Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26]([N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43]([C:21]4[C:18]([CH:19]=[O:20])=[C:17]([N:10]5[N:9]=[CH:8][C:7]6[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=6)[C:11]5=[O:16])[N:24]=[CH:23][CH:22]=4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1

Procedure:
Following the procedure described in Example 123d, and starting with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (200 mg, 0.57 mmol) and 124h (343 mg, 0.83 mmol), 124i was obtained as a yellow solid (300 mg, 86%). MS-ESI: [M+H]+ 611.3
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH:22]2[CH2:24][CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: NC1CC1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(NC3CC3)nc(N)nc21

Procedure:
A solution of 2-amino-4-chloro-7-(2-C-methyl-Θ-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 118, Step B) (21 mg, 0.07 mmol) in cyclopropylamine (0.5 mL) was heated at 70° C. for two days, then evaporated to an oily residue and purified on a silica gel column with CH2Cl2/MeOH, 20/1, as eluent to give the title compound as a white solid (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.73 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (233 mg, 0.70 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (412 mg, 0.88 mmol) in Chloroform (9 mL). DIEA (640 μL, 3.66 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (180 mg, 0.30 mmol, 42%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 49.4 %

Procedure:
The title compound (74 mg) was prepared as in Example 177, Steps C and D, using 215 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 296 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C18H22ClN3, 315.15. found, m/z 316.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.59-7.53 (m, 2H), 7.36-7.30 (m, 2H), 4.48 (m, 1H), 3.44-3.37 (m, 2H), 3.34-3.27 (m, 2H), 3.22-3.15 (m, 2H), 2.81-2.74 (m, 2H), 2.06-1.84 (m, 6H), 1.65-155 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.CO.Cl.[NH2:17][OH:18]>O>[CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[N:17][OH:18]
Reactant: CNC(=O)C(=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NO)c1ccccc1C

Procedure:
To N-methyl-2-(2-methylphenyl)-2-oxoacetamide (5.31 g, 0.03 mol), added were methanol (30 ml) and hydroxylamine hydrochloride (4.17 g, 0.06 ml), and the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-hydroxyiminoacetamide in E-form (4.79 g; yield, 83.1%) and Z-form (0.50 g; yield, 8.7%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[C:3]=1[C:32]#[N:33].CN(C=O)C.[SH:39][CH2:40][C:41]([NH2:43])=[O:42].C[O-].[Na+]>CO>[NH2:33][C:32]1[C:3]2[C:2](=[N:7][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:27])[C:17]4[N:21]([CH3:22])[C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[N:18]=4)[CH2:10][CH2:9]3)=[CH:5][C:4]=2[C:28]([F:31])([F:30])[F:29])[S:39][C:40]=1[C:41]([NH2:43])=[O:42]
Reactant: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c(C#N)c(Cl)n3)CC2)nc2ccccc21
Reactant: NC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c4c(N)c(C(N)=O)sc4n3)CC2)nc2ccccc21
Temperature: 60 °C

Procedure:
6′-Chloro-4-[2-hydroxy-2-(1-methyl-1H-benzoimidazol-2-yl)-ethylamino]-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (344.0 mg, 0.718) mmol was dissolved into 2 mL of dry DMF. To this was added a 1.09 M MeOHic solution of mercaptoacetamide (1.00 mL, 1.09 mmol) and a 1 M solution of MeOHic NaOMe (2.87 mL, 2.87 mmol). The reaction mixture was heated at 60° C. for 2 h. LC-MS indicated complete conversion to the mercaptoacetamide adduct. The reaction was then heated at 80° C. overnight. The reaction mixture was concentrated on a rotary evaporator with heating to 70° C. to give a dark orange oil. The oil was dissolved into a minimal amount of MeOH, applied to a SIO2 column and eluted with 0–10% MeOH/CH2Cl2 and 0–10% MeOH/CH2Cl2-1% NH3) to give 213.7 mg, 55.8%, of the title compound. ES+ 534.3 m/z (MH+)
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[F:12][C:13]([F:36])([F:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[C:17]=1[NH:16][C:14](=[O:15])[C:13]([F:36])([F:35])[F:12])([O-:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2.4 ml (0.0258 mol) of acetic anhydride and 1.1 ml (0.025 mol) of 98% strength nitric acid are added in succession to 10 g (0.0235 mol) of 5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole in 20 ml of glacial acetic acid at room temperature. After the mixture has been stirred for 20 hours, it is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is extracted with 400 ml of 5% strength aqueous sodium carbonate solution. The aqueous phase is acidified and extracted with 200 ml of methylene chloride. The combined organic phases are dried over magnesium sulphate and freed from the solvent in vacuo. 8.6 g (77.6% of theory) of 4-nitro-5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole of melting point 136° C.-137° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15][O:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCC(O)CO1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CCCCOCc2ccccc2)CCCC(=O)CO1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Dry celite (50 g) and 2-(4'-benzyloxybutyl)-2-methyloxepane-6-ol (6.9 g, 0.02 mol) in methylene chloride are added to a pyridine-chromium trioxide solution [prepared from pyridine (22.4 g, 0.284 mol) and chouromium trioxide (14.2 g, 0.142 mol)] in dry methylene chloride (800 ml) at 10° C. in a nitrogen atmosphere. After 2 hours of stirring the mixture is filtered and the celite cake is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (200 ml), filtered and the solvent is removed at reduced pressure. The crude product is chromatographed on SilicAR CC-7 (150 g) in hexane. Elution with 10% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-2-methyl-oxepan-6-one (11) as a clear colorless oil (5.9 g, 86%).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: OCC(CO)(CBr)CBr
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)OCC(CBr)(CBr)CO1

Procedure:
A solution of 2,2-bis(bromomethyl)-1,3-propanediol (5.0 g, 19.1 mmol), anhydrous acetone (20 mL) and p-TsOH (100 mg) in benzene (75 mL) was refluxed for 12 h, with azeotropic removal of water. The reaction mixture was concentrated under reduced pressure, EtOAc (100 mL) was added and the organic layer was washed successively with H2O (3×30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The white solid obtained was triturated with n-pentane (20 mL) to afford 5,5-bis(bromomethyl)-2,2-dimethyl-[1,3]dioxane (521) as colourless crystals.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(O)CCCCC.N#N.[C:14]([O:18]CCCCCC)([CH3:17])([CH3:16])[CH3:15]>>[C:2]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CCCCCCOC(C)(C)C
Agent: N#N
Solvent: CCCCCCO
Product: CC(C)(C)OC(C)(C)C
Reaction time: 17 h

Procedure:
300 mmoles of i-butene, 100 mmoles of 1-hexanol and 2.5 g of Ti-Si-catalyst powder are stirred in a 100 ml autoclave at a pressure of 40 bar N2 and a temperature of 150° C. over a period of 17 h. 17% of n-hexanol were converted into hexyl t-butyl ether with a selectivity of 90%.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>CCCCCC>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCCCCC
Product: COc1cccc(C(=O)NC2CCc3ccccc32)c1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.6 g, 12.3 mmole) and m-anisoyl chloride (1.9 g, 13.54 mmole) as in Ex. 46; crystallization from EtOAc: hexane gave 2.0 g (7.2 mmole, 59%) white solid, mp: 140° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([C:30]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=C(Cl)N1CCCCC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCN(C(=O)N3CCCCC3)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 1-piperidinecarbonyl chloride
Reaction SMILES: [NH3:1].[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]>O1CCOCC1.ClCCl>[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([NH2:1])=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]
Reactant: N
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ammonia in dioxane (33 mL of 0.5 M) was added to a solution of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoyl chloride (4.64 mmol, prepared as described in Parts A and B of Example 38) in dichloromethane (20 mL), and the reaction was stirred overnight at ambient temperature. An analysis by HPLC indicated the reaction was incomplete; ammonia gas was bubbled through the solution for 10 minutes. The reaction was then stirred for one hour and concentrated under reduced pressure. The residue was triturated with water and isolated by filtration to provide 1.02 g of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanamide. The filtrate was extracted with dichloromethane (3×20 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an additional 0.39 g of product. The combined solids were mixed with material from another run.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[CH2:15][CH:7]2[CH2:8][NH:9][CH2:10]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[CH2:22]([N:9]1[CH2:8][CH:7]2[CH2:15][CH:11]([C:12]3[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=3)[CH2:10]1)[CH3:23]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (300 mg, 1.47 mmol) (prepared using the procedure detailed in J. Med Chem, 2005, 48, 3474-3477) in 5 ml acetone was added potassium carbonate (609 mg, 4.41 mmol) and then ethyl iodide (423 μl, 5.29 mmol). The solution was allowed to stir overnight. The reaction was evaporated under reduced pressure and partitioned between water and EtOAc. The water layer was extracted with 2×10 ml portions of EtOAc and the combined organics dried over magnesium sulfate, filtered and evaporated. The resulting brown oil was chromatographed on a 12 g Isco column using a gradient of 0-10% methanol in methylene chloride to yield 10-ethyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (280 mg, 82%) as a brown oil. 1H-NMR (CDCl3) δ 8.07 (d, J=8.1 Hz, 1H), 7.96 (s, 1H), 7.24 (d, J=8.1 Hz, 1H), 3.17 (dd, J=5.5, 4.8 Hz, 2H), 2.87 (dd, J=5.5, 4.8 Hz, 2H); 2.40-2.20 (m, 5H), 1.75 (d, J=10.6 Hz), 0.85 (d, J=10.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[CH:17][CH:16]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)#[N:2].[OH-].[Na+].CC[OH:30].OO>CS(C)=O.O>[CH3:22][N:21]([CH3:23])[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:4]2[C:3]([C:1]([NH2:2])=[O:30])=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:25][CH:24]=1)=[O:20]
Reactant: CCO
Reactant: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
4-[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]-N,N-dimethylbenzamide (83 mg, 0.250 mmol) and 5 N sodium hydroxide (0.351 mL, 1.753 mmol) were taken up in DMSO (1 mL)/EtOH (1 mL) and warmed to 60° C. Hydrogen peroxide (0.329 mL, 3.76 mmol) was added dropwise and stirring continued at 60° C. for 15 minutes. Room temperature was attained, water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine (×2), dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (25-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc followed by 15% MeOH—CHCl3) gave 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[H-].[Na+].O[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]3[CH2:40][C@:30]4([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]4=[O:39])[CH2:29][C:24]=3[CH:25]=2)[N:20]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]4[CH2:40][C@:30]5([C:38]6[C:33](=[N:34][CH:35]=[CH:36][CH:37]=6)[NH:32][C:31]5=[O:39])[CH2:29][C:24]=4[CH:25]=3)[N:20]=2)[C:3]1=[O:13]
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Reactant: CC1(C)CC(c2ccccc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2)N(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)Nc3ncccc32)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of (±)-3,3-dimethyl-5-phenylpyrrolidin-2-one (221 mg, 0.893 mmol, described in Intermediate 51) in DMF (0.5 mL), at ambient temperature, was added sodium hydride (60% dispersion in mineral oil; 37 mg, 0.923 mmol). The resulting mixture was stirred for 30 min, then (S)-2-(chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (100 mg, 0.298 mmol, described in Intermediate 7) was added and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with H2O (0.1 mL) and purified directly by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2466; calculated m/z=547.2452 for C32H31N6O3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([CH:11]([C:38](=[O:40])[NH2:39])[O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]=1)=[O:17])(C)C.N1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:31][O:30][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][C:25]=1[O:28][CH3:29])[C:18]([C:16](=[O:17])[C:15]1[CH:35]=[CH:36][CH:37]=[C:13]([O:12][CH2:11][C:38](=[O:40])[N:39]3[CH2:46][CH2:45][S:44][CH2:43][CH2:42]3)[CH:14]=1)=[N:19][CH:20]=[C:21]2[C:32]([OH:34])=[O:33]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC(C(N)=O)C(C)C)c3)c2cc1OC
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCSCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropyl-carbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.04 ml of thiomorpholine (0.4 mmol). The mixture was shaken for 15 minutes at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-[3-(2-oxo-2-thiomorpholin-4-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [NH2:1][NH2:2].O.[C:4]([CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](O)=[O:10])(=O)[CH3:5]>CCO>[CH3:5][C:4]1[CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](=[O:10])[NH:1][N:2]=1
Reactant: NN
Reactant: CCCC(CC(=O)O)C(C)=O
Solvent: O
Solvent: CCO
Product: CCCC1CC(=O)NN=C1C
Temperature: 85 °C

Procedure:
NH2NH2—H2O (6.94 ml, 143 mmol) is added to a solution of 3-acetyl-hexanoic acid (18.8 g, 119 mmol) in EtOH (150 ml), and the mixture is refluxed (oil bath 85° C.) for 4 hours. The solvent is removed in vacuo and water (100 ml) and EtOAc (100 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (3×100ml). The combined extracts are washed with brine (150 ml), dried (Na2SO4) and evaporated. 6-methyl-5propyl-4,5-dihydropyridazin-3-one is obtained as a light yellow oil, and is used in the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:35]1([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH2:37][CH2:36]1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:38][CH:35]3[CH2:37][CH2:36]3)=[C:50]([OH:51])[CH:14]=2)[CH:8]=1
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1Sc1ccccc1CC1CC1

Procedure:
The title compound was prepared by Method A using 3'-phenyl acetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 88° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.25 (d, 2H), 0.53 (dd, 2H), 1.14 (m, 1H), 2.67 (d, 2H), 6.94 (m, 1H), 7.03 (s, 1H), 7.11 (m, 2H), 7.33 (m, 1H), 7.44 (d, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.75 (d, 2H), 7.86 (m, 2H), 8.08 (s, 1H).