Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(S(=O)(=O)NC3CCCCC3)cc2)cc1
Reaction time: 8 h

Procedure:
4-(4-Nitrophenoxy)benzenesulphonyl chloride (Example 1) (18.8 g), cyclohexylamine (6.5 g), anhydrous potassium carbonate (8.3 g) and acetone (100 ml) were refluxed together for 4 hours. On concentration and addition of water, an oil separated which solidified overnight. From ethanol on addition of light petroleum (b.p. 60°-80° C.), 4-(4-nitrophenoxy)-N-cyclohexylbenzenesulphonamide was obtained in the form of crystals, m.p. 94° C.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:16]3[C:17]([O:21][CH3:22])=[N:18][N:19]([CH3:20])[C:15]=3[NH:14][S:10]([C:9]3[C:4]4[C:5](=[N:1][S:2][N:3]=4)[CH:6]=[CH:7][CH:8]=3)(=[O:12])=[O:11])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2cccc3nsnc23)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 3.9 %

Procedure:
To a solution of 4-dimethylaminopyridine in anhydrous pyridine at 0° C. under an atmosphere of nitrogen was added 2,1,3-benzothiadiazole-4-sulfonyl chloride (142 mg) in pyridine (1.5 ml). After 10 min the reaction was treated with 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated under reduced pressure, the residue diluted with brine (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (eluent of 55% water in acetonitrile to 30% water in acetonitrile over 8 mins, then 30% water in acetonitrile for 13 mins. Phenomenex Magellen™ 150 mm×21.5 mm column, 40° C.) to yield the title compound as an off-white solid (7 mg).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: C=Cc1ccc2nnn(O)c2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(Cl)cc3)c2c1
Temperature: 10 °C
Yield: 83.4 %

Procedure:
In benzene (100 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5 g) under stirring and thereto is added dropwise a solution of p-chlorobenzenesulfonyl chloride (10.6 g) in benzene (100 ml) under cooling to 10° C. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water (200 ml) and then extracted with ethyl acetate (150 ml, twice). The combined extracts are washed with water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 30 ml. To the mixture is added n-hexane and the mixture is allowed to stand at a cooled place. The precipitated crystals are separated by filtration to give 1-(p-chlorobenzenesulfonyloxy)6-vinyl-1,2,3-benzotriazole (13.9 g), melting point: 125° C. The filtrate is further concentrated and the resulting residue is dissolved in ethyl acetate (10 ml). To the solution is added n-hexane and the mixture is allowed to stand at a cooled place to give additionally the desired product (1.0 g).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)C>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)cc1
Reaction time: 5 h

Procedure:
6.5 g of palmitoyl chloride are added to 40 ml of pyridine containing 7 g of 2-(4-benzylpiperidino)-4'-hydroxypropiophenone and the mixture is stirred for 5 hours. It is diluted with 100 ml of diethyl ether and left to stand overnight. The precipitate is then collected by filtration, washed and dried. 11 g of a product which melts at 185°-192° C. with decomposition are thus isolated.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O.CN(C)C=O>CCOCC>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:3][CH2:2]1
Reactant: O=C(O)CCCCCCCCC1CC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCC1CC1

Procedure:
A mixture of 0.85 g. of 9-cyclopropylnonanoic acid, 0.45 ml. of thionyl chloride (density 1.656) and 0.10 ml. of dimethylformamide (density 0.945) in 10 ml. ether is stirred overnight at room temperature. The upper layer of the reaction mixture is then separated and the solvent removed by evaporation to yield 9-cyclopropylnonanoyl chloride to which is added at 0° under nitrogen 1.4 g. of 9-octadecen-1-ol and 40 ml. of ether. To this mixture is added dropwise 0.52 ml. of pyridine (density 0.98). The reaction mixture is then stirred 1/2 hour at 0° and overnight at room temperature. The mixture is filtered, 3 equivalents of water are added and then the mixture is stirred for one hour. Ether is added to dilute the reaction mixture which is washed in turn with 2N sulfuric acid (2 × 50 ml.), 10% aqueous sodium carbonate (2 × 50 ml.), water (2 × 50 ml.) saturated aqueous copper sulfate, water (2 × 50 ml.) and saturated aqueous sodium chloride (1 × 50 ml.). The solution is then dried over calcium sulfate and the solvent removed by evaporation to yield 9-octadecenyl 9-cyclopropylnonanoate which is purified by thin layer chromotography (15% ether/hexane solvent).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]2[O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[CH:13]([C:14](O)=[O:15])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:25]=1[NH2:26]>>[C:1]([C:5]1[CH:22]=[CH:21][C:8]2[O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[CH:13]([C:14]([NH:26][C:25]3[C:24]([Cl:23])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[O:15])[C:7]=2[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: CC(C)(C)c1ccc2c(c1)C(C(=O)Nc1c(Cl)cccc1Cl)c1ccccc1CO2
Yield: 69.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-(tert-butyl)-6,11-dihydrodibenz[b,e]oxepine-11-carboxylic acid obtained in Example 42 (Compound D) in place of Compound A and 0.49 g of 2,6-dichloroaniline in place of aniline to obtain 0.92 g of Compound 45.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6](=[O:17])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=1)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][C:30](=[O:31])[N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[CH3:18])[CH2:14][CH2:13]2)[CH3:16])=[CH:34][CH:35]=1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: CN[C@H]1CC[C@H](OCC(=O)N(C)CCN(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)CO[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.55 mmol) of trans-N-(2-dimethylamino-ethyl)-N-methyl-2-(4-methylamino-cyclohexyloxy)-acetamide in 4 mL of CH2Cl2 were added 0.14 mL (0.8 mmol, 1.5 eq) of N,N-diisopropylethylamine followed by 0.08 mL (0.58 mmol, 1.1 eq) of 4-bromophenyl chloroformate. The mixture was stirred at RT for 2 h, and the solution was added to a mixture of NaHCO3 solution and CH2Cl2. The phases were separated and the inorganic one was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 yielded 174 mg (67%) of trans-(4-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methoxy}-cyclohexyl)-methyl-carbamic acid 4-bromo-phenyl ester as colorless oil, MS: 470 (MH+,1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7](C=S(=O)=O)=[N:8][C:4]=2[CH:3]=1.ClC1C=CC2N=C(C=S(=O)=O)N(CC3C=C[C:42]4[O:45]COC=4C=3)C=2C=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]([O:45][CH3:42])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)=Cc1nc2ccc(Cl)cc2n1Cc1ccc2c(c1)OCO2
Reactant: O=S(=O)=Cc1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2

Procedure:
448 mg of a mixture comprising 5-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole and 6-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole was dissolved in 20 ml of methanol, followed by the addition of 10 ml of 28% sodium methoxide. The obtained mixture was heated under reflux for 1.5 hours, cooled with ice, neutralized with 10% aqueous hydrochlic acid, and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum. The residue was subjected to silica gel column chromatography to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](/[CH:27]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]C)=[O:36])[CH:30]=2)[N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[C:35]([C:31]1[CH:30]=[C:29](/[CH:28]=[CH:27]\[C:8]2[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:39])=[O:2])[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:34]=[CH:33][CH:32]=1)([OH:37])=[O:36]
Reactant: COC(=O)CCc1nc(/C=C\c2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(/C=C/CCCCOc2ccc(/C=C\c3cccc(C(=O)O)c3)nc2CCC(=O)O)cc1
Yield: 88.9 %

Procedure:
Under the conditions of example 3 C, 82 mg of 3-{6-[2-(3-methoxycarbonyl-phenyl)-(1Z)-1-ethenyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester in 2.5 ml of methanol and 1 ml of tetrahydrofuran is saponified with 2 ml of 2n sodium hydroxide solution and worked up. 69 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:28]=1)=O)C>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:28]=3)=[O:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnn(CCN2CCCC2)c1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnn(CCN4CCCC4)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester, the title compound was obtained as white solid (13% yield). MS: m/e=457(M+H+), mp 190-192° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=O)[C:10]=12)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([Cl:22])[C:10]=12)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ncn2c1c(=O)[nH]c1ccccc12
Product: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Temperature: 25 °C
Yield: 47 %

Procedure:
4-Oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (9 g) was suspended in 200 ml of phosphorus oxychloride and the mixture was heated with stirring until it became a clear solution. After cooling to room temperature, the solution was concentrated under vacuum. The residual oil was taken up in chloroform and was put through a short silica gel dry column (chloroform as eluant). The product was obtained from column as an off-white colored solid (4.5 g, 47% yield), m.p. 128°-130° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].N>CO.[Ni]>[CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CN)cc1
Yield: 43 %

Procedure:
Combine 4-ethanesulfonyl-benzonitrile (0.7 g, 3.5 mmol), Raney® 3201 nickel (slurry in water, 0.1 g), 2N ammonia in methanol (20 mL) and hydrogenate at 50 psi for 17 h. Filter the reaction mixture through a pad of Celite® and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound as a yellow oil (0.3 g, 43%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[C:18](OCC)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[O:27]=[C:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Reaction time: 2 h

Procedure:
A solution of dimethyl methylphosphonate (115.5 g.) in 2.1 l. of tetrahydrofuran is treated, while stirring at -65° C., with a solution of butyl lithium (660 ml. 1.6 M. in hexane). A solution of ethyl hydrocinnamate (93.5 g.) in 225 ml. of tetrahydrofuran is added at -65° C. Stirring is continued at -65° C. for 2 hrs. and then at about 25° C. for 16 hrs. Acetic acid (70 ml.) is added and the mixture concentrated under reduced pressure. The residue is partitioned between dichloromethane and water. The organic phase is dried and concentrated. Distillation yields the title compound, b. 188°-191° C./2 mm., having a mass spectral peak at 256.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[I:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Ic1ccc(-c2nc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
In a 300 mL three-neck flask were put 15 g (44 mmol) of 4-iodo-N-(2-hydroxyphenyl)benzamide and 24 g (0.14 mol) of para-toluenesulfonic acid monohydrate. The atmosphere in the flask was replaced with nitrogen. To this mixture was added 300 mL of toluene. The resulting mixture was stirred under a nitrogen stream at 110° C. for 4 hours. After that, this reaction mixture was added to about 300 mL of water, followed by extraction with ethyl acetate. Then, the organic layer and the extract were combined and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered through Celite. The resulting filtrate was concentrated to give a solid. This solid was recrystallized with a mixed solvent of ethyl acetate and hexane to give 11 g of a white solid in a yield of 75%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3ncccc32)n1

Procedure:
To a solution of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide (0.047, 0.12 mmol) in DMF (0.4 mL) was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (17 uL, 0.27 mmol). After 2 h the reaction mixture was partitioned between H2O and ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product was submitted to prep HPLC for further purification. Retention time (min)=4.407, method [8], MS (ESI) 403.1 (M+H). 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.07 (s, 1H), 7.56 (d, J=8.1 Hz, 1H) 7.41 (d, J=5.1 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H) 6.81 (s, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.47-3.42 (m, 2H), 3.03-2.98 (m, 2H).
Reaction SMILES: [NH:1]([C:27]([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C@H:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:45]>CO.C1C=CC=CC=1>[NH:1]([C:27]([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C@H:2]([C:24]([O:26][CH3:45])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of Fmoc-L-Cys(Trt)-OH (2.34 g, 4.00 mmol) in methanol (4.0 mL) and benzene (16 mL) was added TMS-diazomethane (2.40 mL, 4.80 mmol). After 1 hour, the mixture was concentrated in vacuo to afford Fmoc-L-Cys(Trt)-OMe which was used in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:17]=[C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:11]2=[N:12][CH:19]=1)([O-:15])=[O:14]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1ccnn1C1CCOCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2c(cnn2C2CCOCC2)c1
Temperature: 108 °C
Yield: 67.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.6 g, 9.6 mmol) in 70% acetic acid (15 mL) is added nitromalonaldehyde (1.3 g, 9.6 mmol) and the reaction mixture is heated to 108° C. for 3 h. The solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography using a gradient of 20% ethyl acetate/petroleum ether to afford the title compound as a pale yellow solid (1.6 g, 70%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[F-:13].[K+]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(F)c1ccc(I)cc1

Procedure:
p-Iodobenzenesulfonyl chloride (593 g, 1.96 mol), prepared as described in Example 1(a) above, is dissolved in 2.5 L of acetone and placed in a 5 L three-neck round-bottom flask fitted with a heating mantle, mechanical stirring and a water-cooled condenser. Potassium fluoride (126 g, 2.17 mol) and about 25 mL of water is added and the reaction is heated at reflux for approximately 5 hours. On cooling, the reaction mass is filtered and the solvent removed to provide a crude solid, which on purification, by distillation under high vacuum, affords p-iodobenzenesulfonyl fluoride as a white solid; yield 504 g (90%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:13]3[O:14][CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:28]>CO>[NH2:28][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Temperature: -55 °C

Procedure:
A solution of compound 5.6 (28.8 mg, 0.057 mmol) in MeOH (3 mL) was transferred to a steel bomb, cooled to −50 to −60° C., and treated with a saturated solution of ammonia in MeOH (10 mL). The reactor was sealed and heated at 118° C. overnight. The reaction vessel was cooled (0-5° C.), opened carefully and the reaction mixture was evaporated to dryness. The crude product was dissolved in MeOH, adsorbed onto silica gel and purified by flash column chromatography on silica gel using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluents to give the desired compound 5.7 (20.7 mg) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:4]([C:21]2[C:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1.CCN(CC)CC.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH:39]1([CH2:38][O:37][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:21]=2[C:4]2[CH:5]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C:7]3[CH2:8][O:9][C:50](=[O:52])[NH:1][C:2]=3[N:3]=2)[CH2:40][CH2:41]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c3c(n2)NC(=O)OC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethyl-carbamate (0.050 g, 0.089 mmol) and Et3N (0.074 mL, 0.531 mmol) in THF (10 mL) was added triphosgene (0.013 g, 0.044 mmol) in one portion. The mixture was stirred at 0° C. for 1 hr, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (ethyl acetate) gave tert-butyl 2-[(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)-oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)amino]ethylcarbamate as colorless oil (0.036 g, yield; 69%).