Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].C([Si](Cl)(C)C)CCC.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[C:30]([Si:27]([CH3:29])([CH3:28])[O:1][C@H:2]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[C@]12CCC[C@H](O)[C@@H]1CCCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@]2(C)C(=O)CCC[C@@H]12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2.3 g (12.6 mMol) of (4aR,5S,8aS)-5-hydroxy-8a-methyl-octahydro-naphtalen-1-one in 63 ml of dimethylformamide are added under stirring and argon atmosphere 3.74 g (24.8 mMol) of tertio-butyl-dimethyl-silylchloride and 1.94 g (28.5 mMol) of imidazole. The reaction mixture is heated to 100° C. for 4 hours, then additional 3.74 g of tert-butyl-dimethylsilylchloride and 1.94 g of imidazole are added and the reaction mixture is kept overnight at 100° C. The reaction mixture is poured onto ice-water and extracted three times with diethylether. The combined organic extract is washed once with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed over 250 g of silicagel with hexane/ethylacetate 9/1 to yield 3.17 g (85%) of low melting cristalline (4aR,5S,8aS)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-octahydro-naphtalen-1-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][CH3:24])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([NH2:20])=[C:18]([NH:23][CH3:24])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CNc1nc(C(=O)OC)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1nc(C(=O)OC)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1N
Reaction time: 4 h
Yield: 92.2 %

Procedure:
In a dry reaction bottle, 6.54 g (R)-1-[2-methoxycarbonyl-5-nitro-6-methylaminopyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (16 mmol) was added and dissolved in 200 mL ethanol. 0.65 g 10% Pd—C was added at room temperature. The stirring was continued for 4 h by introducing hydrogen gas. The reaction solution was filtrated, and evaporated to dryness to afford 5.6 g light yellow solid with a yield of 92.3%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][N:21]=[N:20][C:19]=2[C:23](OC)=[O:24])=[CH:14][CH:13]=1.Cl>O1CCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][N:21]=[N:20][C:19]=2[CH2:23][OH:24])=[CH:16][CH:17]=1
Reactant: COC(=O)c1nnsc1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1nnsc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Diisobutylaluminum hydride (1.5N toluene solution, 10 ml) was added to a solution of methyl 5-(4-fluorophenyl)-1,2,3-thiadiazole-4-carboxylate (1.19 g) in tetrahydrofuran (30 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into an aqueous dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give [5-(4-fluorophenyl)-1,2,3-thiadiazol-4-yl]methanol (0.80 g, yield 76%) as a yellow oil.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9](=O)([O-])[O-:10].[Ca+2]>CO>[CH3:9][O:10][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C1CCCCC1Cl
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COC1CCCCC1=O
Yield: 80 %

Procedure:
2-methoxycyclohexanone was prepared by dissolving 132 gm. 2-chlorocyclohexanone in 600 ml. of methanol in the presence of 50 gm. calcium carbonate and heating the suspension at 160° C. for 15-20 minutes. After removal of the methanol, the calcium chloride was precipitated by the addition of methylene chloride to the residual material. The calcium chloride was removed by filtration and the filtrate was distilled to yield an 80-85% yield of 2-methoxycyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][C:22]3[CH:23]=[C:24]([Cl:28])[CH:25]=[N:26][CH:27]=3)=[C:16]([CH:20]=2)[C:17](O)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH3:33]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][C:22]3[CH:23]=[C:24]([Cl:28])[CH:25]=[N:26][CH:27]=3)=[C:16]([CH:20]=2)[C:17]([NH2:33])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a stirred solution of the acid from Example 10 (20 mg, 0.046 mmol) in CH2Cl2 (0.5 mL) and pyridine (0.5 mL) was added thionyl chloride (17 mL, 0.228 mmol). After one hour, the solution was evaporated and placed under vacuum overnight. The residue was then dissolved in MeOH (1 mL) and CH2Cl2 (1 mL) and NH3 (0.12 mL, 0.227 mmol, 0.757 M solution in ethanol) was added dropwise. The mixture was stirred for 8 hours and the solvent was evaporated. The residue was purified by chromatography (1:1 hexane/diethyl ether) to yield 7.3 mg of the title compound (37%).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[O:9]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>C(O)C>[NH2:1][N:2]1[C:6](=[O:7])[C:5](=[CH:20][C:19]2[CH:22]=[CH:23][C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[S:4][C:3]1=[S:8]
Reactant: NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S
Yield: 68.6 %

Procedure:
To a solution of 3-aminorhodanine (1.00 g) in ethanol (20 ml) were added 4-phenoxybenzaldehyde (1.47 g) and piperidine (57 mg), and the mixture was heated with reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 3-amino-5-(4-phenoxybenzylidene)-2-thioxothiazolidin-4-one (1.52 g).
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].CO.[C:14](#[N:17])[CH:15]=[CH2:16].Cl>C(O)(C)(C)C>[C:2]([C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:16][CH2:15][C:14]#[N:17])[CH2:16][CH2:15][C:14]#[N:17])(=[O:9])[CH3:1]
Reactant: CCCCCCC(C)=O
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Product: CCCCCC(CCC#N)(CCC#N)C(C)=O
Temperature: 5 °C

Procedure:
In a flask, 600 g of 2-octanone (CH3 (CH2)5COCH3), 500 g of tert-butanol ((CH3)3COH) and 30 g of a KOH/CH3OH solution were mixed and then stirred under ice-cooling. To the resulting solution was added dropwise a solution of 375 g of acrylonitrile (CH2 =CHCN) in 400 g of (CH3)3COH while maintaining the temperature at 5° C. or lower. After completion of the addition, the resulting solution was further stirred continuously for 1 hour, after which this reaction solution was made neutral by addition of dilute hydrochloric acid. The deposited salt was separated by filtration, and the residue was distilled under reduced pressure to obtain 3-acetyl-1,5-dicyano-3-pentylpentane.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([Cl:23])[C:5]2[O:6][C:7]3[C:16]([CH3:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:8]=3[S:9](=[O:12])(=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH:24](=O)[CH:25]([CH3:27])[CH3:26].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>O.CO>[Cl:23][C:21]1[C:5]2[O:6][C:7]3[C:16]([CH3:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:8]=3[S:9](=[O:11])(=[O:12])[CH2:10][C:4]=2[CH:3]=[C:2]([NH:1][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:22]=1
Reactant: CC(C)C=O
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NCC(C)C)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.74 %

Procedure:
To a mixture of the methyl ester of Example 35j (0.1 g, 0.27 mmol), isobutyraldehyde (0.098 g, 1.35 mmol)), trifluoro acetic acid (0.27 mmol) and sodium cyanoborohydride (0.67 mmol) was added MeOH (15 mL) at 0-5° C. The reaction mixture was stirred overnight at room temperature, treated with chilled water, neutralized with 10% aqueous NaHCO3, extracted with EtOAc, concentrated and subjected to hydrolysis as described in Example 11 to obtain the title compound (Tet. Lett. 38, 5831-5834, (1997)). Yield: 64.74%; 1H NMR (DMSO-d6): δ 0.90 (d, 6H, 2CH3), 1.80 (m, 1H, CH), 2.60 (s, 3H, CH3), 2.90 (d, 2H, N—CH2), 5.10 (s, 2H, CH2), 6.70 (s, 2H, Ar), 8.10 (d, 2H, Ar); MS: m/e (EI+) 409 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([CH2:45][O:46][NH2:47])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[N+:38]([C:41]1[CH:42]=[CH:43][C:44]([CH2:45][O:46][N:47]=[CH:1][C:3]2[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=2)[CH2:6][N:7]([C@@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[C:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[O:9])=[CH:48][CH:49]=1)([O-:40])=[O:39]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3ccc([N+](=O)[O-])cc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-(4-nitrobenzyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH:38]([C:45]2([CH3:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]([F:52])=[CH:33][N:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:52][C:34]1[C:35]([NH:37][CH:38]([C:45]2([CH3:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:32][CH:33]=1
Reactant: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCCCC1
Temperature: 115 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.51 g, 1.22 mmol), racemic ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoate, 206a, (0.35 g, 1.02 mmol) and K3PO4 (0.52 g, 2.44 mmol) in 2-methyl THF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.02 g, 0.02 mmol) were added and the resulting mixture was heated at 115° C. in a pressure vial for 4 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-35% EtOAc/Hexanes gradient) to afford 486 mg of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.50 (m, 1H), 8.48 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.01 (m, 3H), 7.20 (m, 2H), 5.12 (m, 1H), 4.88 (m, 1H), 3.89 (q, J=7.4 Hz, 2H), 2.71 (dd, J=14.5, 3.8 Hz, 1H), 2.39 ? 2.32 (m, 1H), 2.31 (s, 3H), 1.60-1.32 (m 10H), 0.95 (t, J=7.4 3H). 0.87 (s, 3H); LCMS Gradient 60-98%, 0.1% formic acid, 7 minutes, C18/ACN, Retention Time=2.81 minutes (M+H) 599.19.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.CN(C)/[CH:12]=[C:13](/[C:19](=[O:28])[C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1F)\[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>>[I:26][C:24]1[CH:25]=[C:20]2[C:21](=[CH:22][CH:23]=1)[N:9]([CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]2=[O:28]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(CCN2CCOCC2)c2ccc(I)cc2c1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
2-Morpholinoethanamine (0.88 g, 6.7 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.38M, 18 mL, 7 mmol) and the mixture was heated at 40° C. for 3 h. The solvent was removed in vacuo and the resulting residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (5 mL) and potassium carbonate powder (1.2 g, 10 mmol) was added. The reaction was heated at 70° C. for a further 3 h then cooled to room temperature. The crude reaction mixture was placed into a fridge for a 3 h. The solid precipitate that formed was collected by filtration, washed with a small amount of dimethylformamide, followed by water, then dried under high vacuum.
Reaction SMILES: [OH:1][C:2]1[C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Br[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:24][S:21]([N:20]1[C:19]2=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=[C:2]2[O:1][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(NS(C)(=O)=O)cc2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(S(C)(=O)=O)CCO3

Procedure:
1,1-dimethylethyl 7-hydroxy-8-[(methylsulfonyl)amino]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.55 g) and 1,2-dibromoethane (0.23 ml) in the presence of potassium carbonate (0.4 g) were heated in acetone/water (1/1, 8 ml) for 6 h at reflux. Volatiles were evaporated under reduced pressure, the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined organic layers were concentrated and submitted to column chromatography to provide the title compound (0.75 mmol) as a white slightly hygroscopic solid. MS (m/z): 383 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][C:17]([F:20])([F:19])[CH3:18])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:20][C:17]([F:19])([CH3:18])[CH2:16][CH2:15][C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(F)(F)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(F)(F)CCC1(O)CCNCC1

Procedure:
The solution of tert-butyl-4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carboxylate (0.932 g, 3.2 mmol) in the solution of HCl in 1,4-dioxane (3M, 5 mL) was stirred at room temperature for 1 hour. The solution was evaporated to dryness under reduced pressure to give the product which was used in the next step without further purification. LC-MS: m/z 194.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[Si:29]([O:36][CH2:37][C:38]([CH3:50])([CH3:49])[O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Si:29]([O:36][CH2:37][C:38]([CH3:50])([CH3:49])[O:39][C:40]1[CH:41]=[CH:42][C:43]([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][C:11]=3[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=2[CH3:28])=[CH:44][CH:45]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.6 g), [4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronic acid (0.83 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution (6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.76 g, 89%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([Cl:27])[N:20]=[C:19]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[C:32](Cl)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:32]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([Cl:27])[N:20]=[C:19]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1)(=[O:4])=[O:3])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
To a stirred solution of 1-((2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (67.0 mg, 0.145 mmol) in pyridine (1.0 ml) under nitrogen at room temperature was added benzoyl chloride (168 μl, 1.45 mmol) dropwise. The pale orange solution was stirred at room temperature for 12 hours then saturated sodium bicarbonate solution added. The mixture was extracted four times with ethyl acetate. The compound organic phase was washed with water, twice with saturated copper sulfate solution, water, brine and dried (magnesium sulfate). The solvent was removed in vacuo and the residue chromatographed (silica gel, 2% methanolmethylene chloride) to give 1-((2'-((benzylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (63.4 mg, 77%) as a white solid; 1H NMR (300 MHz, CD3OD) δ8.30 (dd, J=7.7, 1.7 Hz, 1H), 7.65-7.42 (m, 5H), 7.40-7.30 (m, 2H), 7.29-7.18 (m, 3H), 6.90 (d, J=8.2 Hz, 2H), 5.54 (s, 2H), 3.84 (s, 3H), 2.62 (t, J=7.8 Hz, 2H), 1.64 (quin, J=7.8 Hz, 2H), 1.32 (apparent sext, 2H), 0.87 (t, J=7.3 Hz, 3H); FAB-MS: 568 and 566 (M+H).
Reaction SMILES: [C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1>CO.[Pd]>[C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1ncn2[C@H]1C=C[C@@H](CO)O1
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Yield: 44.5 %

Procedure:
A solution of 7 (1.27 g) in methanol (325 ml) was hydrogenated at 15 psi in the presence of 10% Pd/C (0.65 g). The reaction mixture was filtered through celite and the filtrate was evaporated. Crystallization of the crude product from methanol gave 0.57 g of 10: mp 186°-188° C. (Lit. mp 185°-187° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(N)CCCCC1N.[NH:21]1[C:25]2=[N:26][CH:27]=[N:28][C:29]([NH2:30])=[C:24]2[CH:23]=[N:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C>[N:11]1[NH:12][C:8]([C:4]2[CH:3]=[C:2]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([NH2:30])=[C:24]4[CH:23]=[N:22]3)[CH:7]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: Brc1cccc(-c2ccn[nH]2)c1
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(-c2ccn[nH]2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 0 %

Procedure:
5-(3-bromo-phenyl)-1H-pyrazole (0.3 g, 1.0 eq, 1.34 mmol) and cyclohexane-1,2-diamine (0.03 g, 0.2 eq, 0.27 mmol) were added to a pre-stirred mixture of 1H-Pyrazolo[3,4-d]pyrimidin-4-ylamine (0.22 g, 1.2 eq, 1.62 mmol), copper iodide (0.013 g, 0.5 eq, 0.68 mmol) and potassium phosphate (0.6 g, 2.1 eq, 2.84 mmol) in DMF (8 ml) under an inert atmosphere. The reaction mixture was then stirred at 110° C. for 24 hours, and allowed to cool to room temperature. Ethyl acetate (8 ml) was then added to the reaction mixture which was then filtered through a plug of silica, which was then washed with a further portion of ethylacetate (20 ml). The filtrate was concentrated to dryness in vacuo and the resultant residue was purified by column chromatography using DCM/MeOH (95:5) as eluent to yield the title compound as an off-white solid (0.9 mg, 0.0003 mmol, 0.2%). LCMS: [M+H]+=277, Rt=1.80 min, 93% purity.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[Cl-].[NH4+].[N-:35]=[N+:36]=[N-:37].[Na+].[OH-].[Na+]>CN(C=O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]4[N:35]=[N:36][NH:37][N:30]=4)=[CH:31][CH:32]=3)[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: CCOCCn1cc(C2CCN(CCCOc3ccc(C#N)cc3)CC2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2CCN(CCCOc3ccc(-c4nn[nH]n4)cc3)CC2)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 0.108 g (0.25 mmol) of 4-(3-{4-[l-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzonitrile in 1.5 mL of anhydrous DMF, 0.110 g (2 mmol) of ammonium chloride and 0.135 g (2 mmol) of sodium azide were added. The crude mixture was heated at 110° C. for 18 hours and after cooling at room temperature, 1 mL of an aqueous solution of 2N sodium hydroxide was added. The mixture was taken to pH=6 and the aqueous phase was extracted with ethyl acetate. After purification by flash cromatography over silica gel 0.05 g (41% yield) of the desired product were obtained.