Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].N#CN.[K].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[C:2]([NH:3][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)#[N:1]
Reactant: N#CN
Reactant: CSc1nccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nccc(NC#N)n1

Procedure:
Cyanamide (1.05 g.) was added to potassium t-butoxide (2.8 g.) in DMF (10 ml.) with stirring to produce a fine suspension of potassium cyanamide. To this was added 4-chloro-2-methylthiopyrimidine (4 g.) and the mixture stirred at ambient temperature for 17 hours. The DMF was evaporated in vacuo and the residue suspended in water (20 ml.), the pH adjusted to 11 with dilute aqueous sodium hydroxide and the mixture extracted with EtOAc (2×10 ml.). The aqueous layer was separated, acidified to pH 3 with dilute hydrochloric acid and the precipitate collected, washed with water and dried to give 4-cyanoamino-2-methylthiopyrimidine, m.p. 189-191 (decomp.).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:29])([F:28])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:29][C:6]([F:5])([F:28])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(I)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(I)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.49 ml, 0.49 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-[1-(4-iodophenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (0.150 g, 0.33 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 1 hr, then warmed to rt and stirred at rt for 19 hr. MeOH (10 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.121 g (83% yield) of yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1ccccc1Cl
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1ccccc1Cl)NCCO[N+](=O)[O-]
Yield: 31.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.79 g of 2-chlorophenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.31 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].C(O)=O.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[C:17]1=O)[CH2:23]2>C1(C)C=CC=CC=1>[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[NH:5][C:4]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:3]=1[O:2][CH3:1])[CH2:23]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COc1cc(C)cc(OC)c1N
Solvent: O=CO
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC)c1NC1C2CC3CC(C2)CC1C3
Yield: 52 %

Procedure:
2.1 g of 2,6-dimethoxy-4-methylaniline are dissolved in 10 ml of toluene, 0.5 ml of formic acid is then added to this solution and the mixture is heated to gentle reflux, under inert atmosphere, and 0.93 g of 2-adamantanone, dissolved in 10 ml of toluene, is added dropwise at this temperature. The reaction mixture is heated at reflux for 48 hours, is then evaporated to dryness and the residue is taken up in 30 ml of 2N hydrochloric acid. The insoluble white crystals are filtered and discarded. The acidic filtrate is extracted with dichloromethane. The organic extracts are washed with a 5% aqueous sodium bicarbonate solution and then with water and the organic phases are then dried over anhydrous sodium sulphate. Evaporation leaves a colourless residue which is purified by flash chromatography on a column of silica gel, eluent: toluene/ethyl acetate 7/3 (v/v) in order to obtain N-(2-adamantyl)-2,6-dimethoxy-4-methylaniline; M.p.=100° C., Yield 52%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[CH:9]=1>O1CCCC1>[O:22]1[C:21]2[CH:25]=[CH:26][C:18](/[CH:17]=[CH:16]/[C:15]([NH:14][C:10]3[CH:9]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:28])=[O:4])[CH:13]=[CH:12][CH:11]=3)=[O:27])=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: COC(=O)/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1

Procedure:
(Method G4) 1N NaOH solution (2.56 ml, 2.56 mmol) was added to a solution of 3-[3-[[(E)-3-(1,3-benzodioxol-5-yl)-1-oxo-2-propenyl]amino]phenyl]-(E)-2-propenoic acid methyl ester (3a) (0.30 g, 0.85 mmol) in tetrahydrofuran (4.0 ml), and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was washed with diethyl ether. The title compound was obtained as a white solid (0.24 g, 84%). 1H NMR (DMSO-d6, HMDSO), δ: 6.09 (2H, s); 6.43 (1H, d, J=16.0 Hz); 6.60 (1H, d, J=16.0 Hz); 6.89-7.76 (8H, m); 7.92 (1H, br s); 10.16 (1H, br s); 12.38 ppm (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([CH2:15][CH:14]=[CH2:13])[C:6]#[N:7])[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C#N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A solution of 3-chlorobenzyl cyanide (2.00 g, 13.2 mmol) in 15 mL of THF was added over 30 min to a suspension of sodium hydride (60% dispersion in mineral oil, 636 mg, 15.9 mmol) in 5.0 mL of dry THF. After stirring 2 h at room temperature, the mixture was cooled to -20 ° C., a solution of allyl bromide (1.14 mL, 1.59 g, 13.2 mmol) in 3.0 mL of THF was added, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was quenched with a solution of 1.6 g of ammonium chloride in 100 mL of water. The aqueous layer was extracted with 3×50 mL of ethyl ether and the combined organic layers were washed with 50 mL of brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 20-40% dichloromethane in hexane. Additional purification by flash column chromatography on silica gel, eluting with 5% ethyl ether in hexane gave 897 mg of the title compound as an amber oil. 1NMR (400 MHz, CDCl3): δ 7.36-7.30 (m, 3H), 7.25-7.21 (m, 2H), 5.78 (ddt, 1H, J=17, 10, 7 Hz), 5.21 (bd, 1H, J=10 Hz), 5.20 (dq, 1H, J=17, 1 Hz), 3.84 (t, 1H, J=7 Hz), 2.70-2.57 (m, 2K). Mass spectrum (EI): m/z=191 (M+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=O)=[N:33][CH:34]=1)=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:35]([C:32]4[CH:31]=[CH:30][C:29]([C:27]([OH:28])=[O:26])=[CH:34][N:33]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil (1.45 g, 4.33 mmol), from Example 1, part (d) above, in dichloromethane (25 mL) was added the intermediate 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.78 g, 5.52 mmol) and diisopropylethylamine (Aldrich, 0.84 g, 6.5 mmol). This reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was taken up in 1N sodium hydroxide and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with acetic acid and the product precipitated from the reaction mixture to provide 6-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)nicotinic Acid (1.44 g, 56%) as a green solid. 1H-NMR (300 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.10 (d, J=3.1 Hz, 1H), 8.43 (m, 1H), 8.12 (m, 1H), 6.71 (br s, 1H), 4.12-3.60 (br m, 4H), 1.80-1.40 (m, 11H), 1.35-0.91 (m, 11H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Reaction time: 18.5 h
Yield: 78.2 %

Procedure:
A THF (60 mL) solution of 2-carboxymethyl-4-nitrobenzoic acid (3.0 g, 13.3 mmol) was treated with borane-THF complex (53.3 mL, 53.3 mmol) over 15 min at 0° C. The reaction was stirred for 18.5 hrs, quenched with THF/water (1:1, 30 mL), water (20 mL) added and the layers separated. The aqueous layer was backwashed with THF (30 mL), the combined organic phase was washed with brine, dried with magnesium sulfate, and the solvent removed under vacuum to give the product as a white solid (2.05 g, 78%) mp 79-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Li])CCC.[O:16]1[CH2:20][CH2:19]OS1(=O)=O.C(=O)=O.Cl.CC1CCCO1>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:19][CH2:20][OH:16])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=S1(=O)OCCO1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CSc1nc(Cl)c(CCO)c(Cl)n1
Reaction time: 0.5 h
Yield: 758.5 %

Procedure:
To a vial containing 4,6-dichloro-2-(methylsulfanyl)pyrimidine (200 mg, 0.102 mmol) in THF (10 mL) was added n-butyllithium (0.554 mL, 1.38 mmol, 2.5 M in hexane) at −78° C. and the resulting mixture was stirred for 30 min. 1,3,2-dioxathiolane 2,2-dioxide (172 mg, 1.39 mmol) was added at −78° C. and stirring was continued for 2 h. The reaction vial was removed from the dry ice bath, 6 N HCl (3.5 mL, 21 mmol) was added, and the mixture was stirred at room temperature for 18 h. 2-Methyltetrahydrofuran (20 mL) was added and the solution was washed with a 1:1 mixture of brine/water and then with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified via silica gel chromatography using a gradient of EtOAC/heptane (30-50%) to give the title compound (185 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.84 (t, J=5.4 Hz, 1 H), 3.61 (q, J=6.3 Hz, 2 H), 2.93 (t, J=6.8 Hz, 2 H), 2.52 (s, 3 H). m/z (APCI+) for C7H8Cl2N2OS 239.0 (M+H)+.
Reaction SMILES: [C:1]1([CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(C(=O)OCc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g, 15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) and N,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for 7 hours. The reaction was allowed to cool to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethylacetate and water, and the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, ethyl acetate) to provide benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscous oil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that the sample is a mixture of enantiomers in a 38.2 to 58.7 ratio. The separation of the enantiomers were effected as follow: the product was dissolved in 120 mL of ethanol/heptane (1:1) and injected (5 mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20 μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at 220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) were retrieved as viscous oil. 1H NMR (CDCl3, δ=7.26, 500 MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08 (d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H). RT=2.10 (Cond. III); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C20H25N2O2: 325.19. found 325.20.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=[O:23])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([Mg]Br)[CH:27]=[CH2:28].CCOCC.[NH4+].[Cl-]>C1COCC1>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]([OH:23])[CH2:28][CH:27]=[CH2:26])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C=O
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C
Temperature: 25 °C

Procedure:
A solution of N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-formyl-4-methylisoxazole-3-carboxamide (53 mg, 0.153 mmol) in THF (1.5 mL) was cooled to 0° C. and 1M allylmagnesium bromide in Et2O (337 μl, 0.337 mmol) was added dropwise over 15 mins. The reaction mixture was warmed to room temperature and saturated NH4Cl (aq) was added. The aqueous layer was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the organic solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.Cl.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:20][CH2:21]2)=[CH:22][CH:23]=1
Reactant: C#CCCS(C)(=O)=O
Reactant: Clc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(Cc2ccc(Cl)cc2)CC1
Yield: 85 %

Procedure:
A mixture of 1-mesylbut-3-yne (2.22 g, 15.0 mmol), 4-(4-chlorobenzyl)piperidine hydrochloride (2.95 g, 12.0 mmol), K2CO3 (4.97 g, 36.0 mmol) in 50 mL of CH3CN is allowed to reflux for 12 hr. The inorganic salt is removed through a short column of silica gel and washed with EtOAc (3×30 mL). Evaporation of solvents gives a residue, which is purified by flash chromatography giving the product as pale yellow oil (2.67 g, 85%): 1H NMR (CDCl3) 1.31 (m, 2 H), 1.50 (m, 1 H), 1.59 (m, 2 H), 1.96 (m, 3 H), 2.38 (m, 2 H), 2.48 (m, 2 H), 2.55 (m, 2 H), 2.88 (d, J=11.1 Hz, 2 H), 7.04 (d, J=8.1 Hz, 2 H), 7.26 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]Br)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[Na].[CH3:38][SH:39]>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][S:39][CH3:38])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na]
Product: CSCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
N.m.r. in solvent C: 1.44 (s, 9H), 4.75 (d, 2H), 5.92 (m, 1H), 6.56 (s, 1H), 6.7-6.9 (m, 2H), 7.29 (s, 15H). 2. N.m.r. in solvent C: 3.4 (m, 2H), 3.9 (d, 1H), 4.45 (d, 1H), 4.9 (m, 2H), 5.02 (d, 1H), 5.7 (m, 1H), 5.95 (d, 1H), 6.83 (s, 1H), 6.9 (d, 1H), 7.32 (s, 15H). 3. The starting material was prepared by reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate (UK Patent Application 2017702A) with the sodium salt of methyl mercaptan and hydrolysis of the resulting ester to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-methylthioethoxyimino)acetic acid.
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:5]=1[CH2:6][C:7]1[C:11]([C:12](=[O:25])[CH:13]([C:23]#[N:24])[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])=[N:10][N:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=12)([OH:3])=[O:2].[CH2:36](I)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([CH:13]([C:12]([C:11]1[C:7]2[CH2:6][C:5]3[C:32](=[CH:33][CH:34]=[CH:35][C:4]=3[C:1]([O:3][CH2:36][CH3:37])=[O:2])[C:8]=2[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:10]=1)=[O:25])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])#[N:24]
Reactant: CCI
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(C(=O)O)cccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1Cc1c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn(-c3ccccc3)c1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
3-(5-Carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) dissolved in dimethylformamide (25 ml) is reacted with ethyl iodide (1.55 g) in the presence of anhydrous potassium carbonate (1.4 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with 1N HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH2Cl2 /methanol to yield 1.9 g of 2-cyano-3-(5-ethoxycarbonyl-1,4-dihydro -1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 233°-236° C. dec.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:17](=[O:19])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[CH:12][CH:13]=2)[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Yield: 75.5 %

Procedure:
To a solution of appropriate (4-adamantan-1-yl-phenoxy)-acetic acid (150 mg, 0.523 mmol), 2-amino isonicotinic acid methyl ester (159.3 mg, 1.04 mmol) and DMAP (127.9 mg, 1.04 mmol) in DMF (6 ml) was added PyBOP (545 mg, 1.04 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with ethyl acetate, separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by flash chromatography on silica gel (EtOAc:hexanes=1:9 to 1:1) to afford of 2-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.166 g, 75% yield).
Reaction SMILES: N[C:2]1[C:11]([O:12]C)=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[ClH:23].N([O-])=O.[Na+]>O>[Cl:23][C:2]1[C:11]([OH:12])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1cc2c(c(N)c1OC)c(=O)c(C(=O)O)cn2C1CC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c(Cl)c1O)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a pale brown suspension of 5-amino-1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9 g, 29.6 mmol) in con. HCl (60 mL) stirred at 0° C. was added dropwise a cold solution of sodium nitrite (2.143 g, 31.1 mmol) in Water (20.00 mL). Stirring continued at 0° C. for 1 h. LCMS indicated completion of reaction. HCl (80 mL, 2633 mmol) was added and the mixture was heated at 95° C. for 6 h. LCMS indicated completion of reaction. The reaction mixture was cooled down to rt and then poured into water. The precipitates were collected by filtration and dried to afford 5-chloro-1-cyclopropyl-6-hydroxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7.4 g, 23.89 mmol, 81% yield) as a pale yellow solid. LCMS: [M+H]+: 310.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([OH:27])(=O)=[O:25])=[N:7]1.[CH3:32][N:33](C=O)[CH3:34].S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([N:33]([CH3:34])[CH3:32])(=[O:25])=[O:27])=[N:7]1
Reactant: CN(C)C=O
Reactant: COc1c2n(c3c(S(=O)(=O)O)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COc1c2n(c3c(S(=O)(=O)N(C)C)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-sulfonic acid (32 mg, 68 μmol), anhydrous DMF (11 μL, 0.14 mmol), and thionyl chloride (1.05 g, 8.84 mmol) in anhydrous acetonitrile (0.6 mL) was heated at 80° C. for 30 minutes. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous acetonitrile (3 mL) and treated with a solution of dimethylamine in THF (1 mL, 2 M). The mixture was stirred at room temperature for one hour and treated with aqueous sodium hydroxide (0.5 mL, 1 M). After stirring at room temperature for one hour, the product mixture was concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the title compound.