Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11].[Li]CCCC>C1COCC1>[C:3]([C:4]1[C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])#[CH:2]
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 3-(2,2-Dibromoethenyl)-2-(4fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (2.677 gm, 5.63 mmol) in dry THF (25 ml) was cooled to -78° C. and treated with n-BuLi (1.6M in hexane, 7.75 ml, 12.4 mmol) over a 1 minute period. After stirring at -78° C. for one hours, the deep green solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted once with Et2O. The Et2O extract was washed with brine, dried (Na2SO4), filtered and stripped to give a yellow solid. The solid was recrystallized from a minimum amount of hot hexane to afford analytically pure 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as yellow crystals (1.572 gm, 89%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[CH3:9][N:10]([C@@H:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][N:28]1CC[C@H:30](O)[CH2:29]1)[C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:5]([O:4][C@H:1]1[CH2:30][CH2:29][N:28]([CH2:27][C@@H:26]([N:10]([CH3:9])[C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CCN(C[C@H](c2ccccc2)N(C)C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
30 ml of acetic anhydride and 15 ml of triethylamine are added to 5.0 grams (11.0 mmol) of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, and the mixture is heated for two hours on a steam bath. The reaction mixture is subsequently evaporated to dryness, and the residue is taken up in ether and washed with bicarbonate solution. The organic phase is subsequently dried, and the solvent is distilled off. The resultant residue is purified by column chromatography on silica gel with diethyl ether/methanol (99:1) as eluent. The resultant crude product of N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide can be purified further by taking up in diethyl ether, precipitation by addition of ethereal HCl, filtering-off of the resultant crystals under reduced pressure, washing of the crystals with ether and drying in air (Rf=0.6 (TLC on silica gel 6 F254 with dichloromethane/methanol (8:2) as eluent)).
Reaction SMILES: C(O)C.[NH2:4][OH:5].C[O:7][C:8](=O)[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]>C1COCC1>[OH:5][NH:4][C:8](=[O:7])[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Ethanol (1.0 mL) and a 50% aqueous solution (1.0 mL) of hydroxylamine were added to a THF (1.0 mL) solution of 4-{3-[(4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]propyl}morpholine (0.11 g) as obtained in Example 4-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=90/10), and then recrystallized from ethyl acetate/hexane to obtain N-hydroxy-N′-methyl-2-[methyl({4′-[3-(morpholin-4-yl)propoxy]biphenyl-4-yl}carbonyl)amino]propanediamide (Compound 7, light brown solid) (43 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[CH3:25][O:26][CH2:27][CH2:28][NH2:29].ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: COCCN
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCNC(=O)c1cccc(-c2cc(-c3ccc(O)c(C)c3)nc(=O)[nH]2)c1
Yield: 35.6 %

Procedure:
To a solution of 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (16.9 mg, 48 umol) and 2-methoxyethanamine (3.0 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound 3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]-N-[2-(methyloxy)ethyl]benzamide (5.4 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:25])([F:26])[F:24])=[C:13]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C(F)(F)F)cc2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Off-white solid. MS (m/e): 316.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:16]([O:20][C:21]([NH:23][CH2:24][C@@:25]1([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31][C@H:30]2[C@@H:26]1[CH:27]=[C:28]([CH2:32][O:33]CC1C=CC(OC)=CC=1)[CH2:29]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][C@@:25]1([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:31][C@H:30]2[C@@H:26]1[CH:27]=[C:28]([CH2:32][OH:33])[CH2:29]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(COCC2=C[C@H]3[C@@H](C2)C[C@@]3(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@]1(CNC(=O)OC(C)(C)C)C[C@@H]2CC(CO)=C[C@@H]21
Temperature: 0 °C

Procedure:
Water (1.4 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (831 mg, 3.66 mmol) were added to a methylene chloride solution (25 mL) of tert-butyl(±)-[(1R,5R,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-3-{[(4-methoxybenzyl)oxy]methyl}bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.19 g, 2.44 mmol) with stirring at 0° C. The mixture was stirred at this temperature 0° C. for 1 hour and further stirred at room temperature for 1 hour. Then, the reaction was terminated by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (571 mg, 64%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][CH:17]([C:21]3[N:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:24][CH:25]=3)[CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)([OH:3])=[O:2].[CH2:30](O)[CH3:31].S(=O)(=O)(O)O.N.C(Cl)(Cl)[Cl:40]>>[ClH:40].[C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][CH:17]([C:21]3[N:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[S:24][CH:25]=3)[CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:30][CH3:31])=[O:2]
Reactant: ClC(Cl)Cl
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1
Reactant: CCO
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Product: Cl
Temperature: 0 °C

Procedure:
0.5 g (0.0012 mol) of N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine is dissolved in 150 ml of chloroform and, while stirring, 2 ml ethanol and 0.25 g of concentrated sulphuric acid are added, and the the mixture is heated to reflux with a water trap for one hour. The mixture is then cooled, ice-water is added, the mixture is made alkaline with ammonia and the phases are separated. The aqueous phase is then extracted again by shaking with chloroform, and the organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting residue is dissolved in ether, ethereal hydrochloric acid is added, the mixture is evaporated to dryness, and the residue is triturated with acetone and filtered off with suction.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](O)(O)(O)O.[Cl:40]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[C:30]([Cl:40])[CH:29]=[C:28]2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OCl
Agent: O[Si](O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cc(Cl)cc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
To a mixture of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-cyanopyrrole (900 mg) and silicic acid (100 mg) in carbon tetrachloride (15 ml) was added a solution of tert-butyl hypochlorite (222 mg) in carbon tetrachloride (10 ml) in water bath, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (15:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-4-chloro-2-cyanopyrrole (290 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[C:21]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:4]2[C:3]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[C:2]([F:1])[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[C:5]=2[F:18])=[CH:25][CH:24]=1)#[N:22]
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(Nc2c(F)c3c(c(F)c2Nc2ccc(C#N)cc2)C(=O)c2ccccc2C3=O)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-Tetrafluoroanthraquinone and 25 g of p-cyanoaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 150° C. for about 3 hours. After completion of reaction, p-cyanoaniline was distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 2.46 g of 2,3-bis(p-cyanoanilino)-1,4-difluoroanthraquinone (Dye 18') (yield 72,3 mol %). The physical properties of Dye 18' and analytical values defining the compound are tabulated in table 23.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[CH3:18])(=O)C.O1CCCCC1OCCCCCCCCCC=CC=CC>CO.O>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]=[CH:17][CH3:18]
Reactant: C/C=C/C=C/CCCCCCCCCOC(C)=O
Agent: CC=CC=CCCCCCCCCCOC1CCCCO1
Solvent: O
Solvent: CO
Product: CC=CC=CCCCCCCCCCO
Yield: 66 %

Procedure:
To prepare (E,E)-10,12-tetradecadien-1-ol acetate (I), the tetradecadiene (D) (5.6 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water was added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3 g crude 10,12-tetradecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.4 g (66% yield based on the dodecenenitrile (B)).
Reaction SMILES: COC1C=C2C(CCC(C(O)=O)C2)=CC=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][C:25]2=[O:28])=[CH:20][CH:19]=1.[CH2:29]([O:31][C:32](=O)[O:33]CC)[CH3:30].[H-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH2:29]([O:31][C:32]([CH:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:25]1=[O:28])=[O:33])[CH3:30]
Reactant: CCOC(=O)OCC
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: COc1ccc2c(c1)CC(C(=O)O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccc(OC)cc2C1=O
Temperature: 60 °C
Yield: 96.4 %

Procedure:
The starting 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid, which is a known product, can be prepared as follows: a solution of 7-methoxy-3,4-dihydronaphthalene-1(2H)-one (66.4 g, 0.376 mol) in anhydrous tetrahydrofuran (350 ml) is added in 1 hour to a mixture of distilled diethylcarbonate (116 ml, 0.957 mol), 80% sodium hydride (39.7 g, 1.32 mol) and anhydrous tetrahydrofuran (350 ml) heated to 60° C. The thus obtained reaction mixture is refluxed for 4 hours and then cooled. Acetic acid is then added dropwise up to acidic pH and water is added until complete dissolution of the precipitate occurs. The solution is extracted with ethyl ether, the organic phase is washed with water and with a sodium bicarbonate solution, dried and evaporated to dryness. The thus obtained oily product is purified by distillation under reduced pressure yielding 90 g of 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid ethyl ester. B.p.0.4 mmHg 160°-165° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1.O.[NH2:33][NH2:34].C(=O)([O-])O.[Na+]>CN(C=O)C>[S:28]1[CH:29]=[CH:30][C:26]([CH2:25][C:24]2[C:3]3[C:4](=[O:23])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:27]1
Reactant: O=C(Cc1ccsc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccsc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(3-thienylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (80 mg, 0.18 mmol) produced in Synthesis Example 42 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 44 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, recrystallized from methanol, and dried to give 3-(3-thienylmethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (47 mg, yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]3[C:15](=[N:16]O)[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]3[CH:15]([NH2:16])[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c3n(c2c1)CCCC3=NO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(C)c3n(c2c1)CCCC3N
Temperature: 45 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
A solution of 6,7,8,9-tetrahydro-3-methoxy-10-methylpyrido[1,2-a]indol-9-one oxime (2.2 g, 9 mmol) in ethanol (50 mL) containing 10% sodium hydroxide (36 mL) was treated with Raney alloy (3.15 g) at 35° C. over 20 minutes. The reaction mixture was stirred at 45° C. for 18 hours, then poured into ice water (100 mL), saturated with sodium chloride. The product was extracted with ether (3×75 mL), dried and evaporated. The residue was dissolved in toluene (30 mL), and extracted with 3% hydrochloric acid (50 mL). The aqueous layer was separated, and basified with 50% sodium hydroxide upon cooling. The product was extracted with chloroform, dried over MgSO4, filtered, and evaporated. The dark oily residue was chromatographed on silica gel (50 g). Elution with chloroform afforded 1.87 g (91%) of the desired amine as an amber oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH2:11][CH2:10][C:9]3=[C:12]([C:17]([OH:19])=O)[S:13][C:14]([S:15][CH3:16])=[C:8]3[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]2[CH2:11][CH2:10][C:9]3=[C:12]([C:17]([NH2:27])=[O:19])[S:13][C:14]([S:15][CH3:16])=[C:8]3[C:6]=2[N:7]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1nc2c(s1)CCc1c(C(=O)O)sc(SC)c1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCc1nc2c(s1)CCc1c(C(N)=O)sc(SC)c1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Ethyl-4,5-dihydro-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (0.47 g) was suspended in tetrahydrofuran (15 ml); oxalyl chloride (0.29 g) and then N,N-dimethylformamide (6 l) were added. After this mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (8 ml); this suspension was added to a solution of diethyl 4-aminobenzylphosphonate (0.40 g), triethylamine (0.17 g) and tetrahydrofuran (15 ml) at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, it was poured over water (150 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield N-[4-]diethoxyphosphorylmethyl)phenyl]-2-ethyl-4,5-dihydro-8-methylthiothieno[3,4-e]benzothiazole-6-carboxamide (0.69 g, 85%), which was then recrystallized from ethanol-hexane. Yellow needles. Melting point 179-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=1)=[S:21])[NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=3)=[S:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
From 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (42.8 mg, 0.17 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (61.1 mg, yield 68%).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C@@H:30]([CH2:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1>ClCCl>[F:53][C:51]1[CH:52]=[C:47]([CH:48]=[C:49]([F:54])[CH:50]=1)[CH2:46][C@H:30]([NH:29][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH:6]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: CCCN(CCC)c1cc(C(=O)O)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3ccnc(N(CCC)CCC)c3)CC2)c1
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(Dipropylamino)isonicotinic acid (0.206 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole was added (0.142 g) and the mixture was stirred for 2 h at room temperature, at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol (0.284 g) in dichloromethane was added. The mixture was allowed to stir overnight and then was partitioned between dichloromethane, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was chromatographed on silica gel using methanol/dichloromethane (4/96) to give N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-(dipropylamino)isonicotinamide (0.268g). MS (ESI+) for C33H38F2N4O2+H1 m/z 561.30 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:5].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)CCl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N+:15]([O-:30])=[CH:14][CH:13]=[CH:12]2)=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cccc2cccnc12)c1c(Cl)cccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1cccc2ccc[n+]([O-])c12)c1c(Cl)cccc1Cl
Yield: 45.7 %

Procedure:
A solution of 8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and m-chloroperbenzoic acid (71 mg) in ethylene chloride was stirred for 1 hour at 40° C. To the mixture was added 5% sodium thiosulfate solution, and the mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from dichloromethane-methanol to give 8-(2,6-dichlorobenzoylamino)quinoline 1-oxide (48 mg).