Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1)[CH3:7].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[C:15]1([S:21]([N:13]2[CH:9]([O:8][CH2:6][CH3:7])[CH:10]=[CH:11][C:12]2=[O:14])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC1C=CC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
7.37 cm3 of a 1.6M solution of n-butyllithium in n-hexane is added to a solution of 1.5 g of 1,5-dihydro-5-ethoxy-2H-pyrrol-2-one in 40 cm3 of tetrahydrofuran cooled to -35° C., operating at -35°/-30° C. The mixture is agitated for 20 minutes, then cooled to -40° C., and while maintaining the temperature between -38° C. and -40° C., a solution is added of 2.08 g of benzene sulphonyl chloride in 10 cm3 of tetrahydrofuran. The temperature is allowed to return to the ambient, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1). 1.15 g of the expected product is obtained. m.p. 117°-119° C., crystallized from ethyl ether.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](O)=[O:32])[CH:26]=1>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[O:32])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)c1cccnc1
Product: Cl
Product: O=C(NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1)c1cccnc1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and pyridine-3-carboxylic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[CH:11]=[C:10]1[CH3:30])[CH:7]=[CH2:8].CN(C)[CH:33]=[O:34]>ClCCl>[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[C:11]([CH:33]=[O:34])=[C:10]1[CH3:30])[CH:7]=[CH2:8]
Reactant: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Phosphorus oxychloride (425 μl, 4.56 mmol) was added at room temperature to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (1 g, 3.04 mmol) prepared in Step 3 in a mixture of anhydrous dichloromethane (20 ml) and N,N-dimethylformamide (353 μl, 4.56 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, and then filtered. The resulting solid was washed with water and 1M sodium acetate (30 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The resulting solid was washed with water and then dried to give 350 mg of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](O)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:14])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.O[N:29]1C2C=CC=CC=2N=[N:30]1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:29][NH2:30])=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2F)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)C1(c2ccc(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 41.4 %

Procedure:
A solution of the compound (26.55 g, 102.5 mmol) obtained in Example 14-3), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.6 g, 112.7 mmol), 1-hydroxybenzotriazole monohydrate (17.26 g, 112.7 mmol), triethylamine (42.9 mL, 307 mmol), and tert-butoxycarbonylhydrazide (16.3 g, 123 mmol) in N,N-dimethylformamide (400 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. A 4 M solution (60 mL) of hydrochloric acid in 1,4-dioxane and methanol (300 mL) were added to the obtained partially purified product, and the mixture was stirred at room temperature for 6.5 h. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, hexane was added to the obtained partially purified product, and the solid was collected by filtration to obtain the title compound (11.6 g, 42%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].[OH2:28].N1C=C[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[O:27][C:30](=[O:28])[CH2:31][CH3:32])[CH3:2]
Reactant: O
Reactant: c1ccncc1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CC
Reaction time: 8 h

Procedure:
2β-Ethoxy-3α-hydroxy-5α-pregnane-11,20-dione (500 mg.) in pyridine (2.5 ml.) was treated with pripionic anhydride (2.5 ml.), and the solution was left at room temperature overnight. Water was added, and the mixture was extracted with chloroform. The extract was washed with dilute hyrochloric acid, dried over sodium sulphate and evaporated to an oil which was purified by preparative tlc to give the title compound (295 mg.) as a colourless foam [α]D + 107°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:11][OH:12])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(C=NO)cn1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methyl-5-formyl-pyrimidine (180 gm) and hydroxylamine hydrochloride (128 gm) in 50% v/v aqueous methanol (3600 ml) was added sodium carbonate (94 gm). The reaction mixture was stirred at 30° C. for 0.5 h. The resulting suspension was cooled and filtered at −10° C. to provide single isomer of title compound in 113.5 gm quantity (56%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH:7]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:19][C:5]1[CH:4]=[C:3]([CH3:22])[C:2]([OH:1])=[CH:7][C:6]=1[S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2N)cc1
Yield: 91.4 %

Procedure:
A mixture of 2-methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-Acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum leaving N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide as a solid (2.5 g, 81%). A solution of N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide N-[4-(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide (1.7 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CS(C)=O>[O:26]1[CH:24]([CH3:22])[CH:25]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Temperature: 25 °C

Procedure:
2.8 gm (10 mmols) of 2-(4-hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 20 ml of dimethylsulfoxide, and the solution was mixed, while stirring, with 1.35 gm (10 mmols+20%) of potassium tert. butylate. Subsequently, 2.8 ml of epibromohydrin were added, and the reaction mixture was stirred at room temperature until the reaction had gone to completion. After pouring the reaction mixture into ice water, the crystalline precipitate formed thereby was suction-filtered off, washed well with water and dried.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N12CCCN=C1CCCCC2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:27])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
Process B: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (561 mg) was dissolved in toluene (20 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) was added and perfluoro-1-octanesulfonylfluoride (0.93 mL) was then added dropwise while the mixture was chilled in an ice water bath. After stirred at 2° C. for 1 hour, the reaction mixture was poured on a silica gel pad and was eluted with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow oil (447 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][CH2:26][CH:28]3[CH2:29][O:30]3)=[O:9])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: ClCC1CO1
Reactant: Cn1ccc2c(C(=O)c3ccccc3O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc2c(C(=O)c3ccccc3OCC3CO3)cccc21

Procedure:
Using the procedure of Step A of Example 3, 3 g of the product of Step D, 6.6 g of potassium carbonate and 4.7 ml of epichlorhydrin were added in 5 stages. After a total of 48 hours at reflux, filtration was carried out. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed as indicated in Example 2 to obtain 3.7 g of the expected product.
Reaction SMILES: S[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[S:8](=[O:12])(=O)(O)[OH:9].[Cl:13][O-].[Na+]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:8]([Cl:13])(=[O:12])=[O:9]
Reactant: [O-]Cl
Reactant: O=S(=O)(O)O
Reactant: Sc1ccccn1
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Cl)c1ccccn1
Yield: 77 %

Procedure:
Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid (50 mL) and the mixture was stirred. Sodium hypochlorite solution (chlorine content 5%, 126 mL) was added dropwise over 1.5 hr, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with water (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 2.45 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCOC1(c2ccc(I)cc2)CCOCC1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: CCOC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 68.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60.4 mg) was reacted with tetrahydro-4-(4-iodophenyl)-4-ethoxy-2H-pyran (66.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-ethoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (68.9 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/ethyl acetate=4/1) was used for purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[CH2:34]([NH2:37])[CH:35]=[CH2:36]>CO>[OH:1][CH:2]([CH2:3][NH:37][CH2:34][CH:35]=[CH2:36])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(OCCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: C=CCN
Solvent: CO
Product: C=CCNCC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reaction time: 8 h

Procedure:
1-{1-[4-(4-Oxiranylbutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (4.6 g) is dissolved in methanol (100 ml), and thereto is added allylamine (10 ml), and the mixture is stirred overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=10:1) to give 1-{1-[4-(5-hydroxy-6-allylaminohexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2.5 g) as colorless oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:53]1([CH2:59]O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1(C)C=CC=CC=1.CCOCC>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([S:24]([C:21]2[CH:22]=[CH:23][C:14]([O:13][CH2:59][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])(=[O:26])=[O:25])[CH2:32][CH2:31]1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DEAD (0.24 ml, 1.51 mmol) was slowly added to a mixture of methyl 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoate (may be prepared as described in Description 70; 430 mg, 1.37 mmol), Ph3P (395 mg, 1.51 mmol) and phenylmethanol (163 mg, 1.505 mmol) in toluene (15 ml) cooled in an ice bath at 0° C. The mixture was stirred for 2 h at room temperature. Ether was added to the mixture and the mixture was filtered. The filtrate was evaporated to yield the title compound. 260 mg.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg (0.21 mmol) spiro[piperidin-4,4′-pyrido[2.3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 65 mg (0.21 mmol) 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.84 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[Na]CC(=O)CC(OC)=O.[Na]>CO>[C:9]([C:8]1([C:7]([O:13][CH3:14])=[O:12])[CH2:4][CH:3]1[CH:2]=[CH2:1])(=[O:10])[CH3:11]
Reactant: ClC/C=C/CCl
Reactant: COC(=O)CC(C)=O
Agent: COC(=O)CC(=O)C[Na]
Agent: [Na]
Solvent: CO
Product: C=CC1CC1(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 1-acetyl-2-vinylcyclopropane-1-carboxylate was prepared by the reaction of 1,4-dichlorobutene-2 and methyl acetoacetate using the classical condensation procedure. For the reaction, methyl sodioacetoacetate was prepared by first reacting 36.6 grams sodium metal with 500 mls anhydrous methanol and then adding 185.6 grams of the methyl acetoacetic ester. The resulting solution was then added dropwise, at a rate sufficient to maintain reflux, to 100 grams 1,4-dichlorobutene-2 in 200 mls methanol under a nitrogen atmosphere. After addition was complete, refluxing was continued for 3 hours followed by stirring overnight at ambient temperature. The resulting reaction product (IA) was then stripped under reduced pressure after filtering to remove insoluble salts. Fractional distillation yielded 55 percent yield of a product (IB) consisting predominantly of the desired vinylcyclopropane product (boiling point 83.5° C.-85.0° C. at 4.5 mm Hg; nD22° 1.4705). Nuclear magnetic resonance spectroscopy and gas chromatographic analysis of IB showed the product to consist of 85.7 percent methyl 1-acetyl-2-vinylcyclopropane-1-carboxylate and 14.3 percent 4-carbomethoxy-5-methyl-2-vinyl-2,3-dihydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8].[C:11](Cl)(Cl)=[S:12]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:11](=[S:12])[NH:9][C:5]2=[N:6][C:7]=1[I:8]
Reactant: Nc1cc(Cl)c(I)nc1N
Reactant: S=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: S=c1[nH]c2cc(Cl)c(I)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMAP (15.4 g, 126 mmol) was added to a THF (200 mL) solution of 5-chloro-6-iodopyridine-2,3-diamine (17 g, 63.1 mmol). Thiophosgene (4.9 mL, 63.1 mmol) was then added drop-wise via addition funnel under nitrogen and allowed to stir at rt for 1 h. The mixture was then partitioned between ethyl acetate (500 mL) and 2N HCl (100 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated to give the desired product as a white powder, which was used in the next step without further purification. LC-MS: calculated for C6H3ClN3S 311.5, observed m/e: 311.91 (M+H)+ (Rt 1.69/5 min).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[CH2:19][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])=[CH:30][CH:29]=1)[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 26.8 %

Procedure:
To a cold (0° C.) solution of (4-aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.130 g, 0.33 mmol) in CH2Cl2 (3.5 mL) was added benzyl isocyanate (45 μL, 0.36 mmol) and the resultant solution was stirred for 100 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2—CH3OH—NH4OH) provided the free base of the title compound (0.047 g, 28%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]([CH3:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([CH3:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cc(C)nn1-c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.8 %

Procedure:
To a 100 mL flask, methyl 1-(3,5-dichloropyridin-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (1.00 g, 3.49 mmol), tetrahydrofuran (10 mL), water (10 mL) and sodium hydroxide (0.14 g, 3.49 mmol) were added sequentially. After being stirred for 40 minutes at room temperature, all of the starting materials had disappeared. Then water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL) and the aqueous layer was acidified with concentrated hydrochloric acid to pH of 2˜3, and extracted with ethyl acetate (3×80 mL), the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (0.91 g) as a white solid in 96% yield. Melting point: 227-228° C.