Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][C:23]1[C:31]2[C:30]([CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]([CH2:42][CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])[C:34]3=[O:48])=[CH:29][S:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCCC2.Cl>O.C1COCC1>[C:1]([NH:47][S:44]([CH2:43][CH2:42][N:35]1[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:33]([CH2:32][C:30]2[C:31]3[C:23]([CH3:22])=[CH:24][CH:25]=[CH:26][C:27]=3[S:28][CH:29]=2)[C:34]1=[O:48])(=[O:46])=[O:45])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCS(N)(=O)=O)c4ccccc43)c12
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(CCS(=O)(=O)NC(=O)c4ccccc4)c4ccccc43)c12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Benzoic acid (6.1 mg, 0.050 mmol) is dissolved THF (0.50 mL) and 1,1′-carbonyl diimidazole (9.1 mg, 0.056 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid amide (10 mg, 0.025 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.007 mL, 0.050 mmol) is added. The mixture is stirred for 16 hr at room temperature. 1.0 M HCl solution (1.0 mL) is added followed by water (10 mL). The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 6% MeOH in EtOAc affords 11 mg (85%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid benzoylamide. LCMS (ESMS): m/z 506.25 (M+H+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](OC)=[O:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1COCC1>ClCCl>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:27])([F:28])[F:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A 25-mL round bottom flask was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.069 g, 0.17 mmol) and dichloromethane (6 mL) at 0° C. A 1M solution of DIBAL-H in THF (0.70 mL, 0.70 mmol) was added and the resulting solution was stirred at 0° C. for 1 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then absorbed onto silica (2 g) and concentrated under reduced pressure. Purification by column chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent afforded the title compound (0.055 g, 87%) as a white solid. MW=366.38. M.p. 48-50° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.51 (s, 1H), 7.23 (d, J=7.5 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 5.38-5.32 (m, 1H), 4.58 (t, J=5.5 Hz, 1H), 4.09 (s, 2H), 3.56 (q, J=6.0 Hz, 2H), 2.68 (t, J=7.0 Hz, 2H), 2.00-1.89 (m, 2H), 1.77-1.66 (m, 4H), 1.66-1.55 (m, 2H); APCI MS m/z 367 [M+H]+.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH3:11])=[O:8])=[O:4]>C(O)(=O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 6 h

Procedure:
Boc-Gly-Gly-Ala-Pro-OBzl (30.0 g, 0.061 mole) was dissolved in glacial acetic acid (300 mL) and 3.0 g of 10% Palladium on activated charcoal was added. This mixture was hydrogenated at 40 psi for 6 h. The reaction mixture was faltered through celite and the solvent was removed in vacuum. The resulting residue was triturated with ether, filtered, washed with ether, and dried to obtain Boc-Gly-Gly-Ala-Pro-OH.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:22])=[O:5])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Reaction time: 1 h

Procedure:
433 mg (1.43 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester in 10 ml of 90 aqueous TFA were allowed to stand at room temperature for 1 h. The mixture was concentrated and coevaporated with toluene. Yield: 402 mg.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[CH:13]>CN(C=O)C.CCN(CC)CC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
To the solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF (60 mL) and Et3N (60 mL) was added 2-ethynylpyridine (3.0 g, 45 mmol), Pd(PPh3)2Cl2 (600 mg) and CuI (200 mg) under N2. The reaction mixture was stirred at 60° C. for 12 h. The mixture was diluted with water and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.98 (d, J=1.8, 6.9 Hz, 1H), 7.87-7.80 (m, 2H), 7.42-7.39 (m, 1H), 7.05 (brs, 2H), 6.80 (d, J=6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:40])[CH3:39])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Product: CC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47) but using acetyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl>C(OCC)(=O)C.ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A 500 ml round bottom flask was loaded with 4-nitrobenzoyl chloride (10.2 g, 53.9 mmol) and dichloromethane (100 ml) and cooled to 0° C. Pyridine (10 ml, 124 mmol) was added, followed by tert-butyl piperazine-1-carboxylate (10.2 g, 54.8 mmol) (solid, in portions) while stirring at 0° C. After the addition was completed, the ice bath was removed and the reaction mixture stirred while allowing the reaction to warm to room temperature overnight. The mixture was poured into a separating funnel loaded with 250 ml ethyl acetate and 250 ml 1N aq. HCl. The layers were separated, the organic layer washed one more time with 1 M aq. HCl, then with sat. aq. NaHCO3 solution (2×), then brine (1×), then dried over MgSO4, filtered and concentrated in vacuum. 12.9 g tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate were isolated as a white solid. MS (ESI) m/z 280 (M+H—C4H8), 236 (M+H-BOC). 1H NMR (CDCl3) δ ppm 8.28 (d, 2H, J=8.6), 7.57 (d, 2H, J=8.6), 3.76 (bs, 2H), 3.53 (bs, 2H), 3.39 (bs, 2H), 3.33 (bs, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A mixture of 4-ethoxycarbonylphenyl boronic acid (23.11 g, 119 mmol), 2,4-dichloropyrimidine (16.90 g, 113 mmol), toluene (230 mL) and aqueous sodium carbonate (2 M, 56 mL) was stirred vigorously and nitrogen was bubbled through the suspension for 15 minutes. Tetrakis(triphenylphosphine)palladium[0](2.61 g, 2.26 mmol) was added. Nitrogen was bubbled through for another 10 min., the mixture was heated to 100° C., then at 75° C. overnight. The mixture was cooled, diluted with ethyl acetate (200 mL), water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml) and the two organic extracts were combined. The organics were washed with brine, filtered through sodium sulfate, concentrated, and the resultant solid was triturated with methanol (100 mL) and filtered. The solids were washed with methanol (2×30 mL) and air dried. This material was dissolved in acetonitrile (150 mL) and dichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days. The solution was filtered, the solids were washed with dichloromethane (2×100 mL), and the filtrate concentrated to give ethyl 4-(2-chloropyrimidin-4-yl)benzoate as anoff-white solid (17.73 g, 60%)—additional washing with dichloromethane yielded a further 1.38 g and 0.5 g of product. 1H NMR (300 MHz, d6-DMSO) δ 8.89 (1H, d, J=5.0 Hz); 8.32 (2H, d, J=8.7 Hz); 8.22 (1H, d, J=5.5 Hz); 8.12 (2H, d, J=8.7 Hz); 4.35 (2H, q, J=7.1 Hz); 1.34 (3H, t, J=7.1 Hz); LC-ESI-MS (method B): rt 7.3 min.; m/z 263.0/265.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2.[CH3:15][C:16]1[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]([CH3:23])=[CH:19][C:20]=1[CH:21]=[CH2:22].C([O-])([O-])=O.[Na+].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH3:13][N:12]([CH3:14])[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:22]=[CH:21]/[C:20]3[CH:19]=[C:18]([CH3:23])[N:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]=3[CH3:15])[CH:3]=2)[CH:8]=1
Reactant: CN(C)c1ccc2cc(Br)ccc2c1
Reactant: C=Cc1cc(C)n(-c2ccccc2)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2ccc3cc(N(C)C)ccc3c2)c(C)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
Dry DMF (10 mL) was added by syringe to the mixture of 6-bromo-N,N-dimethylnaphthalen-2-amine (200 mg, 0.8 mmol), 2,5-dimethyl-1-phenyl-3-vinyl-1H-pyrrole (236 mg, 1.2 mmol), Na2CO3 (254 mg, 2.4 mmol), n-Bu4NCl (224 mg, 0.8 mmol) and Pd(OAc)2 (8 mg, 0.33 mmol). The reaction mixture was stirred at 100° C. for 3 hrs, then quenched with water (20 mL) and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. After purified by column chromatography (hexane/EtOAc=500:1), the target compound was obtained as brown yellow solid (50 mg, 17%). MS [M+]=366, LC-MS: tR=3.28 min.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([Cl:30])[CH:17]=1.Cl>O1CCCC1>[Cl:30][C:18]1[CH:17]=[C:16]([CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][C:19]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(Cl)c1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.50 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.40 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-chlorobiphenyl-2-carbonitrile (2.30 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (1.35 g) and 28% sodium methoxide (4.09 g) in methanol (30 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (1.95 g, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].NC(N)=[O:13].OO.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: NC(N)=O
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
The procedure of R. Balicki and L. Kaczmarek, Syn. Comm., 23, 3149 (1993)was used. Into a 1 L round bottom flask equipped with a magnetic stirrer was added acetone (60 mL), water (60 mL) , 2-chloro-6-fluorobenzonitrile (14.5 g, 93.5 mmol), urea (22.5 g, 374 mmol), 30% hydrogen peroxide (42.4 g, 374 mmol), and potassium carbonate (1.3 g, 9.0 mmol). The resulting slurry was stirred at room temperature overnight. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were added and the mixture was allowed to stir for an additional 2 hr. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were again added and the mixture was allowed to stir overnight. The acetone was removed in vacuo, the residue extracted with methylene chloride, the organics were combined, washed with brine, dried (MgSO4) and the solvent removed in vacuo to give 15.8 g (97.5% yield) of 2-chloro-6-fluorobenzamide (97% pure by GC): mp140-141° C.; 1H NMR (CDCl3) d 7.2-7.4 (m, 2H), 7.0 (m, 1H), 6.3 (s, b, 1H), 5.9 (s, b, 1H).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[NH:2]1.[C:13]([O:16][C:17](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:13][O:16][CH:17]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:12])[NH:2][C:3]1=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2C(=O)N1
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 4H-Isoquinoline-1,3-dione (1.5 g, 9.3 mmol) in 22.5 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (2.0 mL, 18.6 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour, at which point a beige precipitate formed, product. Upon cooling to room temperature, more product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.47 g of 4-Methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.C(N)CC.[CH2:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)[CH2:18][CH3:19]>>[CH2:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:8](=[O:9])[CH3:7])=[CH:24][CH:23]=1)[CH2:18][CH3:19]
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCCN
Product: CCCNC(=O)c1ccc(NC(C)=O)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-propyl amine in the amidation step. This yields N-n-propyl4-nitrobenzamide (CPI1047).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]([CH2:31]Cl)=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:34]>CC(C)=O>[CH2:1]([N:8]([CH2:28][C:29]([CH2:31][I:34])=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(CI)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(chloromethyl)prop-2-en-1-yl]amino}succinate from step 1b (8.7 g) and NaI (8.0 g) in acetone (100 mL) was stirred at RT overnight. The solid was filtered off and the filtrate concentrated. The residue was treated with methylene chloride and filtered through a pad of silica gel to give 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate (9.2 g). MS (ESI): 550.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+].Cl>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:25])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazine-3-one ((2-34)-(1)-39) (62.8 mg), dimethylsulfoxide (0.5 ml), and 3.8% by weight of aqueous sodium hydroxide solution (0.5 ml) were added under a nitrogen atmosphere at room temperature, and stirred at 70° C. for 4 hours. Then, to the reaction mixture was added 3.5% by weight of hydrochloric acid (4 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 37.5 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:11]1([C:14]2[O:15][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=2)[CH2:13][CH2:12]1
Reactant: NC(=O)C1CC1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1coc(C2CC2)n1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
Ethyl 4-chloroacetoacetate (20.0 g, 122.0 mmol) was added to cyclopropanecarboxamide (3.52 g, 41.5 mmol) in toluene (100 mL) and 1,4-dioxane (100 mL). The mixture was refluxed at 120° C. for 17 hours then evaporated in vacuo. The crude solid was purified by silica gel column chromatography eluting with 80:20 petroleum ether: EtOAc to afford the title compound as a white solid (50%, 4.00 g).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:18]#[C:19][CH:20]2[CH2:22][CH2:21]2)=[CH:13][C:14]=1[N+:15]([O-])=O)=[O:9]>C(O)C>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:18]#[C:19][CH:20]2[CH2:21][CH2:22]2)=[CH:13][C:14]=1[NH2:15])=[O:9]
Reactant: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: COC(=O)c1sc(C#CC2CC2)cc1N

Procedure:
Tin chloride (11.8 g) was added to a solution of 5-cyclopropylethynyl-3-nitrothiophene-2-carboxylic acid methyl ester (6.26 g) in ethanol (250 ml), and the reaction mixture was heated to reflux for 4 h. The solvent was then removed in vacuo, and the residue was taken up again in ethyl acetate and washed with sat. Rochelle salt solution. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The product with the molecular weight of 221.27 (C11H11NO2S) was obtained in this way; MS (ESI): 222 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:8][N:9]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:30])[F:31])[CH:22]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.8 %

Procedure:
A blue-green suspension of 5-methyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 3.03 mmol), molecular sieves 4A, 3-(trifluoromethoxy)benzeneboronic acid (1.25 g, 6.05 mmol), copper (II) acetate (824 mg, 4.54 mmol) and pyridine (0.48 ml, 6.05 mmol) in 14 ml CH2Cl2 was stirred under argon atmosphere and at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The aqueous phases were extracted twice with CH2Cl2, the combined organic layers dried over magnesium sulfate, and evaporated. The residue was treated with EtOAc:toluene, 1:9, filtered off. The filtrate was evaporated and chromatographed twice (amino-phase silica gel, toluene:EtOAc 9:1) to afford the title compound as a colorless oil (638 mg, 54%). MS: 392.1 (MH+).