Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.Br[C:25]1[C:26](=[O:43])[N:27]([CH3:42])[C:28]2[N:33]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:32]=[CH:31][C:29]=2[N:30]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:25]3[C:26](=[O:43])[N:27]([CH3:42])[C:28]4[N:33]([C:34]5[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=5[F:41])[N:32]=[CH:31][C:29]=4[N:30]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(=O)c(Br)nc2cnn(-c3c(F)cccc3F)c21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 125 °C

Procedure:
A mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (520 mg, 1.63 mmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (505 mg, 1.48 mmol) in 3.5 mL of dioxane and 1.5 mL of 2 N Na2CO3 was heated in a microwave at 125° C. for 25 min. It was diluted with EtOAc and washed with 1 N NaOH. The EtOAc layer was separated, dried and concentrated. Purification of the crude material on an ISCO 40 g column (with 30-75% EtOAc in Hexanes) provided N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylb enzamide as an off white amorphous solid. MS (ES+): 454.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.CCN(CC)CC>CCO>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 0 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mol), 4-chloro-6-(trifluoromethyl)quinazoline (48 mg, 0.20 mol) and Et3N (100 mg, 1.0 mol)in EtOH (2 ml) was added to a microwave reaction tube, sealed, and heated in a microwave oven at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (3%–5% (NH4OH/MeOH)/CH2Cl2) to give 25 mg of the title product, (1R,2S,5R)-methyl 5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=508.24.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[N:13]([C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:14]=[N-:15]
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccnc2c(F)cccc12
Yield: 93.2 %

Procedure:
A mixture of 2.08 g (0.0114 mol) of 4-chloro-8-fluoroquinoline, 1.12 g (0.0172 mol) of sodium azide, and 4.10 g ((0.0127 mol) of tetrabutyl ammonium bromide in 70 mL of dichloromethane and 25 mL of water was refluxed overnight. The layers were then separated and the organic layer was washed once with water, passed through phase separating paper, and concentrated to an oil, which was triturated with ether. The solid was filtered and the filtrate was concentrated to give 2.0 g of the title product.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.[O-][O-].[Na+].[Na+]>C(#N)C.O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [O-][O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Yield: 55.9 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) is dissolved with stirring in acetonitrile (40 ml). The resulting solution is stirred while p-toluene- sulphonyl chloride (2.38 g, 12.5 mmol) added. The reaction mixture is cooled in an ice-water bath. A solution of sodium peroxide (2.42 g, 31 mmol) in water (30 ml) is added dropwise over 20 minutes. After a further 2 hours the reaction mixture is filtered under vacuum and the filtrate evaporated in vacuo. Water is added and the resulting solid collected, and washed with water and ether to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.63 g, 56%) with spectra identical to authentic material.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:20][C:19]1[CH:21]=[CH:22][C:16]([CH3:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: Cc1ccc(N)cc1
Solvent: CO
Product: Cc1ccc(N=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-methylaniline (0.31 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.56 g, 2.4 mmol, yield: 90%) as colorless needles.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)CCC>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCO
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 100 grams (1.0 mole) of hydantoin, 151 grams (1.0 mole) of 4-nitrobenzaldehyde, 77 grams (1.0 mole) of ammonium acetate, 120 grams (2.0 moles) of acetic acid, and 200 ml of n-butanol were held for 3 hours at reflux temperature. After the cooling, there were obtained 219 grams of 5-(4'-nitrobenzylidene)-hydantoin, corresponding to 94% of the theory based on hydantoin. The product had a melting point of 253°-254° C. and homogeneous by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH:5]=O.COC1C=CC(C)=CC=1[C:21](=C)[C:22]([OH:24])=[O:23].C(O)(=O)C=C>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COc1ccc(C)cc1C=O
Reactant: C=C(C(=O)O)c1cc(C)ccc1OC
Agent: C=CC(=O)O
Product: COc1ccc(C)cc1CCC(=O)O
Yield: 899.7 %

Procedure:
10 mmol of the appropriate aldehyde are dissolved with 1.1 eq. of triethyl phosphonoacetate in 7 ml THF. At 0° C. 1 eq. of DBU is added and the reaction mixture is stirred over night at room temperature. Then, the reaction mixture is diluted with water, acidified with aq. HCl and extracted with diethyl ether. The organic layer is dried over MgSO4 and the solvent removed. This acrylic acid ester is used without further purification. The crude acrylic acid ester is suspended in 20 ml 1N NaOH and stirred over night. After the reaction is completed, the reaction mixture is acidified with 1N HCl and extracted with diethyl ether. The organic layer is dried over MgSO4 and the solvent evaporated; the desired acrylic acid is obtained in almost pure form. 11 mmol of the acrylic acid are dissolved in 20 ml MeOH, 1 eq. of NAHCO3 and 200 mg Pd/C (10%) are added and the reaction hydrogenated over night at room temperature and normal pressure. Filtration of the reaction mixture over Celite and removal of the solvent affords the desired product in good yield in pure form. In case one of the products is not sufficiently pure, one can also purify them via flash chromatography. According to the above-mentioned procedure, the following compound can be prepared: 2 g of 2-methoxy-5-methyl-benzaldehyde is transformed to 2.2 g of (2-methoxy-5-methyl-phenyl)-acrylic acid. 21 g of the before-mentioned acrylic acid are hydrogenated to yield 20 g of the desired 3-(2-methoxy-5-methyl-phenyl)-propionic acid. Further relevant starting compounds can be prepared similarly.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[Cl:8][C:9]1[C:18]2[N:17]([CH3:19])[O:16][C@H:15]3[NH:20][C@H:21]([C:23]([O:25][C@@H:26]4[C@:35]5([OH:36])[C@@H:30]([C@H:31]([CH:38]([CH3:40])[CH3:39])[CH2:32][CH2:33][CH:34]5[CH3:37])[CH:29]=[C:28]([CH3:41])[CH:27]4[OH:42])=[O:24])[CH2:22][C@@:14]3([OH:43])[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:8][C:9]1[C:18]2[N:17]([CH3:19])[O:16][C@H:15]3[NH:20][C@H:21]([C:23]([O:25][C@@H:26]4[C@:35]5([OH:36])[C@@H:30]([C@H:31]([CH:38]([CH3:39])[CH3:40])[CH2:32][CH2:33][C@H:34]5[CH3:37])[CH:29]=[C:28]([CH3:41])[C@H:27]4[O:42][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])=[O:24])[CH2:22][C@@:14]3([OH:43])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCOC(=O)Cl
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Allyl chloroformate (17.4 mg) was added to a stirred, cooled (0° C.) solution of (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 50 mg) and 4-dimethylaminopyridine (35 mg) in dichloromethane (5 ml) under an atmosphere of nitrogen. After 30 minutes, the reaction was allowed to warm to room temperature over 15 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with aqueous citric acid (10% w/w, 3×15 ml) and dried (MgSO4). After evaporation of solvent in vacuo, the residue was purified by flash column chromatography on silica (5 g) eluting with 1:1 ethyl acetate:hexane to give the product (44 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]([C:21]([O:23][CH3:24])=[O:22])=[CH:12][N+:11]=1[O-].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:12]1[N:11]=[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)[n+]([O-])c1
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1Cl

Procedure:
A mixture of 2-(2-fluoro-5-methoxyphenyl)-3-isobutoxy-5-(methoxycarbonyl)pyridine 1-oxide (600 mg) and phosphoryl chloride (5.0 mL) was heated under reflux for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (315 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: COC(=O)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
A solution of (1R,2S)-methyl 2-((S)-3-(benzyloxy-carbonylamino)-2-oxopyrrolidin-1-yl)-5-oxocyclo-hexanecarboxylate (3.1 g, 8 mmol) in DMSO (7 ml) was treated with t-butylamine (1.75 g, 24 mol) and stirred for 10 minutes before Ti(i-OPr)4 (6.8 g, 24 mol) was added and the resulting mixture was stirred at room temperature for 2.5 h. Then NaBH4 (0.3 g, 8 mol) was added and stirred for 1.5 h before diluting slowly with methanol (gas evolution) and the resulting solution stirred an additional 1 h. While stirring vigorously, a sat'd solution of NaHCO3 was added, and the resulting suspension was filtered through Celite. The filter cake was washed thoroughly with CH2Cl2 several times and the combined washes were transferred to a separatory funnel. The organic layer was separated and washed with water and brine, concentrated and the residue chromatographed on silica gel (5% MeOH/CH2Cl2-8% NH4OH/MeOH/CH2Cl2) to give 3.0 g (80%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexane-carboxylate. MS found: (M+H)+=446.30. Also obtained was 400 mg of the isomeric (1R,2S,5S)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate. MS found: (M+H)+=446.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][S:6][CH2:5][S:4][CH2:3]1.CCCCCC.C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH:5]1[S:6][CH2:7][N:2]([CH3:1])[CH2:3][S:4]1
Reactant: C[Si](C)(C)Cl
Reactant: CN1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CSC([Si](C)(C)C)SC1

Procedure:
5-Methyl-1,3,5-dithiazine, 2.7 g, was dissolved in 20 ml of tetrahydrofuran and 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -73° C. The mixture was stirred at the same temperature for an hour. Then, 2.4 g of trimethylsilyl chloride was dropwise added to the mixture at the same temperature. After completion of the dropwise addition, the temperature of the reaction mixture was gradually elevated to 0° C. and then stirred for 90 minutes to give crude 2-trimethylsilyl-5-methyl-1,3,5-dithiazine. Without purifying the crude product, 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added thereto at -10° C. followed by stirring for 30 minutes. After cooling to -73° C., a solution of 4.5 g of 4-phenoxypropiophenone in 10 ml of tetrahydrofuran was dropwise added. After completion of the dropwise addition, the temperature was gradually elevated to room temperature followed by stirring for 14 hours. After saturated sodium chloride aqueous solution was added to the mixture, it was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =2 : 1) to give 5.5 g of the product.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]>ClCCl>[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)o1
Reaction time: 0.05 h
Yield: 74.2 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 280 mg, 0.78 mmol) in 5 mL of dichloromethane was added triethylamine (240 mg, 2.37 mmol). The mixture was stirred for 3 min followed by the addition of 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (210 mg, 0.94 mmol). The stirring was continued for 2 h at room temperature and then the reaction was quenched with 20 mL of saturated NaH2PO4. The mixture was extracted with Ethyl acetate (40 mL) and the organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-50% Ethyl acetate/hexanes) gave 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-furan-2-carboxylic acid methyl ester as a clear oil (295 mg, 74%). ESI/CI-MS m/z 508 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]([OH:10])[CH3:9].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[N:28][CH:29]=2)[NH:26][CH2:25][CH2:24][CH2:23]3)O1>>[Cl:11][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:24]2[CH:25]=[N:26][C:27]3[NH:28][CH2:29][CH2:20][CH2:21][C:22]=3[CH:23]=2)[C:7]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(O)c1c(Cl)cncc1Br
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2

Procedure:
1-[3-Chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol is synthesized according to the procedure of Suzuki Coupling Method VI using 1-(3-bromo-5-chloro-pyridin-4-yl)-ethanol (which is prepared according to Step 1 of Example 78) and crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (that is prepared according to Step 4 of Example 105).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(N3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(4-(2-hydroxyethyl)phenyl)isoindoline-1,3-dione (926 mg, 3.46 mmol) was dissolved in dichloromethane (15 mL), cooled to 0° C. and p-toluenesulfonyl chloride (991 mg, 5.2 mmol) was added, followed by pyridine (0.56 ml, 6.93 mmol). The reaction was stirred at room temperature for 16 h and concentrated. The residue was dissolved in ethyl acetate (60 ml), washed with water (20 ml), saturated aqueous NaHCO3 (2×15 ml), brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude tosylate was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C(O[CH:13](N(C)C)[N:14]([CH3:16])[CH3:15])(C)(C)C>CN(C)C=O>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccncc1
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccncc1
Yield: 80.2 %

Procedure:
A solution of 47 g 4-picoline and 105.5 g bis(dimethylamino)methyl tertiary-butyl ether in 125 ml dimethylformamide (DMF) was heated at 140° C. under nitrogen for 18 hours. The solvent was removed in vacuo and the crystalline residue dissolved in boiling cyclohexane (about 3 L). The solution was filtered through filter paper containing charcoal and concentrated in vacuo to give 60 g (80%) 4-(2-dimethylamino-1-ethenyl)pyridine as light orange crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[NH:20][C:21](=O)[CH2:22][C:23]([C:25]1C=C[CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.[C:35](O)([C:37](F)(F)F)=[O:36]>C(Cl)Cl>[CH3:14][C:12]1[C:11]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]2[N:20]=[C:21]([C:22]3[CH:28]=[C:27]([CH:26]=[CH:25][CH:23]=3)[C:31]#[N:32])[CH2:37][C:35](=[O:36])[NH:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)CC(=O)c2cccc(C#N)c2)c(NC(=O)OC(C)(C)C)cc1C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-methyl-4-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M79) (0.17 g, 0.37 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (74 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:20])=[O:13])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: CNc1ccccc1
Product: CN(C(=O)C1c2ccccc2COc2ccc(Br)cc21)c1ccccc1
Yield: 49.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.41 g of N-methylaniline in place of aniline to obtain 0.63 g of Compound 43.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])=[CH:12][NH:11][N:10]=1.IC.[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH3:28])[N:11]=[CH:12][C:13]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12)=[O:16]
Reactant: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3cccnc23)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(-c2c(NC(=O)c3cnn4cccnc34)cnn2C)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.255 g, 0.767 mmol, 1 eq) in 10 mL N,N-dimethylformamide is added iodomethane (60.0 μL, 0.964 mmol, 1.26 eq) and cesium carbonate (0.562 g, 1.72 mmol, 2.25 eq). The reaction mixture is stirred at 40° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The mixture of regioisomeric products was separated and purified by flash chromatography on silica gel (20 to 90% ethyl acetate in dichloromethane) to yield: 84.3 mg (32%) of N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 9.30 (d, 1H), 8.65 (s, 1H), 8.47 (d, 1H), 8.27 (s, 1H), 7.27 (d, 1H), 7.23-7.19 (m, 3H), 3.91 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), and 81.8 mg (31%) of N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 9.30 (d, 1H), 8.61 (s, 1H), 8.43 (d, 1H), 8.01 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H) 7.20 (m, 2H), 3.62 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H).