Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[N:4]=1.[H-].[Na+].[Cl-].[NH4+].[CH3:34][OH:35]>>[CH3:34][O:35][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[CH:9]=2)[N:4]=1
Reactant: CO
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,2-Dimethylpropyl 4-[4-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1-piperazinecarboxylate (106 mg) obtained in Example 32 was dissolved in methanol (2 mL), and oily sodium hydride (10 mg) was added thereto and stirred at room temperature for 15 minutes, and then aqueous saturated ammonium chloride solution was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 2.5 mg of the entitled compound as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: Cc1ccc(C=O)cc1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 4-methylbenzaldehyde (0.5 g, 4.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.10 g, 81%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[N+:18]([O-:20])=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
One gram of 3-isopropylaniline and 0.8 gram of triethylamine were dissolved in 50 ml of THF, cooled to 0° C. and agitated. A solution prepared by dissolving 1.37 grams of 2-nitrobenzoyl chloride in 20 ml of THF was dropwisely added. After agitating for 30 minutes, the reaction mixture was filtered and THF in the filtrate was distilled off under reduced pressure. The residue was extracted with benzene, and rinsed with 3N-HCl, a saturated sodium bicarbonate solution and water successively in this order. The benzene layer was dried by adding anhydrous magnesium sulfate and then benzene was distilled off under reduced pressure to obtain the desired product. The yield was 1.79 grams (85%), and the product had a melting point of 65.5° to 68.5° C. and an IR absorption peak at 1660 cm-1 (c=0).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:19](#[N:21])[CH3:20]>>[OH:9][CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH2:20][C:19]#[N:21]
Reactant: O=Cc1cccc(OCC(O)c2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCC(O)c2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(2-hydroxy-2-phenylethoxy)benzaldehyde gave 3-hydroxy-3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propanenitrile as a yellow oil. Yield (0.97 g, crude): MS: 284 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1)=[CH2:18]>[OH-].[Na+].[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(=O)O)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(n(CCc3ccc(C(=O)O)nc3)c3ccc(Cl)cc23)CC1
Temperature: 90 °C
Yield: 2.5 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.85 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butyl ammonium chloride (11 mg, 0.042 mmol) followed by 5-vinylpicolinic acid (140 mg, 0.94 mmol). The reaction mixture was heated at 90° C. for overnight and was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 8 mg of 5-(2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinic acid as the TFA salt.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:27][N:26]=2)=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2,6-diamine (20 mg, 0.15 mmol) described in Manufacturing Example 13-1-3 and 2-(6-benzyl-pyridin-3-yl)-acetohydroximoyl chloride (79 mg, 0.30 mmol) described in Manufacturing Example 210-1-7 was added triethylamine (46 mg, 0.45 mmol), which was stirred for 30 minutes at 50° C. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=20:1) to obtain the title compound (43 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.C(OCC)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([C:12]([CH3:14])=[O:13])[C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=Cc1ccc(F)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
8.69 g (7×10-2 mol) of p-fluorobenzaldehyde, 9.11 g (7×10-2 mol) of ethyl acetoacetate, 0.24 g (2.8×10-3 mol) of piperidine and 0.84 g (1.4×10-2 mol) of glacial acetic acid were dissolved in 40 ml of dry benzene dehydrated by molecular sieve, and the mixture was refluxed under heating at 100° C. for about 3 hours for azeotropically removing water. After confirming the disappearance of the starting materials by thin layer chromatography, the reaction solution was cooled to room temperature, and 50 ml of ethyl ether was added thereto. The mixture was washed three times with 100 ml of water and twice with 100 ml of a saturated sodium chloride aqueous solution. The ether solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure by an evaporator. The residual oil was left to stand overnight in a refrigerator. The solid thereby obtained was recrystallized from hexane to obtain 14.08 g (yield: 85.2%) of slightly yellow prism crystals. Melting point: 80°-82° C.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.C([O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(=O)C>C(O)(=O)C>[OH:13][C:14]1[C:15]([C:6](=[O:7])[CH3:5])=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cc(OC(C)=O)cc(OC)c1OC
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)O
Product: COc1cc(O)c(C(C)=O)c(OC)c1OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Boron trifluride etherate (13.0 mL) was added dropwise to a solution of 3,4,5-tri-methoxyphenyl acetate 4 (6.78 g, 30 mmol) in glacial acetic acid (10 mL). The mixture was stirred at 70° C. for 2 h. Then the mixture was poured onto crushed ice (80 g). The light brown oil was separated and distilled under reduced pressure to furnish light yellow oil (5.56 g, 82%); 1H NMR (CDCl3, 200 M Hz) δ 13.42 (br s, 1H), 6.23 (s, 3H), 3.82 (s, 3H), 3.99 (s, 3H), 3.88 (s, 3H), 3.79 (s, 3H), 2.65 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 203.3 (s), 161.8 (s), 160.0 (s), 155.2 (s), 134.7 (s), 108.4 (s), 96.0 (d), 60.9 (q, 2C), 56.0 (q), 31.8 (q).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[I:17]Cl>CO>[I:17][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: ClI
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(N)ccc(I)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a well stirred solution of 2-methyl-3-nitroaniline (10 g, 66 mmol) in methanol (150 mL) was added sodium hydrogencarbonate (264 mmol) followed by 1.0 M solution of iodine monochloride (72 mmol) at room temperature. After stirring for 1 h, the solvent was removed, diluted with ether, washed with 10% aqueous sodium thiosulfate solution. The solvent was removed and the crude iodide was in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44]([F:47])([F:46])[F:45])=[CH:39][C:38]=2[C:48]2[CH:53]=[CH:52][N:51]=[N:50][CH:49]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([N:18](CC2C=CC(OC)=CC=2OC)[C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1.C(Cl)Cl>>[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44]([F:45])([F:46])[F:47])=[CH:39][C:38]=2[C:48]2[CH:53]=[CH:52][N:51]=[N:50][CH:49]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([NH:18][C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:16])=[O:17])[CH:14]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(F)c(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(F)c(C(F)(F)F)cc2-c2ccnnc2)cc1F
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
Trifluoroacetic acid (500 uL, 6 mmol) was added to a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (22 mg) in methylene chloride (5 mL, 70 mmol). After stirring 20 min, the reaction mixture was concentrated onto diatomaceous earth and purified by automated flash chromatography (4 g SiO2, methylene chloride to 9:1 methylene chloride-methanol) to afford the product as a tan solid (6 mg, 9%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([CH3:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[C:22]([CH3:35])[CH:21]=1)[CH2:13][CH2:12]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(Cl)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (5 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (188 mg, 1.7 mmol), 6-chloro-1,2,3,4-tetrahydro isoquinoline hydrochloride salt (165 mg, 0.8 mmol), and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and filtered through silica gel. Purification by preparative thin layer chromatography afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CCN(CC)CCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.616 g) is dissolved in DMF (4 mL), and K2CO3 (0.93 g, 6.72 mmol) and 2-bromo-N,N-diethylethylamine hydrobromide (0.88 g, 3.35 mmol) are added. The reaction mixture is heated to 90° C. for 16. The mixture is partitioned between CHCl3 and water. The organic layer is concentrated in vacuo to give an oil. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.10 g of a brown oil. Crystallization from ethyl acetate/hexane gave 0.013 g of the title compound as a solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=1[OH:24].[C:25]([O:29][C:30](=[O:36])[NH:31][C@H:32]([CH3:35])[CH2:33]O)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]([O:29][C:30](=[O:36])[NH:31][C@H:32]([CH3:33])[CH2:35][O:24][C:15]1[C:16]([F:23])=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[F:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](COc1c(F)ccc([N+](=O)[O-])c1F)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Diethylazodicarboxylate (328 μL, 2.09 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (243 mg, 1.39 mmol), ((R)-2-hydroxy-1-methyl-ethyl)carbamic acid tert-butyl ester (292 mg, 1.67 mmol) and triphenylphosphine (547 mg, 2.09 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (333 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.4, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.2 Hz), 4.76 (1H, br s), 4.23-4.12 (2H, m), 4.07-3.95 (1H, m), 1.44 (9H, s), 1.34 (3H, d, J=6.8 Hz)
Reaction SMILES: CO[C:3]([C:5]1[N:9]=[C:8]([CH2:10][CH3:11])[O:7][N:6]=1)=[O:4].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:10]([C:8]1[O:7][N:6]=[C:5]([C:3]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[O:4])[N:9]=1)[CH3:11]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1nc(C(=O)OC)no1
Product: CCc1nc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)no1

Procedure:
Following the procedure of Example 1A, 5-ethyl-1,2,4-oxadiazol-3-carboxylic acid methyl ester is reacted wth p-(β-aminoethyl)-benzenesulfonamide to yield p-[β-(5-ethyl-1,2,4-oxadiazole-3-carbonylamino)ethyl]-benzenesulfonamide in almost quantitative yield, M.P. 159°-160°C. The compound can be recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](Cl)=[O:9].C(Cl)Cl.[NH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH2:15])=[O:9]
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: N
Solvent: ClCCl
Product: NC(=O)c1c(Cl)cncc1Cl
Temperature: 0 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid chloride (0.54 g, 2.6 mmol) was dissolved in CH2Cl2 (2.6 mL, 2.6 mmol) and NH3 (2.0 M in dioxane) (6.5 mL) was added. The reaction mixture was cooled to 0° C. for 30 min. The residue was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC on silica gel to yield 3,5-dichloropyridine-4-carboxamide (0.135 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:25])C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH2:8][CH:9]1[C:15]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[O:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:25]
Reactant: O=C1Nc2ccccc2OC2(CCCCC2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: NC1C(=O)Nc2ccccc2OC12CCCCC2
Reaction time: 18 h
Yield: 132.8 %

Procedure:
3-(Dibenzylamino)-3H-spiro[benzo[b][1,4]oxazepine-2,1′-cyclohexan]-4 (5H)-one (0.3875 g, 908 μmol, Eq: 1.00) and 20% Pd(OH)2/C (0.47 g, 3.35 mmol, Eq: 3.68) were combined with MeOH (100 mL) and acetic acid (0.1 mL) and the mixture was hydrogenated at 50 psi. After 18 h, the mixture was filtered through Celite, the filtrate concentrated, the residue dissolved in MeCN/H2O and lyophilized to afford of the title compound as an off-white solid (0.297 g, 100%) which was used without purification. MS m/z 247.0 (MH+)
Reaction SMILES: [Na].[C:2]([SH:6])([CH3:5])([CH3:4])[CH3:3].[CH2:7]([C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CO>[CH2:7]([CH:14]([CH2:19][S:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)S
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(CSC(C)(C)C)Cc1ccccc1

Procedure:
To sodium (3.05 g, 133 mmol) in methanol (135 ml) was added tert-butylmercaptan (17.0 ml, 151 mmol). After 20 min methyl a-benzylacrylate (17.05 g, 96.8 mmol) in methanol (100 ml) was added and after 1 h at room temperature the mixture was heated at reflux for 17 h. After cooling, the mixture was acidified with 2M HCl (70 ml), concentrated, taken up in ether, washed with water and brine, then dried over MgSO4 and evaporated to 23.59 g (92%) of an oil. 1H NMR (CDCl3) δ 7.15-7.35 (m, 5H), 3.63 (S, 3H), 2.60-3.05 (m, 5H), 1.28 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](O)(=O)[CH2:22][OH:23]>O1CCOCC1>[CH2:18]([N:11]1[C:12](=[O:13])[C:14]2[NH:17][C:21]([CH2:22][OH:23])=[N:16][C:15]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:10])[CH2:19][CH3:20]
Reactant: CCCn1c(=O)c(N)c(N)n(Cc2ccccc2)c1=O
Reactant: O=C(O)CO
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(CO)nc2n(Cc2ccccc2)c1=O
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of the diamino-uracil derivative (from Example 5) (3.6 mmol), glycolic acid (7.3 mmol) and 1,4-dioxane (1 mL) was heated at 100° C. for 1 h. After cooling, a yellow solid precipitated from the solution and it was suspended in a mixture of H2O/EtOH 1:1 (20 mL). After basification with NaOH, the solution was heated at reflux for 3 hours, then cooled to 0° C. and acidified with acetic acid. The product precipitated as a white solid which was collected by filtration and dried. (White solid. Yield 70%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:37]([OH:39])=O)[C:30]2[N:34]=[C:33]([CH3:35])[NH:32][C:31]=2[CH:36]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([NH:40][C:37]([C:29]2[C:30]3[N:34]=[C:33]([CH3:35])[NH:32][C:31]=3[CH:36]=[C:27]([O:26][CH3:25])[CH:28]=2)=[O:39])=[N:42][CH:43]=1
Reactant: COc1cc(C(=O)O)c2nc(C)[nH]c2c1
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)Nc2ccc(C)cn2)c2nc(C)[nH]c2c1
Temperature: 25 °C
Yield: 27 %

Procedure:
HATU (431 mg, 1.13 mmol) was added to a mixture of 6-methoxy-2-methyl-1H-benzoimidazole-4-carboxylic acid (350 mg, 1.0 mmol), 2-amino-5-picoline (134 mg, 1.24 mmol), and DIEA (0.359mL, 2.06 mmol) in DMF (5 mL) while stirring at room temperature. The resulting mixture was stirred at room temperature under N2 atmosphere for 16 hours. The mixture was worked up with water and extracted into chloroform; the organic layer was dried over MgSO4, concentrated. The crude product was purified by flash silicagel chromatography (ISCO) eluting with CHCl3:MeOH (95:5) to gain 85 mg light brown color solid product in 27% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (s, 1 H) 12.41 (s, 1 H) 8.27 (d, J=8.56 Hz, 1 H) 8.23 (s, 1 H) 7.68 (dd, J=8.56, 1.76 Hz, 1 H) 7.51 (d, J=2.27 Hz, 1 H) 7.23 (d, J=2.27 Hz, 1 H) 3.85 (s, 3 H) 2.61 (s, 3 H) 2.29 (s, 3 H). LRMS for C16H16N4O2 m/z 297 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:29]
Reactant: CC(C)CCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 63 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 5-methylhexanoic acid (3.9 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g), and after recrystallization in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (8 g), m.p. 132° C., is obtained.