Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.8 %

Procedure:
To a solution of 3,5-dichlorophenol (5.0 g, 30 mmol) and CH2Cl2 (60 mL) were added tert-butyldimethylsilyl chloride (5.54 g, 36 mmol), N,N-diisopropylethylamine (8.0 mL, 46 mmol), and a catalytic amount of 4-dimethylaminopyridine. The initially exothermic solution was stirred at ambient temperature for 6 h then diluted with CH2Cl2 (40 mL). The mixture was washed consecutively with 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the title compound as a pale yellow liquid (8.8 g, 100%). 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.72 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=2[N:10]=1)(=O)=O.Cl.[CH3:23][NH:24][CH3:25].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:23][N:24]([CH3:25])[C:5]1[N:6]=[CH:7][C:8]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)ncc2C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)c1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of tert-butyl 2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (2.8 g, 8.95 mmol, 1.0 eq.), dimethylamine HCl (1.09 g, 13.42 mmol, 1.5 eq.) and DIPEA (4.37 ml, 25.56 mmol, 4.0 eq.) in NMP (6.5 ml) was stirred for 1 hour at 130° C. in a microwave. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×150 ml). The combined org. phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 18% ethyl acetate in hexane). Yield: 78% (1.95 g, 7.01 mmol)
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([O:18]CC)=O)[CH:13]=[CH:14][C:8]=2[S:7](=[O:22])(=[O:21])[N:6]=1)([CH3:3])[CH3:2].[CH:23]1([C:26](=[N:28]O)[NH2:27])[CH2:25][CH2:24]1.[H-].[Na+].ClCCl>CN(C)C=O.C(O)(=O)C>[CH:23]1([C:26]2[N:28]=[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:8]4[S:7](=[O:21])(=[O:22])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[NH:10][C:9]=4[CH:11]=3)[O:18][N:27]=2)[CH2:25][CH2:24]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)NC1=NS(=O)(=O)c2ccc(Cc3nc(C4CC4)no3)cc2N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g), crushed 4 Å molecular sieves (0.6 g), cyclopropanecarboxamide oxime (0.30 g), and sodium hydride (40 mg of a 60% oil dispersion) in 5 ml of dry dimethylformamide was stirred at room temperature for 45 min. Two drops of glacial acetic acid and 20 ml of dichloromethane were added and the mixture was stirred for 10 min. and filtered through celite. The solvents were removed in vacuo from the filtrate. The remaining oil was stirred with 5 ml of water for 15 min and the resulting precipitate was collected by filtration and dried to give the title compound; m.p. 255-259° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24]([C:29]([F:31])([F:30])[F:28])([OH:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
1-(4′-Benzyloxybiphenyl-4-yl)piperidin-4-one (7.1 g, 19.9 mmol), tetrabutylammonium acetate (0.3 g, 1.0 mmol) and 1,2-dimethoxethane (100 ml) were mixed. While stirring the mixture under ice cooling, trifluoromethyltrimethylsilane (4.11 ml, 27.8 mmol) was added to the mixture and warmed to room temperature, followed by stirring for 6 hours. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (100 ml). While stirring at room temperature, 1 mol/l tetrabutylammonium fluoride in tetrahydrofuran (23.8 ml, 23.8 mmol) was added thereto and stirred at room temperature overnight. Water was added to the residue obtained by distilling off the solvent, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting crude crystal was washed with diethylether to afford the title compound as a white powder (7.6 g, yield 90%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1)(=[O:3])[CH3:2].[F:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=1>ClCCl.C[Si](C1NC(=O)N([Si](C)(C)C)C(=O)C=1F)(C)C>[OH:12][CH2:13][CH2:14][O:15][CH:11]([N:21]1[CH:22]=[C:17]([F:16])[C:18](=[O:24])[NH:19][C:20]1=[O:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C1OCCO1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(OCCO)n1cc(F)c(=O)[nH]c1=O
Yield: 16.1 %

Procedure:
2-Hydroxygenzaldehyde (10 g) was dissolved in acetic anhydride (30 ml) and pyridine (30 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting precipitate was recovered by filtration. The precipitate was dissolved in chloroform (100 ml), washed with water, dried and evaporated to give 2-acetoxybenzaldehyde. To a solution of 2-acetoxy-benzaldehyde (13 g) and ethyleneglycol (10 ml) in benzene (80 ml) was added Amberlist 15 (Rohm and Haas Co.) (3 g) and followed by refluxing for 5 hours. Water generated during refluxing was removed as an azeotropic mixture. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, and then with water, and dried and evaporated. The residue was distilled under reduced pressure to collect a fraction distilled out at 115°-125° C./4 mmHg to give 10 g of 2-(2-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-(2-acetoxy-phenyl)-1,3-dioxolan (19.6 g) in dichloromethane (50 ml), bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 4.2 g of crystalline 1-[α-(2-hydroxyethoxy)-2-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(Cl)CCl>ClCCl>[CH3:37][O:36][N:35]([CH3:34])[C:11](=[O:13])[CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])n1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CON(C)C(=O)Cc1cccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a suspension of 250 mg (1.37 mmol) of (6-nitropyridin-2-yl) acetic acid in 6 mL of dichloromethane was added DIEA (0.72 mL, 4.12 mmol) which resulted in some exotherming (+5° C.) and the suspension becoming a solution. After 2 min cooling, HOBt (263 mg, 1.72 mmol), N,O-dimethylhydroxylamine HCl (167 mg, 1.72 mmol) was added to the solution followed by EDC (329 mg, 1.72 mmol) and the resulting mixture stirred at room temperature overnight under nitrogen atmosphere. The solution was transferred to a separatory funnel and washed with 1 M HCl which caused an emulsion. Methanol was added to break up the emulsion and the aqueous was partitioned off. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. Purification via preparative TLC plate (2×1000 μM) eluting with 50% ethyl acetatehexane afforded the title compound (236 mg, 76%) as a white solid. LC-MS: C9H11N3O4 calculated 225.20 found m/z (ES) 226 (MH)+. 1HNMR (500 MHz, DMSO) δ:8.56 (d, J=2.0 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.04 (dd, J=2.0, 8.3 Hz, 1H), 4.02 (br s, 2H), 3.88 (s, 3H), 3.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1)=[O:5]
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1cccc(B(O)O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To make compound (6a), a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238° C.(dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.08–7.19 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.42–7.50 [m, 1H, Ar—H], 7.54–7.60 [m, 1H, Ar—H], 7.60–7.68 [m, 2H, Ar—H], 7.73–7.78 [m, 3H, Ar—H].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[NH:38][NH2:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([NH:39][NH:38][C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)c(C)nc21
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)c(C)nc21
Reaction time: 18 h
Yield: 54.7 %

Procedure:
Intermediate 60 (0.253 g, 0.83 mmol), EDC (0.223 g, 1.17 mmol) and HOBT (0.135 g, 1.0 mmol) in DMF (5 ml) was stirred at 20° C. for 30 minutes. t-Butyl carbazate (0.110 g, 0.83 mmol) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in DMF (5 ml) additional EDC (0.159 g0) and HOBT (0.112 g) added. After 30 minutes t-butyl carbazate (0.019 g) was added and stirring continued for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo. The material was applied to a SPE cartridge (silica, 10 g) and eluted with cyclohexane:ethyl acetate (1:1 followed by 2:1) to afford Intermediate 62 as a white solid (0.19 g). LCMS showed MH+=419; TRET=2.35 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([P:8]([C:16]2[N:21]=[C:20]([Br:22])[CH:19]=[CH:18][CH:17]=2)[C:9]2[N:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH:23]O.O>C(Cl)(Cl)Cl>[Br:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([P:8](=[O:23])([C:9]2[N:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]=2)[C:4]2[N:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:21]=1
Reactant: OO
Reactant: Brc1cccc(P(c2cccc(Br)n2)c2cccc(Br)n2)n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=P(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension, heated to boiling, of 50.2 g (100.0 mmol) of tris(2-bromo-6-pyridyl)phosphine in 500 ml of chloroform was admixed with intensive stirring dropwise with a mixture of 11 ml of 35% by weight H2O2 and 50 ml of water, which afforded a clear solution. After stirring under reflux for 5 h, the solution was allowed to cool to room temperature. The solution was washed with 500 ml of water, and the organic phase was removed and concentrated to 50 ml under reduced pressure. After standing for 2 h, the precipitated crystals were filtered off, washed three times with 100 ml of n-hexane and then dried at 70° C. under reduced pressure. The yield at a purity of 99.0% was 47.1 g (90.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7]([CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCOc2c(I)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCOc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
14.40 g (50.0 mmol) of 4,4-dimethyl-8-iodochroman and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 22 ml (55.0 mmol) of n-butyllithium (2.5M in hexane) are added dropwise at −78° C., the reaction mixture is stirred for 30 minutes, then 4.2 ml (55.0 mmol) of DMF are added and the mixture is allowed to return to room temperature. The reaction mixture is poured onto an aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 10.40 g (100%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[Li][CH3:14]>CCOCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([OH:12])[CH3:14])=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCOCC
Product: CC(O)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To 4-quinolinecarbaldehyde (2 g, 12.73 mmol) in 20 ml anhydrous ether, MeLi (1.4M, 10 ml, 13.9 mmol) was added dropwise over a period of five minutes at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solution was partitioned between ether (20 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give 1.43 g (59%) of the product which was then used as such for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([C:16]1[NH:17][C:18]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([Cl:28])=[C:25]([OH:27])[CH:26]=2)[N:20]=1)([CH3:15])[CH3:14]>ClCCl.CO>[Cl:28][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:16]([C:13]([CH3:14])([CH3:15])[CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[NH:17][C:18]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:26][C:25]=1[OH:27]
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CNC(=O)Nc1ccc(Cl)cc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of 4-chlorophenylisocyanate (46 mg, 0.3 mmol) in dichloromethane (5 ml) was treated with a solution of Example 3 (103 mg, 0.3 mmol) in methanol (1 ml). After stirring at room temperature for 30 min the solution was concentrated under reduced pressure and the residue chromatographed on silica gel eluting with dichloromethane/methanol (10:1) to the give the title compound (72 mg, 48%) as a pale yellow solid; MS(ES+) m/e 496/498/500 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:16]3[CH:21]4[CH2:22][CH2:23][CH:17]3[CH2:18][C:19](=O)[CH2:20]4)[O:12]CCO2)=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.O.Cl>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:28]([C:29]([CH:19]2[CH2:18][CH:17]3[N:16]([CH2:15][CH2:14][CH2:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:12])[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:25])=[CH:27][CH:26]=1
Reactant: O=C1CC2CCC(C1)N2CCCC1(c2ccc(F)cc2)OCCO1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(CCCN1C2CCC1CC(C(=O)c1ccc(F)cc1)C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the resulting suspension is added dropwise with stirring, a solution of 3.33 g. (0.01 mol) 8-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-8-azabicyclo[3.2.1]octan-3-one in 50 ml. dry tetrahydrofuran over 20 minutes while the reaction temperature is maintained between -65° C. to -75° C. The cold reaction mixture is then permitted to stir for 11/2 hours, then allowed to warm to room temperature, after which it is placed in an oil bath at +60° to 65° for 4 hours. After standing for about 16 hours, 50 ml. of water and 100 ml. of diethyl ether is added and following agitation the layers are partitioned. The aqueous solution is extracted two additional times with diethyl ether and all ethereal extracts are combined, dried over anhydrous sodium sulfate and concentrated to afford a viscous oil. The oil is dissolved in 300 ml. of acetone, 20 ml. of 1.2 N hydrochloric acid is added and the solution stirred for 4 hours. The solution is concentrated in vacuo, 100 ml. of 3 N hydrochloric acid is added and the solution is extracted with 150 ml. of diethyl ether. The hydrochloric acid solution is made basic with 15% sodium hydroxide aqueous solution, then extracted three times with 100 ml. portions of diethyl ether.
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:23][CH:24]([F:26])[F:25])[CH:10]=2)[C:5]1=[O:27])C=C.C(N(CC)CC)C.C(O)=O>O1CCOCC1>[F:26][CH:24]([F:25])[O:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:27])[NH:4][C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(OC(F)F)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: N#Cc1[nH]c(=O)c2ccc(OC(F)F)cc2c1-c1cccc(F)c1

Procedure:
To a solution of 2-allyl-6-(difluoromethoxy)-4-(3-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile in 10 mL dioxane were added triethylamine (0.363 mL) and formic acid (0.079 mL). The solution was sparged with argon for 10 min, then Pd(PPh3)4 was added, and the reaction was heated to 100 C for 2 h. The reaction was concentrated to dryness, then partitioned between CH2Cl2 and and 50% brine. The organic solution was dried (MgSO4) and concentrated to dry solid. Flash chromatography (5-45% EA/hex, 1% MeOH, 40 g silica) provided 110 mg of 6-(difluoromethoxy)-4-(3-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile. The material was approximately 80% pure and was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18]C=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22].[CH:46]1C=CC=CC=1>>[CH3:14][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:46]=[CH:26][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:1])[CH3:3])[C:10]=1[OH:11])([CH3:15])[CH3:13]
Reactant: c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Product: CCOC(=O)C=CCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 72 h

Procedure:
Triethylamine (1.1 ml, 7.6 mmole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (18.2 g, 76 mmole) in methanol (200 ml) and stirred for 30 minutes. Freshly distilled acrolein (12.8 g, 0.23 mole) was added and the solution stirred at room temperature. Chromatography on silica gave 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanal. To a solution of the aldehyde (2.0 g, 6.8 mmole) in benzene (20 ml) under argon was added in one portion (carbethoxymethylene)triphenylphosphorane (2.36 g, 6.8 mmole). The mixture was heated at reflux for 20 hours, allowed to stand at room temperature for three days, and then concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]=[CH2:35])(=[O:33])=[O:32])[CH2:4]1)[CH3:2].CCN(C(C)C)C(C)C.[NH:45]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[N:46]1>C(O)CC.C(Cl)Cl>[C:50]([C:48]1[CH:49]=[N:45][N:46]([CH2:35][CH2:34][S:31]([NH:30][C@@H:5]2[CH2:6][C@H:7]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:3]([CH2:1][CH3:2])[CH2:4]2)(=[O:32])=[O:33])[CH:47]=1)#[N:51]
Reactant: C=CS(=O)(=O)N[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reactant: N#Cc1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)CCn2cc(C#N)cn2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethenesulfonamide (0.065 g, 0.13 mmol, prepared using K.1 from Example #8 Step M and 2-chloroethanesulfonyl chloride with TEA), DIEA (0.30 mL, 1.7 mmol) and 1H-pyrazole-4-carbonitrile (0.047 g, 0.51 mmol, American Custom Chemicals Corp) in n-PrOH (2.0 mL) was stirred for about 2 h at about 60° C. then at about 80° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude residue was dissolved in DCM (10 mL), washed with saturated NaHCO3 (5 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 2-(4-cyano-1H-pyrazol-1-yl)-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)ethanesulfonamide (0.024 g, 42%): LC/MS (Table 1, Method b) Rt=1.63 min; MS m/z: 454 (M+H)+.