Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6](#[N:10])[CH2:7][CH2:8]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[C:1]([O:5][CH2:8][CH2:7][C:6]#[N:10])(=[O:4])[C:2]#[CH:3]
Reactant: N#CCCO
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: C#CC(=O)OCCC#N
Yield: 28.5 %

Procedure:
A solution of 98 g of propiolic acid (1.4 moles), 99.5 g of hydracrylonitrile (1.4 moles), 2 g of p-toluenesulfonic acid and 200 ml of chloroform were refluxed, using a Soxhlet extractor filled with 3 A molecular sieves to remove the water generated during the esterification. A total reflux time of 94 hours was employed. The reaction was cooled, poured into water and extracted with chloroform. The combined extracts were washed with dilute bicarbonate solution, dried (MgSO4), and concentrated to give 49.2 g (29 percent) of a liquid used without purification.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.C(N(CC)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[S:25][CH3:26])C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]2[C:16](=[O:27])[CH2:26][S:25][C:18]=2[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1SC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)SCC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 13 mL, 20.8 mmol) was added slowly to a solution of diisopropylamine (2.91 mL, 20.8 mmol) in THF at −78° C. The mixture was stirred under nitrogen for 30 min and N,N-diethyl-4-methoxy-2-(methylthio)benzamide (2.4 g, 9.47 mmol), dissolved in 10 mL of anhydrous THF was added to the reaction dropwise. Stirring was continued at −78° C. for 1 h and the cooling bath was removed. After 12 h, the reaction was cooled back down to −78° C. and a 1:1 mixture of methanol and acetic acid (10 mL) was added to the mixture. The reaction was stirred for 15 min and the cooling bath was removed and allowed to warm up to room temperature. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 15 to 40% ethyl acetate in hexanes to obtain an off white solid. Yield=1.4 g. MS (M−H)-179.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][CH:6]=1.[SH:7][CH2:8][C:9]([OH:11])=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][C:2]1([S:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][O:3]1
Reactant: CC1=CCCO1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC1(SCC(=O)O)CCCO1

Procedure:
A mixture of 2-methyl-4,5-dihydrofuran and 2-mercaptoacetic acid in THF are treated with a catalytic amount of para-toluene sulfonic acid according to the procedure in Example I.A.2. After removal of the solvent, S-(2-methyl-tetrahydrofuran-2-yl) mercaptoacetic acid is obtained. Alternatively, mercaptosuccinic acid is reacted with 2-methyl-4,5-dihydrofuran and then converted to a mercaptosuccinic anhydride derivative by a dehydrating agent such as dicyclohexyl carbodiimide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3C=N[C:19](OC)=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:25]=[C:26](Cl)C1C=CC=CN=1>CO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:26][N:25]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ON=C(Cl)c1ccccn1
Reactant: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccccn3)[C@@H]2C1

Procedure:
The title compound was prepared in an analogous manner as the 4-methoxy-3-pyridyl cycloadduct 3c using chloro oxime 2e. 3e was isolated as a white solid after chromatography with 1.5% methanol/methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:27]=1
Reactant: Cc1ccc(O)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Oc3ccc(C)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-5-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottom flask, dissolved 4-(4-methylpiperazin-1-yl)benzoic acid (1.00 g, 4.50 mmol) in dichloromethane (5.0 mL). Added oxalyl chloride (1.2 mL, 9.1 mmol) and N,N-dimethylformamide (2 drops). Stirred at RT for 2 hours. Concentrated and isolated 4-(4-methylpiperazin-1-yl)benzoyl chloride as an off-white solid. LC/MS of methyl ester (quenched with methanol) revealed an MS (M+H)+ of 235; Calc'd 234.29 for C13H18N2O2 (methyl ester).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:13]C(=O)OC(C)(C)C)[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=2)[N:6]=1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=2)[N:6]=1
Reactant: Cc1nc(-c2cnn(C)c2)cn1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnn(C)c2)cn1N
Reaction time: 18 h

Procedure:
A solution of tert-butyl [2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]carbamate (8.0 g, 29 mmol) in methylene chloride (200 mL) and trifluoroacetic acid (40 mL) was stirred at room temperature for 2.5 hours. After removal of solvents in vacuo, the residue was stirred in 1:1 ethyl acetate/heptane for 18 hours. The resulting solid was isolated by filtration to provide the product as a white solid. Yield: 5.3 g, 18 mmol, 62%. The mother liquor was concentrated in vacuo, and the residue was stirred for 30 minutes in a 1:1:1 mixture of ethyl acetate/heptane/diethyl ether (50 mL); filtration provided additional product as a white solid. Combined yield: 7.8 g, 26.8 mmol, 92%. 1H NMR (400 MHz, DMSO-d6) δ 2.54 (s, 3H), 3.89 (s, 3H), 6.55 (br s, 2H), 7.65 (s, 1H), 7.85 (d, J=0.7 Hz, 1H), 8.11 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=O)[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:29][N+:26]([O-:28])=[O:27])[C:7]=2[N:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1

Procedure:
600 mg (2.27 mmol) of the compound obtained in Step E dissolved in 25 ml of nitromethane are heated at 120° C., for 3 hours in the presence of 440 mg (5.67 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[NH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:14][O:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (1.59 g.), tert-butyl N-aminooxyethylcarbamate (1.40 g.) and methanol (25 ml.) was stirred at room temperature for 6 hours. After removal of methanol from the resultant solution under reduced pressure, the residue was pulverized with diethyl ether. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2.21 g.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C=O)C>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl

Procedure:
Phosphorous oxychloride (84.3 g, 0.55 mol) was added to a stirred suspension of 3-nitroquinolin-4-ol (95.0 g, 0.50 mol) in DMF (500 mL), and an exotherm was observed. After the addition was complete, the solution was heated on a steam bath for 15 minutes. The solution was poured over ice to precipitate 4-chloro-3-nitroquinoline. The 4-chloro-3-nitroquinoline was isolated by filtration, washed with water, and pressed dry. The 4-chloro-3-nitroquinoline was dissolved in dichloromethane (1 L) and the solution was dried over magnesium sulfate and filtered. 2-(2-Aminoethoxy)ethanol (60.7 g, 0.6 mol) and triethylamine (104 mL, 0.75 mol) were added to the filtrate. The resulting solution was heated at reflux for 30 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in dilute aqueous hydrochloric acid and filtered. Ammonium hydroxide was added to the filtrate and a yellow solid formed. The solid was isolated by filtration, washed with water, and dried to provide 104.5 g of 2-{2-[(3-nitroquinolin-4-yl)aniino]ethoxy}ethanol as a yellow solid.
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[F:1][S:2]([F:12])([F:13])([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pentafluorosulfanylbenzoic acid (5.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at RT with exclusion of moisture. Then concentrated sulfuric acid (3 ml) was added and the mixture was stirred at 75° C. After stirring at 75° C. for 5 h, further sulfuric acid (1.5 ml) was added and, after stirring at 75° C. for 2 h, left to stand overnight. Then the mixture was added to ice-water and stirred for 2 h. The precipitate formed was filtered off with suction and dried under high vacuum. 4.2 g of 3-pentafluorosulfanyl-5-nitrobenzoic acid were obtained. A further 900 mg were obtained from the mother liquor after extracting three times with methylene chloride, drying the combined methylene chloride phases over magnesium sulfate and concentrating the solvent. The precipitate was used in the next stage without further purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@H:6]([C:8]1[CH:12]=[CH:11][O:10][N:9]=1)[OH:7])=[N+:2]=[N-:3].F[C:14]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17].[H-].[Na+]>>[N:1]([CH2:4][CH2:5][C@@H:6]([O:7][C:14]1[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17])[C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: [N-]=[N+]=NCC[C@@H](O)c1ccon1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN=[N+]=[N-])c1ccon1
Yield: 78.4 %

Procedure:
The product from step (a) (0.1 g) and 2,5-difluoro-4-chloro-benzonitrile (0.18 g) and sodium hydride (60% dispersion in oil, 0.035 g) were subjected to the procedure described in Example 90(a) to afford the product as a gum (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[S:46]([N:50]=[C:51](OC1C=CC=CC=1)OC1C=CC=CC=1)(=[O:49])(=[O:48])[NH2:47].O>ClCCl>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][S:46](=[O:49])(=[O:48])[NH2:47])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(NS(N)(=O)=O)nc12
Yield: 21.7 %

Procedure:
A mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (150 mg) and diphenyl N-sulfamoylcarbonimidate (85 mg) in dichloromethane (8 ml) was refluxed for 24 hours under nitrogen. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, driver over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1/chloroform:methanol=6:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-sulfamoylamino-1H-benzimidazol-4-yl)carbonylaminobenzamide (38 mg).
Reaction SMILES: [NH2:1][C@@:2]1([CH2:18][OH:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:8]3[C:3](=[CH:4][C:5]([I:17])=[CH:6][CH:7]=3)[C@:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH2:18][OH:19])[C:15]=2[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Solvent: C1CCOC1
Product: O=C(CCl)N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
The (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol) was dissolved in THF (200 mL). The solution was cooled to 0° C., and TEA (1.425 mL, 10.22 mmol) and 2-chloroacetyl chloride (0.707 mL, 9.07 mmol) were added. The reaction was allowed to warm naturally to RT. After 14 h, the reaction was concentrated. The residue was taken up in aqueous 1 M Na2CO3 (50 mL) and the aqueous phase was extracted with 7.5% MeOH-DCM (3×133 mL). The organics were combined, washed with aqueous 1 M Na2CO3 (30 mL), dried over sodium sulfate and concentrated. The residue was dissolved in THF (100 mL) and aqueous 1 M Na2CO3 (15 mL) was added. The reaction was concentrated. The residue was taken up in 5% MeOH-dcm (400 mL) and the organic phase was washed with dilute brine (40 mL), dried over sodium sulfate concentrated to afford crude (S)—N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroacetamide, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].CCN(CC)CC.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[CH:8][CH:7]=1)[C:25](=[O:28])[CH:26]=[CH2:27])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNc1ccc(OCC(F)(F)F)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCN(C(=O)C=C)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To the mixture of but-3-enyl-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-amine (1.56 g, 6 mmol) and NEt3 (1.7 g, 17 mmol) in 30 mL of DCM, acryloyl chloride (0.65 g, 7 mmol) was added slowly into at 0° C. The mixture was stirred at ambient temperature overnight. And then the solution was washed with water (2×15 mL) and brine (2×20 mL), dried with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=20:1) to obtain the title compound (1.6 g, 89%) as colorless oil. LC-MS: 300.1 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[OH:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[OH:18][CH2:19][CH2:20][CH2:21][NH:22][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: NCCCO
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Product: O=C(NCCCO)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 8.5 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 28 μL (0.36 mmol) of 3-hydroxy-propylamine. The aqueous phase is evaporated, the residue is taken up in methanol and then filtered. The filtrate is evaporated and the residue is purified by preparative LCMS to give 8 mg (9%) of N-(3-hydroxy-propyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CCCC)CCCC)CCC.[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O>[C:25]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1N
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1C
Yield: 27 %

Procedure:
A stirred solution of 4-amino-3-methylbenzoic acid (30.2 g), in dry dimethylformamide (300 ml), containing tributylamine (55 ml) was treated with n-hexadecanoyl chloride (61.0 g) in a similar manner to that described in Example 1(i) to give 4-(n-hexadecanamido)-3-methylbenzoic acid (21 g), in the form of white needles, m.p. 194°-196° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:27](Br)[CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][CH:29]([CH3:31])[CH2:28][CH2:27][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[C:14]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:15]1
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Method L Add Cs2CO3 (1.0 g, 1.88 mmol) to a solution of 4-(6-Nitro-1H-indol-3-yl)-benzonitrile, 9, (100 mg, 0.37 mmol) and isopentyl bromide (0.1 mL, 0.75 mmol) in DMF (10 mL). Stir overnight at ambient temperature. Remove the DMF solvent to provide a solid and partition the solid between EtOAc and H2O, Sequentially wash the organic layer with H2O and brine then dry the organic layer over MgSO4. Filter and remove the solvent leaving a solid. Purify by silica gel column chromatography (0-100% EtOAc/hexanes gradient) and concentrated to dryness to afford 180 mg (95%) of the title compound. LRMS (API ES+)=334.3 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([NH2:13])=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.C(O)(=[O:16])C>O>[O:16]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11]([NH2:13])=[O:12])[CH2:7][CH2:8]1
Reactant: NC(=O)NC1CCCc2sccc21
Reactant: CC(=O)O
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21

Procedure:
A sample of 6 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is dissolved in 375 ml. of 50% aqueous acetic acid and 75 grams of ceric ammonium nitrate is added in portions over a 10 minute period with stirring at 25° C. to 35° C. The pale-orange solution is stirred for another 5 minutes and 100 ml. of water is added. The solution is extracted twice with ethyl acetate (450 ml. and 350 ml.) and the combined extracts are washed with 100 ml. of water. The organic extract is evaporated to dryness in vacuo and the brown residue is crystallized from methanol to afford 2.37 grams of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, melting point 237° C. to 238° C. dec. Recrystallization from methanol affords purified product, melting point 245° C. to 246° C. dec.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:35][OH:36]>>[C:16]([O:15][C@@H:9]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([O:36][CH3:35])[O:7][C@H:8]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:20]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)OC(Br)[C@H]1OC(C)=O
Reactant: CO
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (3S,4R,5S,6S)-2-bromo-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.02 g, 3.62 mmol) in methanol (15 mL) was added ZnO (294.5 mg, 3.62 mmol) at 60° C. The reaction mixture was stirred at 60° C. for 1 h. After completion of reaction, as confirmed by TLC, reaction mixture was passed through sintered funnel to remove the solids. The filterate was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:Pet. Ether) to afford title compound (1.1 g, 65%)
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=1)[N:10]=[C:9]2[NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2.[H][H]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([C:11]2[N:10]=[C:9]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[N:32]=[CH:31]4)[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:44])[CH:7]=3)[N:12]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Temperature: 55 °C

Procedure:
A mixture of tert-butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.142 mmol) and 10% Pd/C (0.100 g) in MeOH (20 ml) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was heated at 55° C. for 1 h. The reaction mixture filtered through Celite® washing with MeOH. The filtrate was concentrated in vacuo to give tert-butyl 5-(2-(3-aminophenyl)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.065 g, 0.128 mmol, 90%). HPLC retention time 3.42 mins.