residue is purified by preparative HPLC to give the desired product as a yellow solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(N(CC)CC)C>C(OCC)C>[CH2:20]([O:19][C:17]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)=[N:2][O:1][CH:15]=1)=[O:18])[CH3:21]
Reactant: O/N=C(\Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1conc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (50 g, 241 mmol) in diethylether (1 L) was added a solution of ethyl 3-(N,N-dimethylamino)acrylate (87 mL, 601 mmol) and triethylamine (49 mL, 349 mmol) in diethylether (1 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (50.2 g, 88%) which was obtained as a light yellow solid. MS: m/e=236.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:6]#[N:7]>[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(C#N)ccc1N
Yield: 0.1 %

Procedure:
4-Amino-3-methylamino-benzonitrile (1.17 mg) was prepared by following General Procedure B starting from 3-methylamino-4-nitro-benzonitrile (1.33 g) and Pd/C (10% by weight, 133 mg). The crude product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24](N2CCC(=O)CC2)=[O:25])[N:23]=1>C1COCC1.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[N:23]=1
Reactant: Brc1cccs1
Reactant: CCc1c(C(=O)N2CCC(=O)CC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1c(C(=O)c2cccs2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 2-bromothiophene (0.22 g, 1.36 mmol) in 2 mL THF was added 0.84 mL of a 1.6 M solution of BuLi in hexane under argon at −78° C. with stirring. The stirring was continued for 1 h. To this was added a solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl]carbonyl}-4-piperidinone in 2 mL THF. The resultant mixture was stirred and gradually allowed to warm up to rt overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude product was purified by HPLC to yield [2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl](2-thienyl)-methanone as a solid (60 mg, 31%): Rf=0.13 (1:5 ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Na]>ClCCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Place N-(6-aminopyridin-2-yl)-4-fluorobenzamide (P reparation 37) (2 g, 8.3 mmol)and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane (20 mL). Stir for 1 hr. then add sodium triacetoxyborohydrlde (4.38 g, 20.8 mmol). After stirring for 36 hr., quench with 1 N NaOH and dilute with CH2Cl2. Separate and extract the aqueous layer twice with CH2Cl2, combine organics, dry over MgSO4, and concentrate. Take up the residue in CH2Cl2, and place on two 10 g SCX colulmns. Wash the columns successively with CH2Cl2 and then with methanol. Elute the product with 2M NH3 in methanol. Concentrate and chromatograph on silica gel, eluting with a gradient of 0–10% (2M NH3 in methanol) in CH2Cl2) to give the title intermediate 3.11 g (90%): mass spectrum (ion spray): m/z 415.4 (M+1); mp 82.7° C.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:20])([F:22])[F:21])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Yield: 27.7 %

Procedure:
1-((6-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.292 mmol) was dissolved in a 1:1 DCM:MeOH solution (2 mL) and sodium borohydride (33 mg, 0.876 mmol) added. After 30 min the mixture was quenched by addition of water (1 mL) then concentrated in vacuo. Purification by flash column chromatography-silica gel and elution with 3% MeOH:DCM resulted in a white solid which was recrystallised from isopropanol and freeze dried to give the title compound as a white solid (28 mg, 0.081 mmol, 28%).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([OH:14])([C:10]([F:13])([F:12])[F:11])=[O:9].[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22](C1CCCCO1)[N:21]=[C:20]2[C:32]1[N:37]=[C:36]([O:38][C@H:39]2[CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43][C:40]32[CH2:42][CH2:41]3)[CH:35]=[N:34][CH:33]=1)#[N:16]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[C:8]([OH:14])=[O:9].[CH2:42]1[C:40]2([CH2:43][CH2:44][NH:45][CH2:46][C@@H:39]2[O:38][C:36]2[N:37]=[C:32]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([C:15]#[N:16])[CH:18]=4)[NH:22][N:21]=3)[CH:33]=[N:34][CH:35]=2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)n2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.3 %

Procedure:
Triethylsilane (0.075 mL, 0.468 mmol) and TFA (1.0 mL, 12.98 mmol) were sequentially added to a solution of (4R)-tert-butyl 4-(6-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (99.4 mg, 0.187 mmol) in CH2Cl2 (1.0 mL) and the resulting solution was stirred at 25° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (3.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-1H-indazole-5-carbonitrile 2,2,2-trifluoroacetate (63.2 mg, 0.137 mmol, 73% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (1 H, s), 8.99 (1 H, d, J=11.2 Hz), 8.71 (1 H, s), 8.65 (1 H, d, J=8.2 Hz), 8.35 (1 H, s), 7.86 (1 H, d, J=8.7 Hz), 7.79 (1 H, dd, J=8.6, 1.4 Hz), 5.00 (1 H, s), 3.75 (1 H, d, J=12.9 Hz), 3.47 (1 H, t, J=12.0 Hz), 3.34 (1 H, d, J=12.7 Hz), 3.10-3.22 (1 H, m), 2.37-2.47 (1 H, m), 1.17 (1 H, d, J=14.5 Hz), 0.78-0.90 (2 H, m), 0.61-0.69 (1 H, m), 0.55 (1 H, dd, J=8.7, 4.2 Hz). 19F NMR (377 MHz, DMSO-d6) δ ppm −73.67 (3 F, s). MS (ESI, pos. ion) m/z: 347.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:14][C:11]1([F:13])[CH2:12][NH:8][C@@H:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc([C@H]2CC(F)(F)CN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-8) (0.9 g, 3.0 mmol) in DCM (20 mL) was added TFA (2 mL, 27 mmol) and stirred at room temperature for 2 hours. The reaction was cooled to 0° C. and aqueous NaHCO3 was added while rapidly stirring. The organic phase was separated and washed with aqueous NaHCO3, dried over anhydrous sodium sulfate, filtered and reduced to dryness to yield (R)-4,4-difluoro-2-(3-fluorophenyl)pyrrolidine (I-9) as a light yellow oil that crystallizes on standing. 1H NMR (400 MHz, CD3OD) δ 7.40 (q, J=8.0 Hz, 1 H), 7.23 (d, J=8.8 Hz, 1 H), 7.20 (d, J=10.0 Hz, 1 H), 7.05 (dt, J=8.8, 2.4 Hz, 1 H), 4.41 (dd, J=10.4, 7.2 Hz, 1 H), 3.48 (q, J=12.0 Hz, 1 H), 3.30 (q, J=15.2 Hz, 1 H), 2.74-2.63 (m, 1 H), 2.29-2.14 (m, 1 H). MS m/z 202.1 (M+1)+.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])[N:46]=3)[CH2:38][CH2:37]2)=O)[N:26]=1>COCCOC.C(Cl)(Cl)Cl>[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])[N:46]=3)[CH2:38][CH2:37]2)=[S:10])[N:26]=1
Reactant: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=S)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (88 mg) is added to a solution of cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (I-811, 200 mg) in 1,2-dimethoxyethane (1 ml) and chloroform (0.4 ml). The reaction mixture is stirred at 70-80° C. overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (80 mg, 39%).