Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@H:33]3OC(C)(C)[O:36][C@@H:35]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]3[CH2:34][C@@H:35]([OH:36])[CH2:41][C:42](=[O:43])[O:44]3)[C:10]([CH:28]([CH3:29])[CH3:30])=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
(4R-cis)-1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 mL of tetrahydrofuran and 15 mL of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two crops.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Cl
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of 3-chloro-4-phenyl-1H-pyrrole-2,5-dione (4.84 mmol, 1.0 g) in dry DMF (5 mL) was added 4-methoxyaniline (4.87 mmol, 600 mg) and the reaction mixture was subjected to microwave heating single node 150° C., 15 min, followed by 150° C., 10 min. The solvent was evaporated, and the crude mixture was partitioned between dichloromethane and water. The organic phase was dried over anhydrous Na2SO4, concentrated and the residue was purified on SiO2 (Heptane:EtOAc, 3:1→2:1) to give 457 mg (32%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.27 (s, 1H), 7.09-6.99 (m, 3H), 6.87-6.83 (m, 2H), 6.65-6.60 (m, 2H), 6.52-6.47 (m, 2H), 3.58 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[I-].[K+].[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1.[H-].[Na+]>CN(C)C=O.O>[N:22]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
t-Butyl 4-methylsulfonyloxymethyl-1-piperidinecarboxylate (0.50 g, 1.7 mmol) was dissolved in dimethylformamide (8 ml). To the solution were added potassium iodide (0.37 g), benzimidazole (0.26 g) and 60% sodium hydride in mineral oil (0.088 g), successively, and the mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with water three times, dried over magnesium sulfate and concentrated under reduced pressure. The resulting solid materials were recrystallized from ethyl acetate/hexane to give the titled compound (0.45 g, 1.4 mmol, Yield 82%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13](O)=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[Na]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1snc(-c2cccc(C(F)(F)F)c2)c1O
Agent: [Na]
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)ns1

Procedure:
3-( 3- trifluoromethylphenyl )- 4-hydroxyisothiazole-5-carboxylic acid, sodium salt
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (95 mg, 0.348 mmol), 2,5-dimorpholinoaniline (92 mg, 0.348 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.348 mmol) in MeOH (2.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-8-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72 (1H, dd, J=4.7, 1.6 Hz), 7.87-8.00 (2H, m), 7.64-7.71 (1H, m), 7.31-7.45 (4H, m), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=7.4 Hz), 6.04 (1H, br. s.), 3.90 (4H, t, J=4.9 Hz), 3.68-3.79 (4H, m), 2.99-3.14 (4H, m), 2.86-2.98 (4H, m), 2.42 (3H, s). Mass Spectrum (ESI) m/e=500.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(C=Cc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 35.7 %

Procedure:
Using 3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethenyl]piperidine (153 mg, 0.480 mmol) and 3-(methoxycarbonyl)phenylboric acid (173 mg, 0.960 mmol), the same procedure was followed as in Example 2 to give 77.7 mg (36%) of the desired compound as a yellow powder.
Reaction SMILES: C([O:8][C:9]1[C:10](=[N:29][OH:30])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)C1C=CC=CC=1.[H][H]>[Pd]>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[O:16][C:15]([C:14]3[N:13]=[CH:12][N:11]([CH3:28])[C:10](=[N:29][OH:30])[C:9]=3[OH:8])=[N:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=NO
Agent: [Pd]
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=NO
Yield: 68 %

Procedure:
5-Benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one oxime was hydrogenated at 1 atmosphere of hydrogen in the presence of equal weight of 10% Pd/C to give 68% yield of 6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-5-hydroxy-3-methyl-3H-pyrimidin-4-one oxime (COTI-HIV-1DOxime or, also referred to as COTI-HIV-1). Results are summarized below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[CH2:14]=O.C[O-].[Na+].Cl>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[CH2:14]
Reactant: C=O
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C(C(=O)OC)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichlorophenylacetic acid methyl ester (4.62 mmol) in 9 mL DMSO were added paraformaldehyde (4.85 mmol) and NaOMe (0.23 mmol). The reaction mixture was stirred at RT for 1 h and then poured into ice cold water. The mixture was neutralized with 1M HCl solution and extracted with toluol (3×). The combined organic layers were washed with aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1 to 8/2) gives the desired compound as colorless oil;
Reaction SMILES: [CH2:1]([P:8](=[O:15])([O:12]CC)[O:9]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([P:8](=[O:9])([OH:15])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Solvent: O
Product: O=P(O)(O)Cc1ccccc1
Yield: 82 %

Procedure:
Benzylphosphonic acid was prepared as follows. 200.40 g (878 mmoles) of diethyl benzylphosphonate was combined with 350 ml of distilled water and 350 ml of concentrated (~12 molar) hydrochloric acid. The resulting suspension was heated to reflux under nitrogen for 20 hours, whereupon a clear colorless solution was obtained. From this solution, 130 ml of aqueous distillate was removed. The residue was allowed to cool, forming a thick white slurry which was cooled in situ with an ice bath. The slurry was then filtered dry under vacuum, but not washed due to its fairly high solubility in water. The wet solid was then dried in a vacuum at 120° C. overnight. 123.37 g (82% yield) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[N:6](C(C)=C)[C:5]1=[O:17].Cl>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:17]
Reactant: C=C(C)n1c(=O)n(CCO)c2ccc(C)cc21
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a stirred solution of 46 parts of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one in 168 parts of ethanol are added 48 parts of hydrochloric acid solution and the whole is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the residue is stirred in 250 parts of water. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 22.3 parts (58%) of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-2H-benzimidazol-2-one; mp. 158.7° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:33])([F:32])[F:34])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([N:22]([CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[C:36](=[O:37])[O:38][CH3:39])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C1CCCO1
Yield: 23.7 %

Procedure:
In a suspension of 0.07 g of 55% oily sodium hydride in 10 mL of tetrahydrofuran, a solution of 0.49 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(2-tetrahydrofuranyl)benzoic acid amide in 5 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was stirred at at room temperature for 10 minutes. Then, 0.15 g of methyl chloroformate was added, and continued to stir at the same temperature further for 15 hours. After the completion of the reaction, the reaction was poured in 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.13 g of the aimed product as colorless resinous substance.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(P(CCCC)CCCC)CCC.[CH2:43]([N:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:46](=[O:57])[C:47]1[CH:52]=[C:51]([N+:53]([O-:55])=[O:54])[CH:50]=[CH:49][C:48]=1Br)[CH3:44]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:43]([N:45]1[C:46](=[O:57])[C:47]2[C:48](=[CH:49][CH:50]=[C:51]([N+:53]([O-:55])=[O:54])[CH:52]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]1=2)[CH3:44]
Reactant: CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc([N+](=O)[O-])ccc2c2ccccc21
Temperature: 23 °C

Procedure:
Palladium acetate (129 mg, 0.57 mmol) was added to a suspension of silver carbonate (1.6 g, 5.72 mmol), 1,3-bis(diphenylphosphino)propane (236 mg, 0.57 mmol), tributylphosphine (0.713 ml, 579 mg, 2.86 mmol) and N-ethyl-2-bromo-5-nitro-N-phenyl-benzamide (1.0 g, 2.86 mmol) in DMF (15 ml). The reaction mixture was heated to reflux for 30 minutes and cooled to 23° C. The mixture was filtered through a plug of celite, and the filter cake was washed with ethyl acetate (50 ml). The combined filtrates were washed with saturated sodium chloride (3-30 ml portion), dried over anhydrous sodium sulfate, and were concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) afforded 5-ethyl-8-nitro-5H-phenanthridin-6-one I-16b (111 mg, 14%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=S)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2].[NH3:17]>>[NH2:17][C:8]1[CH:7]2[CH2:14][CH2:15][CH2:16][CH:6]2[C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: N
Reactant: N#Cc1ccc2c(c1)C1CCCC1C(=S)N2
Product: N#Cc1ccc2c(c1)C1CCCC1C(N)=N2
Yield: 81 %

Procedure:
Analogously to Example 4, 8-cyano-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (40 mg, 0.18 mmol) is reacted with 7N methanolic ammonia solution (10 ml) to form 30 mg (81%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.02-7.08 (m, 2H), 6.94-7.0 (t, 2H), 4.85 (s, 2H), 4.2 (s, 2H), 3.80-3.88 (m, 4H), 3.14-3.34 (m, 4H), 2.34 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 351.81, found 352.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18]C(O)=O)=[CH:17][C:12]=2[CH2:11][CH2:10]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[O:9][CH:10]=[CH:11][C:12]=2[CH:17]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2occc2c1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (5.0 mmol) was added to a solution of 2,3-dihydrobenzofuran-5-ylacetic acid (5.0 mmol) and benzoyl peroxide (10 mg) in carbon tetrachloride (100 mL) and refluxed for 3 h. The mixture was cooled to room temperature, filtered and concentrated. The product was recrystallized from ethyl acetate:hexane (2:1) to giving the title compound as a white solid. 1H NMR (CD3OD) δ 7.62 (1H, d, J=2.4 Hz), 7.52 (1H, d, J=0.8 Hz), 7.46 (1H, d, J=8.4 Hz), 7.21 (1H, dd, J=1.6, 8.4 Hz), 6.74 (1H, d, J=3.2 Hz), 3.74 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[C:37]([NH:36][CH:33]1[CH2:34][CH2:35][N:31]([CH2:30][CH2:29][NH:28][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:32]1)(=[O:39])[CH3:38]
Reactant: CC(=O)NC1CCN(CCN)C1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)NC1CCN(CCNC(=O)c2cc(C)[nH]c2/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)C1
Yield: 75.3 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (58.5 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 97 mg (78%) of the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([C:16]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[OH:9])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H]1CCCCC[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@@H]1CCCCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of trans-2-aminocycloheptanol (0.97 g; 7.74 mmol), triphenylmethyl chloride (2.16 g; 7.74 mmol) and triethylamine (2.70 ml; 19.35 mmol) are combined in about 100 ml CH2Cl2 and heated to reflux overnight. After removing the heat, the reaction mixture is concentrated in vacuo and flash chromatographed using hexane:ethylacetate; 9:1 to obtain trans-2-triphenylmethylaminocycloheptanol which is used directly in the next step.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C(S(Cl)(=O)=O)C=CC=1.C([Li])CCC.[CH:34]1([CH:37]=[O:38])[CH2:36][CH2:35]1.Cl>O1CCCC1.CCCCCC.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:37]([CH:34]3[CH2:36][CH2:35]3)[OH:38])[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1CC1
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc(Br)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(Nc1ccccc1)c1cccc(C(O)C2CC2)c1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 970 mg of N-phenyl-3-bromo-benzenesulfonamide, readily prepared from commercially available 3-bromo-benzene sulfonyl chloride, in 55 mL of anhydrous tetrahydrofuran under nitrogen at -78° C. is added 1.9 mL of a 1.6M solution of n-butyllithium in hexane. The solution is stirred for 10 min and then an additional 1.9 mL of n-butyllithium (1.6M in hexane) is added. The solution is stirred for 10 min and then 0.35 mL of cyclopropane carboxaldehyde is added. The solution is stirred for 1 h 30 min and then treated with water and ethyl acetate. The solution is treated with 5% aqueous hydrochloric acid and brine. The layers are separated and the aqueous is extracted with two portions of ethyl acetate. The combined organic layers are dried sodium sulfate (Na2SO4) and concentrated to afford an oil which is chromatographed over silica (eluted with 5% methanol/dichloromethane) to afford 517 mg (55%) of the title product as a clear oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][N:23]4[CH:27]=[CH:26][CH:25]=[C:24]4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][N:23]4[CH:27]=[CH:26][CH:25]=[C:24]4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCn1cccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCn1cccc1-3
Temperature: 50 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
To a solution of methyl 13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2′,1′:3,4][1,4]diazepino[1,2-a]indole-10-carboxylate (88 mg, 0.17 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and 2N hydrochloric acid (2.5 ml) and water were added to the reaction mixture. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2′,1′:3,4][1,4]diazepino[1,2-a]indole-10-carboxylic acid (74 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28]>CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Reactant: CCCN=C=O
Solvent: CN(C)C=O
Product: CCCNC(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.0 g) was dissolved in dimethylformamide (10 ml) and n-propyl isocyanate (0.26 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.2 g of 4 -amino-5-chloro-2-methoxy-N-(1-(4-(3-n-propylureido)butyl)-piperidin-4-ylmethyl)benzamide.