Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(CCc3ccccc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-(2-phenylethyl)piperidine. MS (+ESI) m/z 381 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=1)#[N:20]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCn1c(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, is dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN=[N+]=[N-])cc1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
To a solution of 4-chloro-4′-methoxybutyrophenone (Acros Organics) (22.45 g, 106 mmol) in DMF (300 mL) was added sodium azide (13.7 g, 211 mmol). The solution was heated under N2 (g) at 70° C. for 4 h. The milky reaction mixture was partitioned between ethyl acetate (700 mL) and water (500 mL). The organic layer was washed with another portion of water (500 mL), followed by saturated aqueous sodium bicarbonate (500 mL) and brine (500 mL). The organic layer was dried (sodium sulfate) and concentrated to give an oil (22 g, 95% yield) which solidified slowly upon standing. MS m/e 220; HPLC retention time 3.09 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
9.9 ml of aniline (10.1 g, 108.4 mmol) and 15 ml of triethylamine (11.0 g, 108.4 mmol) were dissolved at 50° C. in 108 ml of methylene chloride. Again at 50° C. 14.1 ml of n-butanesulfonyl chloride (17.0 g, 108.4 mmol) were added dropwise to this solution over the course of 1 h. After 15 minutes of stirring at 50° C. the reaction mixture was extracted twice with 100 ml of water. The resultant crude product in solution in 150 ml of methylene chloride was extracted with 150 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 1–2 using concentrated HCl and was extracted twice with 100 ml of methylene chloride. Drying over magnesium sulphate and removal of the methylene chloride by distillation gave 17.0 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2C=O)c1
Temperature: 120 °C
Yield: 12.9 %

Procedure:
(3-Hydroxy phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2-fluoro-5-methylbenzaldehyde (0.72 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.20 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C1OCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Temperature: 70 °C

Procedure:
A mixture of 6-hydroxyisochroman-1-one (332 mg), methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (284 mg), cesium carbonate (1.28 g) and DMF (8 ml) was heated to 70° C. for 7 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 248.28 (C14H16O4); MS (ESI): 249 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: OCc1ccc(CCl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(N(Cc2ccc(CCl)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
A solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.78 g, 7.63 mmol), 4-chloromethylbenzyl alcohol (1.21 g, 7.70 mmol) and triphenylphosphine (3.93 g, 15.4 mmol) in toluene (150 mL) was stirred under ice-cooling. Diethyl azodicarboxylate (40% toluene solution, 6.98 μmL, 15.4 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 72 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane). Hexane-ethyl acetate was added to the obtained residue, and the resultant insoluble material was filtered off. The filtrate was concentrated to give the title compound (3.65 g, yield 95%) as a red oil.
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Li+:23].P([O-])([O-:27])([S-])=S.[S]>>[OH:27][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:23]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: [O-]P([O-])(=S)[S-]
Agent: [Li+]
Agent: [OH-]
Agent: [S]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]
Temperature: 74 °C

Procedure:
A lithium hydroxystearate grease thickener ws prepared by saponification of a mixture containing 12-hydroxystearic acid (8%) and glyceride thereof (9%) with lithium hydroxide in a mineral oil vehicle at about 174° C. in a closed contactor. After depressuring and dehydration of the thickener in an open kettle sufficient mineral oil was added to reduce the thickener content to about 9.0%. After cooling to about 74° C. a typical grease additive package, consisting of an amine antioxidant, phenolic antioxidant, metallic dithiophosphate, sulfur-containing metal deactivator and nitrogen containing antirust additives, was added.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][OH:9]>>[CH3:8][O:9][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CO
Product: COC(=O)CCC(=O)O
Temperature: 70 °C

Procedure:
To a single-necked, 100 mL round-bottom flask equipped with a teflon stirbar, is added 20 g succinic anhydride dissolved in 50 mL methanol. The flask is equipped with a reflux condenser topped with a septa and argon balloon, and the reaction mixture is heated to reflux (70° C.) in an oil bath (Dow Corning Fluid) for a 16 hr time period. The reaction flask is then allowed to cool to room temperature, the stirbar removed, and the excess methanol removed via rotary evaporator to give 26.4 g of succinic acid monomethyl ester. In the same 100 mL flask containing succinic acid monomethyl ester is added a teflon stirbar, 35 mg palladium dichloride, 1.31 g triphenylphosphine, and 38 mL acetic anhydride, respectively. The flask is equipped with a short-path distillation apparatus with a thermometer, argon balloon, and an attached 100 mL collecting flask in an ice-bath. The reaction flask is heated to a temperature of 230° C. in an oil bath over a 30-40 minute time period, distilling out the excess acetic anhydride, acetic acid byproduct, and methyl acrylate. The reaction is complete after approximately 30 min heating at 230° C. when no more product distills and the solution darkens to a black color due to inactivation of the catalyst. The distillate is then analyzed by NMR to verify the presence of methyl acrylate. The reaction flask is cooled and weighed to determine how much starting material was removed due to reaction (17.9 g, 68% conversion to methyl acrylate).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH3:7].CN(C)[C:21](=[O:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH2:6]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:21](=[O:23])[CH3:22])=[N:16][CH:17]=1)[CH3:7]
Reactant: CCOCCOc1ccc(C)nc1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCOc1ccc(CC(C)=O)nc1
Reaction time: 0.17 h

Procedure:
2.5 ml of a 2.5 M solution of n-butyllithium in hexane are added dropwise at 5° C. to a solution of 1 g (5.5 mmol) of 5-(2-ethoxyethoxy)-2-methylpyridine in 20 ml of tetrahydrofuran. The mixture is stirred at 0°-5° C. for 10 minutes and then 530 mg (6 mmol) of N,N-dimethylacetamide dissolved in a little tetrahydrofuran are added. After stirring at room temperature for 90 minutes, the pH is adjusted to 5 with dilute hydrochloric acid and the tetrahydrofuran is stripped off. The residue is extracted with ethyl acetate, and the organic phase is dried with sodium sulphate and evaporated. Yield: 580 mg (47% of theory), content according to GC/MS:75%.
Reaction SMILES: S(=O)(=O)(O)O.[O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].[Br:18][C:19]1[CH2:23][CH:22]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[N:21]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:20]=1.C(#N)C>O>[Br:18][C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[N:21]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:20]=1
Reactant: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
0.5 ml of concentrated sulfuric acid and 1.4 g of potassium peroxodisulfate were added to a mixed solution comprising 1.0 g of pentyl 3-bromo-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate and 20 ml of acetonitrile, followed by reflux with heating for 3 hours and 20 minutes. After the reaction liquid was stood to cool, the reaction liquid was slowly added to water, followed by stirring for 15 minutes. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8.5/1.5 to 8/2) to obtain 0.47 g of the oily desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]([OH:24])([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:26][C:27]1[CH:34]=[C:33]([CH:32]=[CH:31][C:28]=1[C:29]#[N:30])[O:22][CH2:21][CH2:20][C:19]([OH:24])([CH3:23])[CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:25]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)(O)CCO)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)(O)CCOc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.6 %

Procedure:
To a solution of the compound obtained in Step 1 (348 mg, 1.02 mmol) and 2-chloro-4-fluorobenzonitrile (159 mg, 1.02 mmol) in THF (10 mL) was added potassium t-butoxide (287 mg, 2.56 mmol), and the mixture was stirred at room temperature for 14 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (236 mg, 0.496 mmol, 48.5%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-methoxyindole (2.0 g, 14 mmol) and 4-piperidone hydrochloride hydrate (4.2 g, 27 mmol). The product was isolated as a yellow solid. Yield 2.8 g (90%). mp 190°-193° C. FDMS m/e=228 (M+ of free base).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].CO.[NH3:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:16])=[O:12]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Naphthoyl chloride (2.21 g, 11.6 mmol) was dissolved in a MeOH/NH3 solution (2 M, 20 mL) and was allowed to stir overnight. Volatiles were removed and the resulting white solid was triturated with EtOAc. The solid was filtered and washed with cold EtOAc to yield a white solid which was used without further purification (1.98 g, 100% yield). m.p. 191-192° C. 1H NMR (CDCl3) δ 8.39 (s, 1H, ArH), 7.90 (4H, ArH), 7.57 (m, 2H, ArH). 13C NMR (CDCl3) δ 169.3, 135.0, 132.6, 130.5, 129.0, 128.6, 128.1, 127.9, 127.8, 126.9, 123.7. IR (nujol) vmax cm−1: 3400, 3210, 1650, 1628, 1512, 1510.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[C:16]([Cl:27])[C:15]=1[N+:28]([O-:30])=[O:29]>CS(C)=O>[Cl:27][C:16]1[C:15]([N+:28]([O-:30])=[O:29])=[C:14]([N:7]2[C:8]([Cl:10])=[CH:9][C:4]([NH2:3])=[N:5][CH:6]2[S:11][CH3:12])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSC1N=C(N)C=C(Cl)N1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
7.9 parts of finely powdered 85% potassium hydroxide are dissolved in 70 ml of dimethylsulfoxide. To this solution is added dropwise a solution of 17.6 parts of 4-amino-6-chloro-2-methylmercaptopyrimidine in 80 ml of dimethylsulfoxide at about 15° C., and the reaction mixture is subsequently stirred for half an hour at room temperature. Then 30.5 parts of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene in 100 ml of dimethylsulfoxide are added dropwise at about 115° C. The reaction mixture is stirred overnight at room temperature, then poured into 2 liters of ice-water and extracted with ethyl acetate. The combined extracts are washed repeatedly with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography over silica gel with dichloromethane as eluant. Yield: 22.3 parts of the title compound with a melting point of 171°-175° C.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[N:20]#[C:21]Br.C(Cl)Cl>C(O)C>[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:21]#[N:20])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N#CN1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 131.3 %

Procedure:
A suspension of 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (600 mg, 2.467 mmol) in anhydrous Ethanol (10 mL) was added solid NaHCO3 (1555 mg, 18.51 mmol) followed by cyanic bromide (523 mg, 4.93 mmol) and the mixture was stirred at ambient temperature. The mixture was diluted by 50 mL of CH2Cl2 and the solids were filtered off. The filtrated was concentrated in vacuo to afford to give the title compound (632 mg, 3.24 mmol, >100% yield). 1H NMR (400 MHz, Chloroform-d) δ ppm=4.02 (dd, J=3.8, 11.2 Hz, 2H), 3.42-3.31 (m, 2H), 3.31-3.22 (m, 4H), 2.74-2.61 (m, 4H), 2.59-2.47 (m, 1H), 1.73 (d, J=11.5 Hz, 2H), 1.67-1.49 (m, 2H); LC/MS (m/z) ES+ (ELSD)=196.1 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:25]2[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: Clc1nccnc1Cl
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2s1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
In 250 mL round bottom flask were charged benzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone (6.0 g, 23.5 mmol), 2,3-dichloro-pyrazine (3.48 g, 23.5 mmol), DMSO (60 mL), and cesium carbonate (15 g, 47 mmol). The reaction mixture was stirred at 90° C. for 6 h. The reaction mixture was diluted with cold water and the precipitate was collected by filtration. The crude product was purified by silica gel column chromatography with hexane and ethyl acetate to give the title compound. [M+H]=368.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=1)=[O:7].[CH2:18](OC1C=C(O)C=CC=1OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O1C=CC=C1C(Cl)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:7]
Reactant: COc1ccc(O)cc1OCc1ccccc1
Reactant: COc1ccc(OC(=O)c2ccco2)cc1O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2ccco2)cc1OCc1ccccc1

Procedure:
The compound 3-hydroxy-4-methoxyphenyl 2-furoate was made as follows. An amount of 2.00 gms. of 3-benzyloxy-4-methoxyphenol, 1.00 gms. of triethylamine and 0.10 gms of 4-dimethylaminopyridine were dissolved in 100 ml. of methylene chloride at 0° C. and stirred. To the mixture was added 1.16 gms. of 2-furoyl chloride and the mixture was stirred overnight. The mixture was then washed with equal volumes of 1M hydrochloric acid, saturated sodium bicarbonate and water. The mixture was then dried over magnesium sulfate and the solvent evaporated to yield 3-benzyloxy-4-methoxyphenyl 2-furoate.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.Cl.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:21])[N:45]3[CH2:44][CH2:43][CH:42]([C:39]4[CH:38]=[C:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:41][N:40]=4)[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc(-c3ccccc3)[nH]n2)CC1
Yield: 38.2 %

Procedure:
(S)-2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9, 1 0-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (66 mg, 0.23 mmol) and 4-(5-phenyl-1H-pyrazol-3-yl)piperidine hydrochloride (40 mg, 0.15 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound (34 mg) was obtained as white solid. MS (ESI) 594 (M+H); Rf=1.99.