Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=O)=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]=[N:34][OH:35])=[C:13]([CH:30]=1)[O:14][CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=NO)c1ccccc1C
Yield: 47.3 %

Procedure:
A mixture of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (0.49 g), hydroxylamine hydrochloride (0.1 g) and pyridine (0.1 g) in ethanol (10 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×50 mL) and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and filtered and the solvent is removed in vacuo, to give a yellow oil. Flash chromatography on silica gel, eluting with a mixture of petroleum ether (b.p.40-60° C.) and ethyl acetate (7:1 v/v), gives ethyl (RS)-4-(5-benzyloxy-2-hydroxyiminomethylphenoxy)-4-(2-methylphenyl)butanoate (E:Z ratio 4:1), (0.24 g).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[CH3:10][C:11]([CH3:13])=O.C(O)=O.C(O)=O.Cl.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])(=O)C.[Na+]>[CH2:21]([N:28]1[CH:6]2[CH2:5][CH2:13][CH:11]1[CH2:10][C:3](=[O:4])[CH2:7]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CC(C)=O
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: O=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][NH2:11].CCN(CC)CC.Cl[C:20](=[O:26])[C:21]([O:23]CC)=O.[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][NH2:36])=[N:32][CH:33]=1>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][NH:11][C:21](=[O:23])[C:20]([NH:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH3:27])=[CH:33][N:32]=1)=[O:26]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1ccc(CCN)nc1
Reactant: COc1cc(C)ccc1CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1CNC(=O)C(=O)NCCc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
A mixture of 2 g of (2-methoxy-4-methylphenyl)methanamine (from step 3) and Et3N (3.7 mL, 2 eq) in dry CH3CN (45 mL) was cooled to 0° C. under N2 atmosphere and ethyl 2-chloro-2-oxoacetate (1.47 mL, 1 eq) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours and 2-(5-methylpyridin-2-yl)ethanamine (2.52 g, 1.4 eq, from step 5) was added. The reaction was heated at reflux for 24 hours. After cooling the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (eluent: 25-35% acetone in hexane) and recrystallized from ethyl acetate/hexane and ethanol/water to give 650 mg of N1-(2-methoxy-4-methylbenzyl)-N2-(2-(5-methylpyridin-2-yl)ethyl)oxalamide (15%).
Reaction SMILES: [CH:1]1([C:7]2([C:20]([OH:22])=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl.CN(C=O)C>[C:29]([NH:33][C:20]([C:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH:12]2[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:22])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1C2CCC1CC(C(=O)NC(C)(C)C)(C1CCCCC1)C2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-7) (1.50 g, 4.85 mmol) in CHCl3 (60.0 mL) was slowly added oxalyl chloride (2.67 mL, 5.33 mmol, 2.0 N), followed by addition of DMF (3 drops) as a catalyst. After the bubbling ceased, the mixture was stirred for 30 min and the solvents were removed under vacuum. To the mixture was added t-BuNH2 (5.32 g, 72.7 mmol) and the resulting suspension was warmed up to 80° C. overnight. The solvents were removed under vacuum; the reaction was quenched with 1 N HCl, and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-8) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O.[Cu]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Oc3ccc(F)cc3)c2)cc1
Temperature: 190 °C
Yield: 91.1 %

Procedure:
The mixture of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (2.0 g, 5.54 mmole), 4-fluorophenol (3.1 g, 27.7 mmole), copper oxide (0.5 g, catalyst) and cesium carbonate (5.4 g, 16.6 mmole) in 10 mL of 1-N-methyl-2-pyrrolidinone is heated to 190° C. in a microwave reactor for 30 minutes. The reaction solution is diluted with 150 mL of EtOAc and filtered through celite. The filtrate is washed with 4×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (hexane 100% to hexane 60% and EtOAc 40% by gradient in 20 minutes)) to give 3-(4-fluoro-phenoxy)-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4) (1.98 g, yield 91%) as a light yellow viscose liquid.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([OH:24])=O)=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:24])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CCNC1
Product: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Yield: 84.3 %

Procedure:
The product was prepared in the same manner as described in example 70f using 5-(2-((2-fluoroethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 277 μmol) and pyrrolidine (68.7 μl, 830 μmol) as starting materials. The reaction affords 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide (96.8 mg, 84.4%) as white solid. MS: m/z=415.0 (M+H+).
Reaction SMILES: [C:1]1([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O-:28])(=[O:27])[C:24]([CH3:26])=[CH2:25].[K+]>>[C:23]([O:28][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: C=C(C)C(=O)[O-]
Agent: [K+]
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1

Procedure:
Diphenyl(p-methoxyphenyl)methyl chloride was reacted with potassium methacrylate using the procedure of Example 1 to produce diphenyl(p-methoxyphenyl)methyl methacrylate (hereinafter abbreviated to MTMA).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10](Cl)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:8])[CH3:2].[SH2:24].[Na]>>[CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([SH:24])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: S
Reactant: CCN(CC)CCNC(=O)c1cnc(-c2ccccc2)nc1Cl
Agent: [Na]
Product: CCN(CC)CCNC(=O)c1cnc(-c2ccccc2)nc1S
Yield: 63.6 %

Procedure:
Using the procedure in Preparation 34, 6.4 g (0.02 mol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid (2-diethylamino-ethyl)-amide was reacted with 4.8 g (0.066 mol) of sodium hydrogen sulfide to afford 4.2 g of the title compound, mp 178°-180° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:31]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[C:26]=3[CH:31]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCCO2
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of α-cyanoacetic acid (0.085 g., 1.0 mmol) in 2 mL dichloromethane was added oxalyl chloride (0.262 mL, 3.0 mmol) and one drop N,N-dimethylformamide (˜0.025 mL, cat). The solution is stirred for one hour, during which offgassing is observed, and concentrated in vacuo. The residue was dissolved in 4 mL dichloromethane and this solution was added dropwise to a solution of 6-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.275 g., 1.0 mmol) and triethylamine (0.152 mL, 1.1 mmol) in 3 mL dichloromethane at 0° C. The resulting solution was stirred for 2 hours, concentrated in vacuo and purified by flash chromatography to give 0.146 g (43%) of 3-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-oxo-propionitrile. MS: 343 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:42])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:67]=[C:68]1[CH:72]=[CH:71][C:70](=[O:73])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH2:82])=[O:80]>>[O:73]=[C:70]1[CH:71]=[CH:72][C:68](=[O:67])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH:82][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:42])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:80]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
9 mg (9.8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-({(2S)-1-[benzyl(methyl)amino]-1-oxo-3-phenylpropan-2-yl}amino)-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 73) were reacted in analogy to Intermediate 133 with 10 mg (39 μmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide to give 1.8 mg (15% of theory) of the title compound.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29](=O)[C:28]4[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=4[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=O)[CH:2]([CH3:4])[CH3:3].[OH2:41].[NH2:42][NH2:43]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29]4=[N:42][NH:43][C:31](=[O:32])[C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=54)[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:41])[CH:2]([CH3:4])[CH3:3]
Reactant: O
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1ccccc1)N2
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
A mixture of methyl 3-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (110 mg, 0.20 mmol) in hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (12 mg, yield: 11%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 0.96-0.98 (d, J=6.8 Hz, 6H), 2.68-2.95 (m, 2H), 3.28-3.55 (m, 7H), 4.19-4.22 (d, J=10.0 Hz, 1H), 4.54-4.57 (d, J=10.4 Hz, 1H), 7.03-7.20 (m, 10H), 7.40-7.50 (m, 2H); LC-MS (ESI) m/z: 522(M+1)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15])=O)(C)(C)C.[ClH:16]>C(O)(=O)C>[ClH:16].[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1S
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cnccc1S
Temperature: 0 °C
Yield: 100 %

Procedure:
A 13.78 g (0.06 mol) sample of 3-(t-butyloxycarbonyl)amino-4-mercapto pyridine was dissolved with acetic acid (250 mL) and added to an ice cold solution of ~3N HCl in acetic acid which had been made by bubbling HCl(g) through glacial acetic acid (100 mL). After about four hours the resulting solid was filtered, washed with diethylether and dried in vacuo to yield 10.4 g (~100%) of the title compound. m.p.: >200° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)[Cl:9])=[CH:3][CH:2]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([N:18](CC)CC)C>CCOCC>[ClH:9].[C:4]1([NH:7][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[NH:18])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CCN(CC)CC
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: C1CCNC1
Solvent: CCOCC
Product: Cl
Product: N=C(Nc1ccccc1)N1CCCC1

Procedure:
To 1.74 g (0.01 mole) of phenyl isocyanide dichloride is added 0.71 g (0.01 mole) of pyrrolidine and 1.01 g (0.01 mole) of triethylamine under N2 in dry ether with stirring and cooling. The resulting mixture is allowed to stir for 1/2 hr and the resultant Et3N.HCl is filtered. The filtrate is added to a saturated solution of anhydrous NH3 in isopropanol. The resulting NH4Cl is filtered and the filtrate is concentrated in vacuo to remove excess ammonia, followed by the addition of dry HCl resulting in crystalline product, N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 181°-84° C. after crystallization from methanol-isopropanol.
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=[O:6])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH3:21])[C:17]([C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:18][C:19]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: O=C(Cl)CC1CC1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
2-cyclopropylacetyl chloride (11.83 g, 100.00 mmol) solution in chlorobenzene (60 ml) was added to the stirred solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Kazuhiko Taguchi et al., Tetrahedron Letters, 2005, 46, 4539-4542) (17.10 g, 83.00 mmol) and Zinc (10.87 g, 166.00 mmol) in toluene (100 ml) at 25° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of the reaction was monitored by TLC. The mixture was diluted with a saturated solution of sodium bicarbonate (100 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with water (1×50 ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using 5-10% ethyl acetate in hexanes as an eluent to obtain the title compound 3(7.20 g, 30.1%). MS: m/z 288 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.N1(CCO[C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]3)C=CN=C1>>[N:1]1([CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:8][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: OC(Cn1ccnc1)c1ccccc1
Product: O=C1CCCc2cc(OC(Cn3ccnc3)c3ccccc3)ccc21
Yield: 288.1 %

Procedure:
Following the procedure of Example 78, Step 3, but using 2.63 g (4.0 mmol) of 2-(1H-1-imidazolyl)-1-phenyl-1-ethanol and 2.0 g (12.3 mmol) of 6-[2-(1-H-1-imidazolyl)ethoxy]1,2,3,4-tetrahydro -1-naphthalenone, there was obtained 3.83 g (93.6% yield) of the product as a glass. The structure was confirmed by NMR and mass spectroscopy. MS m/z 333 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc2oc(C(N)=O)cc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2oc(C#N)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To the suspension of 5-methylbenzofuran-2-carboxamide (5.17 g, 29.5 mmol) in 66 mL of anhydrous THF was added TEA (8.23 mL, 59.0 mmol). TFAA (6.25 mL, 44.3 mmol) was added dropwise to the above mixture at 0° C. (internal temperature did not exceed 15° C.). After stirring at 0° C. for 1 hr, the reaction was complete by TLC. The reaction mixture was poured into 610 mL of H2O, and extracted with EtOAc 3 times. The organic layer was washed with sat. NaHCO3, brine and dried over Na2SO4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel flash chromatography, 100% Heptane-8% Ethyl Acetate/92% Heptane, to yield 5-methylbenzofuran-2-carbonitrile (3.65 g). 1H NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.42 (dd, J=8.6, 1.8 Hz, 1H), 7.59-7.67 (m, 2H), 8.03 (d, J=0.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:37]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:40])=[O:39])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
5-Fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride (50 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 505.2. Calcd 505.13. 1H-NMR δ 7.73-7.17 (m, 8H), 6.83 (d, 1H), 6.68 (dd, 1H), 6.50 (dd, 1H), 3.27-3.17 (m, 8H), 2.55 (s, 3H).