Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[O:3]=[C:4]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:21][CH2:20]1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH:13]=1)=[O:8].[C:36](O)(=O)C.N>O.[Zn]>[O:3]=[C:4]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[CH2:21][CH2:20]1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][CH2:17][N:16]([CH3:36])[CH2:15]2)[CH:13]=1)=[O:8]
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCNC2)nn1
Reactant: CC(=O)O
Agent: C=O
Agent: N
Agent: [Zn]
Solvent: O
Product: CN1CCC(n2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)nn2)C1
Reaction time: 0.08 h
Yield: 122.1 %

Procedure:
37% Aqueous formaldehyde (12 mg, 0.4 mmol) solution was added to a stirred solution of 1-pyrrolidin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide (100 mg, 0.15 mmol) in a mixture of acetic acid (37.62 mg, 0.62 mmol) and H2O (0.5 mL) and stirring was continued at ambient temperature for 5 minutes. To the above mixture was added, Zinc powder (39.23 mg, 0.6 mmol) and stirring was continued at ambient temperature for 1 hr. The reaction mixture was cooled, basified with aqueous ammonia solution and extracted with DCM. The organic layer thus collected was dried over sodium sulfate and concentrated under reduced pressure to afford 88 mg (88% Yield) of 1-(1-methyl-pyrrolidin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 481.2. 1H NMR (300 MHz, DMSO-d6): δ 11.2-11.0 (b, 1H), 8.85 (s, 1H), 8.4 (s, 1H), 7.5 (t, 1H), 7.3 (t, 3H), 5.51 (b, 1H), 4.7 (m, 2H), 4.4 (d, 2H), 3.8 (m, 1H), 3.7 (m, 2H), 3.4 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.0 (m, 2H), 1.7-1.5 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C@H:8]2[CH2:12][CH2:11]C(=O)[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.[NH2:25][NH2:26]>C1COCC1>[C:17]([O:16][C:14](=[O:15])[NH:9][C@@H:8]([CH2:7][C:6]1[CH:21]=[CH:22][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=1)[CH2:12][CH2:11][NH:25][NH2:26])([CH3:20])([CH3:19])[CH3:18]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCNN)Cc1ccc(C(F)(F)F)cc1
Yield: 91.4 %

Procedure:
(R)-tert-Butyl 2-(4-(trifluoromethyl)benzyl)-5-oxopyrrolidine-1-carboxylate (1.46 g, 4 mmol) (prepared as shown in Scheme 15) was treated with hydrazine (0.5 mL, 16 mmol) at 50° C. in THF for 30 minutes. The mixture was partitioned between EtOAc and saturated aqueous ammonium chloride, and dried over sodium sulfate. Evaporation provided the desired product as a white amorphous solid (1.27 g, 87%). LCMS (API-ES) m/z: 276 (M-Boc+H+).
Reaction SMILES: Cl[C:2]12[CH2:10][CH2:9][C:5]([CH3:11])([C:6]([Cl:8])=[N:7]1)[O:4][C:3]2=[O:12].[CH2:13]1CCN2C(=NCCC2)C[CH2:14]1.C(O)C>C(Cl)(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([C:3]([O:4][CH2:13][CH3:14])=[O:12])[CH:10]=[CH:9][C:5]=1[CH3:11]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC12CCC(Cl)(N=C1Cl)C(=O)O2
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4,6-Dichloro-1-methyl-2-oxa-5-azabicyclo[2.2.2]oct-5-en-3-one (26-3) (3.0 g, 14.4 mmol, 1 eq) was dissolved in chloroform (30 mL) and DBU (6.5 mL, 43 mmol, 3 eq) was added. After 5 minutes of stirring at ambient temperature, ethanol (0.84 mL, 16 mmol, 1.1 eq) was added and there was a slight exotherm. After 15 minutes of stirring at ambient temperature, the reaction mixture was concentrated and the crude residue was purified by flash chromatography (80 g SiO2, 0-100% EtOAc in hexanes) to afford ethyl 6-chloro-5-methylpyridine-2-carboxylate (26-4) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=7.6 Hz, 1 H); 7.69 (d, J=7.6 Hz, 1 H); 4.47 (q, J=7.2 Hz, 2 H); 2.46 (s, 3 H); 1.43 (t, J=7.2 Hz, 3H). LRMS m/z (M+H) 200.0 found, 200.0 required.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[N:38][CH:39]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[N:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Cc1ccc(N)cn1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccc(C)nc4)c3cc2OC)c1
Yield: 36 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 5-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 36% yield (40 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(CC)CC.O>O=S(Cl)Cl.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
3,4-Dinitrobenzoic acid (50 g, (124 mol) was heated at reflux in SOCl2 (160 ml) for 6 hours. The mixture was then evaporated to dryness in vacuo. The product was dissolved in THF and cooled to 5° C. To this solution, N-methylpiperazine (26.2 ml, 0.24 mol) and Et3N (42 ml) were added dropwise as a solution in THF (50 ml). After stirring overnight at room temperature, the solution was poured into water (1.5 L) and stirred at approximately 5° C. for 0.5 hours. The solid precipitate which formed was collected and dried to give (3,4-dinitrophenyl)-(4-methylpiperazin-1-yl)-methanone (40 g) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([N:17]=[C:18]=[S:19])[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([NH:17][C:18]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:19])[CH2:14][CH2:15][CH3:16]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: CCCCN=C=S
Solvent: CCOCC
Product: CCCCNC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 80 ml. of anhydrous ether is added a solution of 3.45 g. of n-butyl isothiocyanate in 50 ml. of anhydrous ether, dropwise during 5 minutes. The mixture is stirred for 30 minutes and the resulting solid is collected and dissolved in 50 ml. of ethanol. Cooling and the addition of 2 ml. of water gives 4.96 g. of the desired product as white crystals, m.p. 97.5°-98.5° C.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][C:23]([S@@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:22][C:23]([S@@:26](/[N:28]=[CH:20]/[C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)=[O:27])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=N/[S@@](=O)C(C)(C)C)cnc32)cc1
Reaction time: 20 h
Yield: 99.1 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (8.66 g, 28.7 mmol, Preparation #12 Step B) and (S)-2-methylpropane-2-sulfinamide (4.18 g, 34.5 mmol) in DCM (20 mL) at ambient temperature was added anhydrous powdered copper(II) sulfate (13.8 g, 86 mmol). After about 20 h, the reaction mixture was filtered and partially concd in vacuo. Heptane was added to the solution and the resulting solids were collected by filtration and dried in vacuo to provide (S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide (11.5 g, 99%) as a solid. LC/MS (Table 1, Method a) Rt=2.50 min; MS m/z: 405 (M+H)+.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chlorooxoacetate (2.41 mL, 26.1 mmol) was added dropwise over 2 mins to a stirred solution of ethyl cis-4-(4-aminophenoxy)cyclohexanecarboxylate (6.24 g, 23.7 mmol) and diisopropylethylamine (8.25 mL, 47.4 mmol) in DCM (200 mL) and the reaction mixture was stirred at ambient temperature for 16 h. Water (75 mL) was added and the layers were separated. The organic layer was washed with an aqueous solution of hydrochloric acid (1M, 75 mL) and then a saturated aqueous solution of sodium hydrogen carbonate (75 mL), dried (MgSO4) and concentrated in vacuo to provide the title compound as a white solid (8.23 g, 100%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:21]2[C:16](=[C:17]([N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])C.O=CCNS(C1C2C(=C(N(C)C)C=CC=2)C=CC=1)(=O)=O.COC(OC)CNS(C1C2C(=C(N(C)C)C=CC=2)C=CC=1)(=O)=O>>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:21]2[C:16](=[C:17]([N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CCOC(CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OCC
Agent: CN(C)c1cccc2c(S(=O)(=O)NCC=O)cccc12
Agent: COC(CNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCC=O)cccc12

Procedure:
This aldehyde was prepared from acetal 13 at a scale and under conditions identical to those employed for the preparation N-(2-oxoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide from acetal 11. N-(4-Oxobutyl)-5-(dimethylamino)naphthalene-1-sulfonamide was obtained as a light green foam, the total amount of which was used without further purification in the preparation of 14.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][C:22]3[S:23][CH:24]=[N:25][N:26]=3)=[CH:16][C:15]=2[N+:28]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:32][C:2]([Cl:1])([Cl:33])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][C:22]3[S:23][CH:24]=[N:25][N:26]=3)=[CH:16][C:15]=2[NH2:28])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3nncs3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(C(=O)Nc2nncs2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 71.8 %

Procedure:
The product of Example 166A (340 mg, 0.6197 mmol) was reduced with Fe and NH4Cl following the procedure in Example 9E to yield the title compound (231 mg, 72% yield) as a white solid. 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.94 (s, 2 H) 5.59 (s, 2 H) 7.14-7.35 (m, 4 H) 7.42 (s, 1 H) 7.50 (d, J=8.46 Hz, 2 H) 9.22 (s, 1 H) 10.26 (s, 1 H); MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([CH:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][NH:12][CH3:13])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC(OCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.9 %

Procedure:
tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (100 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (8 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo to afford methyl 2-(1-(3-chlorophenyl)-3-(methylamino)propoxy)ethylcarbamate (150 mg, 100%), was used for the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.[C-]#N.[K+].C(O)C[OH:27]>C(Cl)(Cl)Cl>[OH:27][CH2:21][CH2:20][O:19][C:17]([C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18]
Reactant: OCCO
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1Cc2c(C(=O)OCCO)ncn2-c2ccccc2C1=O
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 1.42 g (5 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 100 mg of potassium cyanide and 10 ml of ethyleneglycol is stirred at 130° C. for 6 hours, subsequently diluted with chloroform, washed with water, dried over magnesium sulphate and evaporated. After recrystallisation of the residue from ethyl acetate, there is obtained 2-hydroxyethyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 222°-223° C.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][C@H:5]([N:7]([C@@H](C2C=CC=CC=2)C)C(=O)OCC2C=CC=CC=2)[C@@H:4]([NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH2:3]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:7][C@H:5]1[CH2:6][C:2]([F:1])([F:34])[CH2:3][C@@H:4]1[NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)[C@H]1CC(F)(F)C[C@@H]1NS(=O)(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1N

Procedure:
A solution of benzyl N-[(1S,2S)-4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-N-[(1R)-1-phenylethyl]carbamate (2.24 g, 4.53 mmol) and palladium hydroxide on carbon (20%, 1.59 g, 2.26 mmol) in methanol (65 ml) was stirred under a balloon of hydrogen gas for 17 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 9.2 g of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxamide (Ex. 28, U.S. Pat. No. 4,236,005) in 100 ml of glacial acetic acid, was added in portions 3.0 g of sodium cyanoborohydride at room temperature under nitrogen. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo to give an oil. The oil was triturated with water and a white precipitate formed, and this was collected by filtration, washed with water and then was slurried with saturated sodium bicarbonate solution. The precipitate was again collected by filtration and washed with water. This solid was dissolved in dichloromethane, and then water was added. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave a yellow solid which was recrystallized from acetonitrile to give 7.0 g of the product of the example as a light yellow solid, mp 192°-194° C.
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.C(Br)(Br)[Br:24].C(ON=O)CC(C)C.C(#N)C>CS(C)=O.CCOCC>[Br:24][C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CCOCC
Solvent: CC#N
Solvent: CS(C)=O
Product: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
The product of step (d) (6.0 g) was suspended in DMSO (90 ml) and bromoform (60 ml) was added and the mixture was heated to 100° C. Isopentylnitrite (25 ml) was added and the mixture stirred for 5 min. The mixture was quickly cooled in an ice bath then evaporated to leave an oil. This was repeated three times. Acetonitrile (200 ml) was added and the solid which separated was removed by filtration. The solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane and then 5% ethyl acetate in dichloromethane to give a yellow solid which was slurried with ether then collected. The solid was washed with ether and dried to give the subtitled compound as a colourless solid (8.74 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1N
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-methoxy-phenylamine (220 mg, 0.78 mmol) and 4-isopropylphenylsulfonyl chloride (170 mg, 0.78 mmol) were dissolved in tetrahydrofuran (20 ml). Triethylamine (0.32 ml, 2.34 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (70% conversion). One small portion of 4-isopropylphenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (470 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-100%). Fractions containing the product were combined, the solvent evaporated to yield an oil (143 mg, 40%).
Reaction SMILES: O1C2C=CC(CC(O)=O)=CC=2CC1.S(Cl)(Cl)=O.[CH2:18]([O:20][S:21]([CH:24]([C:28]1[CH:29]=[CH:30][C:31]2[O:35][CH2:34][CH2:33][C:32]=2[CH:36]=1)[C:25]([OH:27])=O)(=[O:23])=[O:22])[CH3:19].O.[NH2:38][CH:39]1[C:46](=[O:47])[N:45]2[CH:40]1[S:41][CH2:42][C:43]([CH3:51])=[C:44]2[C:48]([OH:50])=[O:49].C(=O)(O)[O-].[Na+]>CCOCC.C(OCC)(=O)C>[CH2:18]([O:20][S:21]([CH:24]([C:28]1[CH:29]=[CH:30][C:31]2[O:35][CH2:34][CH2:33][C:32]=2[CH:36]=1)[C:25]([NH:38][CH:39]1[C:46](=[O:47])[N:45]2[CH:40]1[S:41][CH2:42][C:43]([CH3:51])=[C:44]2[C:48]([OH:50])=[O:49])=[O:27])(=[O:22])=[O:23])[CH3:19]
Reactant: CCOS(=O)(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C(O)Cc1ccc2c(c1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOS(=O)(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CSC12)c1ccc2c(c1)CCO2
Reaction time: 2 h

Procedure:
α-Ethoxysulfonyl(2,3-dihydro-5-benzofuranyl acetic acid (5mmole) in 50 ml of dry ether is reacted with about 5.5 mole of thionyl chloride at 20° C. for 4 hours. At the end of this time the solvent is removed to insure that all of the thionyl chloride and hydrochloric acid is removed. The residue is then redissolved in 10 ml of ether. This ether solution is added to 10 ml of water containing 5 mmole of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 10 mmole of sodium bicarbonate. The temperature of the aqueous solution is about 10° C. After stirring for about 2 hours, the pH is adjusted to about 2. Ethyl acetate is added, the mixture is thoroughly agitated and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].C[C:29]([N:31](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Zn]>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:29]#[N:31])=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: CC(=O)N(C)C
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4c3OCO4)c2cc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C#N)c4c3OCO4)c2cc1OC
Temperature: 110 °C

Procedure:
Tris(dibenzylideneacetone)dipalladium (0.0073 g) was added to a mixture of 3-cyano-4-(4-iodo-2,3methylenedioxyanilino)-6,7-dimethoxyquinoline (0.05 g) zinc cyanide (0.015 g), diphenylphosphinoferrocene (0.009 g), zinc powder (0.0035 g) and DMA (2 ml) and the resultant mixture was stirred and heated to 110° C. for 1 hour. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained 3-cyano-4-(4-cyano-2,3-methylenedioxyamino)-6.7-dimethoxyquinoline as a solid (0.014 g); NMR Spectrum: (CDCl3) 3.84 (s, 3H), 4.07 (s, 3H), 6.16 (s, 2H), 6.28 (d, 1H), 6.75 (s, 1H), 6.99 (m, 2H), 7.46 (s, 1H), 8.73 (s, 1H); Mass Spectrum: M+H+ 375.