Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1.[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1)[CH3:13]
Reactant: Clc1ccc2nccn2n1
Reactant: CCO
Agent: [Na]
Product: CCOc1ccc2nccn2n1

Procedure:
Sodium metal (0.55 g) is dissolved in 30 ml of ethanol and, to the solution, is added 3 g of 6-chloroimidazo[1,2-b]pyridazine and the mixture is heated under reflux for 3 hours. The solvent is then evaporated off under reduced pressure and the residue is dissolved in water and the mixture is extracted with methylene chloride. The extracts are combined, washed with saturated solution of sodium chloride and dried over MgSO4. The solvent is then evaporated to give 3.3 g of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 34.6 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (2.2 g, 4.58 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (1.37 g, 7.33 mmol) in dry 1,4-dioxane (4 mL) was added aqueous CsCO3 solution (10 mL, 10 mmol) and Pd(PPh3)2Cl2 (967 mg, 1.38 mmol). After addition, the mixture was heated at 110° C. for 30 min in a microwave. After TLC showed the stating material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (730 mg, 35%). 1H NMR (CDCl3): 1.09 (s, 3H), 1.16 (s, 3H), 1.51 (m, 3H), 2.05-2.20 (4H), 2.40 (m, 1H), 2.84 (m, 1H), 3.59 (s, 3H), 5.64 (m, 1H), 6.62 (m, 1H), 6.96 (m, 2H), 7.14 (m, 2H), 7.28-7.39 (m, 5H), 7.48 (m, 1H), 7.50 (m, 1H). The compound was recrystallized by two methods.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 5-nitroindazole (20.0 g, 123 mmol) in methylene chloride (400 ml) were added 3,4-dihydro-2H-pyran (16.8 ml, 184 mmol) and p-toluenesulfonic acid (4.22 g, 24.5 mmol) at room temperature, and stirred for 2 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (26.6 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1

Procedure:
Starting from compound D1 and 4-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as described for compound D2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]3[C:36]([N+:37]([O-])=O)=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]3[C:36]([NH2:37])=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of methyl 2-[({2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21b, 8.396 g) and tin (II) chloride dihydrate (13.56 g) in methanol (155 mL) was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and to the concentrated residue were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The mixture was stirred for 1 hr, and filtered, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and concentrated under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The ethyl acetate solution of the resultant product was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column (hexane→thexane:AcOEt=5:1→4:1→3:1→2:1→3:2) to give methyl 2-[({2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate (compound 22b) (6.68 g, 84%) as a brown amorphous solid.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:22])=[CH:9][CH:8]=2)[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)[CH2:12][CH2:13]1)[CH3:21])#[N:20]
Reactant: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)F)cc2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](CC#N)N1CCC(N(C(=O)c2cccnc2)c2ccc(OC(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of the above nitrile (0.20 g, 0.65 mmol) and nicotinoyl chloride hydrochloride (0.46 g, 2.6 mmol) in THF (6 mL) was then treated with DIPEA (0.56 mL, 3.2 mmol) and stirred at 80° C. for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (10 mL) and washed with brine solution (2×10 mL). The combined organic extracts were then dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (50:1:0.1 CH2Cl2/MeOH/NH4OH) to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-difluoromethoxy-phenyl)-nicotinamide as a pale yellow oil (104 mg, 39%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:17]([C:20]2[N:27]3[C:23]([S:24][CH:25]=[CH:26]3)=[N:22][C:21]=2[Cl:28])(=[O:19])=[O:18])[CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:28][C:21]1[N:22]=[C:23]2[N:27]([C:20]=1[S:17]([N:9]1[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH2:6][CH2:5][CH2:4][NH2:1])=[CH:8]1)(=[O:18])=[O:19])[CH:26]=[CH:25][S:24]2
Reactant: [N-]=[N+]=NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Yield: 78 %

Procedure:
A mixture of 3-(3-azidopropyl)-1-[(6-chloroimidazo-[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-fluoro-1H-indole (180 mg, 0.41 mmol) and triphenylphosphine (161 mg, 0.62 mmol in THF and water is stirred under nitrogen for 24 h at room temperature and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/2M NH3 in MeOH: 98/2) to afford the title product as an off-white solid, 132 mg (78% yield), mp 139–141° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])(=[O:3])[NH2:2].[N+:14](=[CH2:16])=[N-:15]>C(OCC)C>[S:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH:16]=[N+:14]=[N-:15])[CH:11]=[CH:12][CH:13]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1cccc(C(=O)Cl)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1

Procedure:
11 g of 3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the crystals were filtered off. Melting point: 142° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>O1CCCC1>[OH:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:13][CH:12]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: C=CCOc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reaction time: 4 h

Procedure:
A solution containing 78.8 g of 4-(prop-2-en-1-oxy)benzoyl chloride (obtainable according to DE-A 2,944,591) and 220.0 g of hydroquinone in 400 ml of dry tetrahydrofuran was boiled for 4 hours under reflux. After being concentrated the product was recrystallized from toluene and ethanol (1:1 parts by volume). Melting point: 146° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH2:28])=[N:22][C:23]([NH2:27])=[N:24]2)=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[NH2:27][C:23]1[N:22]=[C:21]([NH2:28])[C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1nc(N)c2ccc(F)cc2n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2ccc3c(N)nc(N)nc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To 3,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.41 g, 1.2 eq) in dimethylacetamide (50 mL) is added slowly sodium hydride (69.5 mg, 1.5 eq) and the resulting mixture is stirred at RT for 0.5 h. Then 7-Fluoro-quinazolin-2,4-diamine (0.342 g, 1 eq) is added and the mixture is stirred at 150° C. for overnight. The reaction mixture is poured into sat'd NaHCO3 aq. solution (300 mL), extracted by EtOAc (3×150 mL). The combined organic layers are dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography to give 1-(2,4-Diamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.5 g, 77.6% yield). LC/MS m/z=336 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][CH:11]=O.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Yield: 70.3 %

Procedure:
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55% strength in water) in 15 mL of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%) of the desired product were isolated in the form of an amorphous white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:12].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[C:11]([C:13]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:14][CH2:15][N:16]([CH:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1)#[N:12]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CCCC(N2CCC(C#N)CC2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(C#N)(C(=O)OCC)CC2)CC1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 13.3 %

Procedure:
LCMS (Method A): m/z 280 (M+H)+ (ES+), at 1.67 min, UV inactive 1.0 M Lithium bis(trimethylsilyl)amide (4.48 mL, 7.17 mmol) was added to anhydrous THF (20 mL) under nitrogen and cooled to −78° C. The solution was treated drop wise with ethyl 4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (0.400 g, 1.43 mmol) as a solution in anhydrous THF (2 mL). The solution was stirred at −78° C. under nitrogen for 1 h, ethyl chloroformate (0.17 g, 1.57 mmol) was added drop wise. The solution was stirred at −78° C. for a further 2 h and then allowed to warm to rt overnight. The reaction mixture was quenched with the addition of water and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol. The organic layer was washed with sat. NaCl sol. and dried by passing through a Biotage Phase Separator cartridge. The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl 4-[4-cyano-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.067 g, 12.7%) as an amber oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: CN1CCN([C@H]2CC[C@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AD) (0.300 g, 0.00068 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.304 g, 0.00102 mol), sodium carbonate (0.180 g, 0.00170 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.155 g, 0.00032 mol): 1H NMR (DMSO-d6, 400 MHz) 8.78 (s, 2H), 8.25 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.65 (m, 1H), 1.44-2.36 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.33.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][CH:23]=1>>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)/[C:8]([NH:27][C:25]2[S:26][C:22]([F:21])=[CH:23][N:24]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc(F)s1
Reactant: CCSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Agent: Cl
Product: CCSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(F)s2)cn1

Procedure:
Condensation of (E)-3-cyclopentyl-2-(6-ethylsulfanylpyridin-3-yl)acrylic acid (Preparation 4, 215 mg, 0.78 mmol) with 5-fluorothiazol-2-ylamine hydrochloride (Preparation 21, 240 mg, 1.55 mmol), by the protocol described in EXAMPLE 5, yielded (E)-3-cyclopentyl-2-(6-ethylsulfanylpyridin-3-yl)-N-(5-fluorothiazol-2-yl)acrylamide: m/z (ES+)=378.2 [M+H]+. Oxidation of this thioether (22 mg, 60 μmol), by the protocol described in EXAMPLE 55, gave the title compound: RTA=3.50 min; m/z (ES+)=394.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(O)C.[Pd]>[NH2:14][C:4]1[C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C)c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(OC)c1N
Yield: 94 %

Procedure:
To a solution of methyl 3-methoxy-4-methyl-2-nitrobenzoate (395 g, 1.75 mol) in ethanol (6700 mL) was added Pd/C (39.5 g) in one portion. The reaction mixture was stirred at room temperature under 50 psi of hydrogen overnight. TLC (petroleum ether/ethyl acetate=3:1) indicated the reaction was complete. The mixture was filtered and the filtrate was evaporated in vacuo to give the crude product, which was re-crystallized from ethanol (1.6 L) to give the title compound (321 g, 93.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH:22][CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:18]=[CH:19][C:20]=1[F:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:28][CH2:29][CH:24]([CH:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[NH:22][C:17]3[CH:18]=[CH:19][C:20]([F:21])=[C:15]([F:14])[CH:16]=3)[CH2:25][CH2:26]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Reactant: O=S(CCCCl)c1ccc(Cl)cc1
Product: O=S(CCCN1CCC(C(Nc2ccc(F)c(F)c2)c2ccc(F)cc2)CC1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 1-chloro-4-[(3-chloropropyl)sulfinyl]benzene and N-(3,4-difluorophenyl)-α-(4-fluorophenyl)-4-piperidinemethanamine.
Reaction SMILES: [C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1)=[O:19])([O:3]CC)=O.CC(C)([O-])C.[K+].C1COCC1.CS(O)(=O)=O>C(O)C>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][N:20]2[C:1](=[O:3])[C:6]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:8][C:7]=3[NH:17][C:18]2=[O:19])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCN1CCN(c2ccccc2OC)CC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3sc(-c4ccccc4)cc3c2=O)CC1
Yield: 51.1 %

Procedure:
A solution of Example 5B (387 mg, 0.762 mmol) in ethanol (5 mL) was treated with 1M potassium t-butoxide/THF (0.84 mL), heated to reflux for 90 minutes, cooled, quenched with 1N HCl(0.84 mL), and partitioned between water and ethyl acetate. The insoluble solid was collected, washed with ethyl acetate, slurried in methanol, treated with methanesulfonic acid (2 equiv), and concentrated. The product was crystallized from ethanol to provide 180 mg the title compound as the bis methanesulfonate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1ccc(O)cc1Cl
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-chloro-4-hydroxybenzonitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=3)[C:30]([CH3:40])=[C:29]2[CH3:41])=[CH:23][CH:22]=1)=[O:14])(C)(C)C>>[CH3:41][C:29]1[N:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]([OH:14])=[O:12])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)[C:36]2[C:31]([C:30]=1[CH3:40])=[CH:32][C:33]([C:37](=[O:38])[NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:34][CH:35]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccs1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccs3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-thiophenemethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)(=[O:14])=[O:15])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18]
Reactant: OC1CCNC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.3 %

Procedure:
To a stirred solution of (RS)-3-pyrrolidinol (0.75 g, 8.6 mmol) in THF (18 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.5 g, 5.72 mmol) and triethylamine (0.88 ml, 6.3 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate), and subsequent crystallization from dichloromethane/MeOH/hexane to yield (RS)-1-(5-chloro-4-nitro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (0.65 g, 36%) as a yellow solid. MS (EI) 312.0 [(M)+], mp 96° C.