Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Si:7]2([CH2:20][CH2:21][CH3:22])[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Cl)=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:16]2[CH2:17][CH2:18][CH:13]([CH:10]3[CH2:11][CH2:12][Si:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:20][CH2:21][CH3:22])[CH2:8][CH2:9]3)[CH2:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[Si]1(c2ccccc2)CCC(C2CC=C(c3ccc(F)cc3)CC2)CC1
Reaction time: 2 h

Procedure:
31.5 g of 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexanone was dropped in 120 ml of a solution of 1.0 mole of p-fluorophenylmagnesium chloride in tetrahydrofuran at a temperature of 40° to 50° C. After agitation at 50° C. for 2 hours, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, followed by extraction with benzene. 1.0 g of p-toluenesulfonic acid monohydrate was added to the benzene phase, followed by distilling off the resultant water under reflux. When the distilling of water stopped, the benzene solution was washed with a sodium hydrogencarbonate aqueous solution, dried and concentrated to obtain crude 4-(4-(4-fluorophenyl)-3-cyclohexenyl)-1-phenyl-1-n-propyl-1-silacyclohexane. This product was dissolved in 100 ml of ethanol and hydrogenated in the presence of 1.0 g of a palladium-carbon catalyst, followed by separation of the catalyst by filtration and concentration to obtain 35.0 g (yield: 88%) of 4-(4-(4-fluorophenyl)cyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane. The results of IR analysis are shown below.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=2)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[O:3].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:2](=[O:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=2)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(N=C=O)c2)n1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(NC(=O)NC(C)(C)C)c2)n1

Procedure:
To a solution of 3-isocyanato-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide prepared as in Example 3 was added 0.8 g of tert-butylamine at ambient temperature with stirring. After sixteen hours, filtration of the reaction mixture and evaporation of the filtrate yielded the desired product which after trituration with ethyl ether and isolation by filtration melted at 137°-145°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].O.[NH2:14][NH2:15]>O>[F:1][C:2]1[CH:12]=[C:6]([C:7]([NH:14][NH2:15])=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cncc(F)c1
Solvent: O
Product: NNC(=O)c1cncc(F)c1
Yield: 83 %

Procedure:
A mixture of 6.7 g of ethyl 5-fluoronicotinate (cf. U.S. Pat. No. 3,637,714) and 6.0 g of hydrazine monohydrate is stirred at 110° C. for 2 hours. After cooling, 30 ml of cold water is added, and the precipitate is collected and washed with cold water to give 5.1 g of crude 5-fluoro-3-pyridinecarbohydrazide. To a stirred mixture of 5.1 g of the hydrazide in 40 ml of pyridine, 6.9 g of p-toluenesulfonyl chloride is added slowly. After the mixture becomes a clear solution, the remaining pyridine is distilled off under reduced pressure, and 30 ml of water is added. The resulting precipitate is collected and washed with water to give 6.6 g of the crude p-toluenesulfonyl derivative. The product is added to 40 ml of ethylene glycol at 120° C., and to the mixture is added with stirring 6.5 g of anhydrous sodium carbonate. The reaction mixture is stirred at 160° C. for 10 minutes and cooled, and 50 ml of water is added. The mixture is extracted with three 100-ml portions of diethyl ether. The combined extracts are dried over magnesium sulfate and concentrated to give 1.1 g of crude 5-fluoro-3-pyridinecarbaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:25]=[CH:24][C:12]3[N:13]=[C:14]([NH:16][C@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]>[CH3:22][CH:21]([CH3:23])[CH2:20][C@@H:17]([NH:16][C:14]1[S:15][C:11]2[CH:10]=[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)[CH:25]=[CH:24][C:12]=2[N:13]=1)[CH2:18][OH:19]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)C[C@H](CO)Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)C[C@H](CO)Nc1nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cc2s1
Temperature: 90 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
To the reaction mixture of (R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol (12 mg, 31 μmol) in 400 μL of DME, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21 mg, 100 μmol), Pd(dppf)2Cl2 (7 mg, 8 μmol) and aq. 2M Na2CO3 (100 μL, 200 μmol) were added. The reaction mixture was stirred at 90° C. for 24 hours. The reaction mixture filtered, purified on prep HPLC and evaporated in vacuo to give (R)-4-methyl-2-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)pentan-1-ol as powder (4.2 mg). ES/MS m/z 424.1 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([Si](C)(C)C)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[Si:21]([CH3:24])([CH3:23])[CH3:22].CCN(CC)CC.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=2[Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)cc2[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of crude tert-butyl (4-bromomethyl-3-trimethylsilylphenyl)trimethylsilylcarbamate (2.57 g, 5.98 mmol) in THF (10 mL) was added Et3N (1.3 mL, 8.97 mmol) and 1-methylpiperazine (1.1 mL, 8.92 mmol). After stirring for 1 h at rt, aq. NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4 (filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide product as a pale yellow oil (1.60 g, 71%).
Reaction SMILES: [C:1]([S:5][C:6]([F:14])([F:13])[C:7]([F:12])([F:11])[C:8]([O-:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Na+].S(OC)(O[CH3:20])(=O)=O>>[C:1]([S:5][C:6]([F:14])([F:13])[C:7]([F:11])([F:12])[C:8]([O:10][CH3:20])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SC(F)(F)C(F)(F)C(=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Product: COC(=O)C(F)(F)C(F)(F)SC(C)(C)C
Reaction time: 8 h
Yield: 42 %

Procedure:
The resulting dark solution, which contained sodium 3-t-butylthiotetrafluoropropionate, was stirred with 69.3 g (0.55 mole) of dimethyl sulfate while the temperature was maintained at 30°. After an initial exothermic reaction subsided, the mixture was stirred overnight and then distilled to give a crude product with bp about 45° (2 mm, 2.6×10-1 kPa). The distillate was washed with 1 liter of water, dried and fractionated to give 52.1 g (42%) of methyl 3-t-butylthiotetrafluoropropionate, bp 55° (2 mm, 2.6×10-1 kPa). IR (neat): 2970 (sat'd CH), 1775 (C=O), 1100-1250 cm-1 (CF). NMR (CCl4): 1H 3.87 (s, 3H, OCH3) and 1.52 ppm (s, 9H, C(CH3)3 ; 19F -86.3 (t, JFF 7.1 Hz, 2F, CF2S) and -117.6 ppm (t, JFF 7.1 Hz, 2F, CF2C=O).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[NH:28][CH2:29][CH2:30][N:31]=2)=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C2=NCCN2)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(Cl)c(-c2ncc[nH]2)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 2-[4-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-5-methyl-pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (45 mg, 0.1 mmol), Dess-Martin periodinane (80 mg, 0.2 mmol) in DMSO (1 mL) was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (20 mL) and washed with water (3×5 mL). The organic layer was dried (Na2SO4), filtered, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give 2-[4-chloro-3-(1H-imidazol-2-yl)-5-methyl-pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone as white powder (32 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.60 (s, 2H), 7.52 (m, 2H), 7.30 (dd, J=8.8, 8.3 Hz, 2H), 5.49 (s, 2H), 3.90 (m, 2H), 2.82 (t, J=5.1 Hz, 2H), 2.22 (s, 3H), 1.95 (m, 2H); MS: (ES) m/z calculated for C21H20ClFN7O [M+H]+ 440.1, found 440.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][CH:12]1[C:18](=O)[NH:17][C:16]2=[C:20]3[C:25](=[N:26][C:27]4=[CH:28][CH:29]=[CH:30][C:14](=[C:15]24)[O:13]1)[CH2:24][CH2:23][CH2:22][CH2:21]3.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][CH:12]1[CH2:18][NH:17][C:16]2=[C:20]3[C:25](=[N:26][C:27]4=[CH:28][CH:29]=[CH:30][C:14](=[C:15]24)[O:13]1)[CH2:24][CH2:23][CH2:22][CH2:21]3
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CNc2c3c(nc4cccc(c24)O1)CCCC3
Reaction time: 0.08 h
Yield: 62 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 15.82 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (2.10 g) in portions; with stirring. After 5 mins, 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.24) was added, and the reaction mixture was stirred at room temperature for four hrs. Ethyl acetate (200 ml) and 10% sodium hydroxide solution (200 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated. The residue was adhered to silica and flash chromatographed (5% triethylamine/toluene). The appropriate fractions were concentrated and the residue was triturated with diethyl ether to yield 2.48 g (62%) of product, mp 169°-170.5° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:15]#[N:16])[CH2:19][CH2:18]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(c2ccc(C(=O)c3cccs3)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 26 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile, 34 parts of 1,2-dibromoethane and 1.6 parts of benzyl triethyl ammonium chloride are added dropwise 60 parts of sodium hydroxide solution 20N (exothermic reaction:temperature rises to 50° C -- cooling is necessary to keep the temperature at 50° C). Upon completion, stirring at 50° C is continued for 4 hours. The product is extracted with toluene. The organic layer is separated, washed three times with water, dried, filtered and evaporated. The solid residue is crystallized from acetonitrile, yielding 12.2 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarbonitrile; mp. 105.8° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C(O)C.O1CCCC1.O>[N:7]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NCCCCCN1CCCCC1
Yield: 59 %

Procedure:
5-Chlorovaleronitrile (10 mmol), 20 mmol of piperidine, 20 mmol of potassium carbonate and a catalytic amount of potassium iodide in 50 ml of ethanol were refluxed for 6 hours. The solvent was removed under reduced pressure, the residue suspended in water and extracted with methylene chloride. The organic layer was purified by column chromatography on silica gel using methylene chloride/methanol/aqueous ammonia (90/10/1) as eluent (Yield: 59%). The product was added dropwise to a suspension of 25 mmol of lithium aluminium hydride in 25 ml of dry tetrahydrofurane at 0° C. After refluxing for 1 hour 10 ml of a saturated solution of sodium/potassium tartrate in water was added dropwise. The residue was filtered off and the filtrate purified by column chromatography on silica gel using methylene chloride/methanol/aqueous ammonia (90/10/1) as eluent. The residue was crystallized with hydrochloric acid from diethyl ether/2-propanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25]([C:27]1([CH2:41]I)[CH2:31][CH2:30][N:29]([C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:28]1)=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25]([C:27]1([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][N:29]([C:32](=[O:40])[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:28]1)=[O:26])[CH3:23]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
4′-Hydroxy-4-biphenyl carbonitrile (329 mg, 1.68 mmol) and potassium carbonate (317 mg, 2.30 mmol) were added to a stirred solution of 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (620 mg, 1.53 mmol) (see Preparation 12) in dimethylformamide (7 mL). The reaction mixture was heated at 80° C. for 18 hours then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (2000 mL), dried over magnesium sulfate then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 3:1→1:1 heptane:EtOAc to afford the title compound as a white solid (517 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[N:43])[CH:37]=4)(=[O:35])=[O:34])=[CH:26][CH:25]=3)[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:43][CH2:42][C:38]1[CH:37]=[C:36]([S:33]([NH:32][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([CH:20]([NH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45])=[N:10][CH:11]=[CH:12]4)[C:21]([OH:23])=[O:22])=[CH:29][CH:28]=2)(=[O:34])=[O:35])[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(CCNS(=O)(=O)c4cccc(C#N)c4)cc3)ccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(CCNS(=O)(=O)c4cccc(CN)c4)cc3)ccc12
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 68C (160 mg) in 10 mL MeOH, was added Pd/C (50 mg). The mixture was hydrogenated at 60 psi for 60 min. The mixture was filtered, concentrated and purified by flash chromatography (0 to 15% MeOH in DCM) to give 68D (108 mg, 66%). MS (ESI) m/z 706.3(M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([C:27]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][C:28]=3[O:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:25]=[CH:26][C:19]=12>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]4[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][C:28]=4[O:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a reaction vial was place a stir bar, NaH (60% in oil, 110 mg), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (70 mg) and THF (3 mL). The mixture was stirred at room temperature for 15 min under N2. {2-[2-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methanesulfonyl-phenoxy]-ethyl}-dimethyl-amine was then added. The mixture was stirred at 80° C. for 30 min. After cooled down to room temperature, the reaction was quenched with H2O and product was extracted with CH2Cl2. The organic extracts were concentrated under vacuum. The residue was purified by silica column chromatography using 20% MeOH/CH2Cl2 as eluent to give 4-{1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. 1HNMR (CDCl3,400 MHz) δ 1.49 (s, 9H), 1.88 (m, 2H), 2.10 (m, 2H), 2.20 (s, 6H), 2.67 (t, 2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.87 (m, 2H), 4.28 (t, 2H), 5.59 (m, 1H), 7.70 (m, 3H), 8.25 (s, 1H), 8.54 (s, 1H). Exact mass calculated for C26H36N6O6S 560.24, found 561.4 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(-n2cccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccn(-c2ccc(OC[C@H]3CCCN3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a 20 mL vial which contained a solution of (R)-2-(4-Pyrrol-1-yl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 1 (220 mg, 0.66 mmol) in dioxane (2 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was removed and the crude was purified by recrystallization from MeOH-ether to yield the desired product (158 mg, 89%); 1HNMR (400 MHz, CDCl3) 7.52 (d, J=9.2 Hz, 2H), 7.27 (t, J=2.0 Hz, 2H), 7.07 (d, J=9.2 Hz, 2H), 6.23 (t, J=2.0 Hz, 2H), 4.28 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 4.12-4.17 (m, 1H), 3.86-3.96 (m, 1H), 3.18-3.27 (m, 2H), 2.06-2.16 (m, 1H), 1.86-2.02 (m, 2H), 1.68-1.78 (m, 1H); LCMS; m/z (ESI+ 243.5, M+1); 93%.
Reaction SMILES: CC(C)([O-])C.[Na+].F[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([O:30][C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([NH2:23])[N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: OC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Nc1nc(OC2CCCCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium tert-butoxide (3.29 g, 34.2 mmol) was added portionwise to cyclohexanol (15 ml) at room temperature. The mixture became very thick and more cyclohexanol (10 ml) was added and the mixture heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added and the mixture heated at 50° C. for 1 hour and then warmed to 60° C. and heated for a further 2 hours at which point LCMS showed complete reaction. The mixture was cooled to room temperature and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated on a water bath at 60° C. The residue was dissolved in dichloromethane and purified on a 70 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 30 mins. Some product-containing fractions were contaminated with cyclohexanol and these were re-purified on a 70 g silica cartridge using a 0-100% ethyl acetate-cyclohexane gradient over 40 mins. Product-containing fractions from the two purifications were combined and evaporated in vacuo to give the title compound as a pale yellow foam (1.59 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:3]2)=[N:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(N2CCCC(N)C2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(N2CCCC(NC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 44 %

Procedure:
This compound was synthesized from 6-(3-aminopiperidin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (75 mg, yield 44%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=2.1 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.00-7.98 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.65-7.61 (m, 2H), 6.77 (d, J=9.2 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H), 4.24-4.21 (dt, J=6.7 Hz, 3.4 Hz, 1H), 4.00-3.98 (m, 1H), 3.91-3.80 (m, 2H), 3.64-3.58 (m, 1H), 2.12-2.05 (ddd, J=13.0 Hz, 8.6 Hz, 4.3 Hz, 1H), 2.03-1.96 (m, 1H), 1.89-1.82 (m, 1H), 1.77-1.69 (m, 1H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 486.13. found: 487.2 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>>[O:1]=[C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1cnc2c(c1)CCCC2O
Solvent: CCN(CC)CC
Product: N#Cc1cnc2c(c1)CCCC2=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (555 mg, 3.19 mmol) in dimethylsuloxide (15 ml) at 23° C. was added triethylamine (1.93 g, 2.66 ml, 19.1 mmol) and sulfur trioxide-pyridin complex (1.52 g, 9.56 mmol). The brown solution was stirred at 23° C. for 2 hours. The reaction mixture was poured on water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and evaporated to give of a light brown solid, which was purified by silica gel flash chromatography with dichloromethane/methanol to give the 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (286 mg, 52% yield) as a light yellow solid. MS (ISP): m/z=173.1 [M+H]+.