Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21].C(O[K])(C)(C)C.O>CS(C)=O.[Hg]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: CC(C)(C)O[K]
Agent: [Hg]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCN(c2nc(CC(=O)c3ccccc3)cc3ccccc23)CC1
Yield: 89.1 %

Procedure:
A mixed solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (1.00 g), acetophenone (1.50 g) and tert-butoxypotassium (1.40 g) in dimethyl sulfoxide (50 ml) was irradiated with light (450 W; mercury-vapor lamp) at room temperature for 5 hr. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then extracted with a 2N aqueous solution of hydrochloric acid (100 ml). The resulting aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, to give 1-(4-ethylpiperazin-1-yl)-3-phenacylisoquinoline (1.0 g) as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][P:8]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.O.[OH-].[Li+]>C1COCC1.O>[CH2:19]([O:18][P:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of the compound of example 73 (8.66 g, 23.02 mmol) in THF (150 mL) was treated drop wise with a solution of lithium hydroxide-mono hydrate (1.97 g, 46.04 mmol) in water (150 mL). The reaction was complete after about 1 h, according to TLC analysis. Most of the solvent was evaporated. The residue was partitioned between water and ether. The organic phase was separated and the alkaline phase was extracted again with ether. It was next acidified with HCl (6M) to pH˜1 followed by several extractions with ethyl acetate. The recombined organic layer was dried over sodium sulfate, filtered, and evaporated to give the product as colorless oil. 1H-NMR(CDCl3, 400 MHz: 1.88(m, 4H); 2.40(t, J=6.9 Hz, 2H); 4.97, 4.96, 5.05(2dd, J1=11.8 Hz. J2=8.11 Hz, 4H); 7.35(m, 10H). 31P-NMR(CDCl3, 400 MHz): 33.15.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Yield: 59 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene, the title compound was synthesized according to Reference Example 17a. Yield: 59%. Melting point: 165-167° C. (Ethyl acetate-hexane)
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12]C(C)C)=[O:10].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O>[OH:31][CH2:35][C:34]1([C:9]([O:11][CH3:12])=[O:10])[CH2:32][CH2:33]1
Reactant: C1CCOC1
Reactant: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1(CO)CC1

Procedure:
The compound (9.0 g) obtained in Referential Example 161 and triethylamine (9.7 ml) were dissolved in tetrahydrofuran (180 ml), and the solution was cooled to −10° C., to which isobutyl chloroformate (9.1 ml) was added dropwise, and the resultant mixture was stirred for 1 hour. On the other hand, sodium borohydride (7.1 g) was dissolved in tetrahydrofuran (100 ml)-water (25 ml) and cooled with ice. While removing insoluble matter by filtration, the solution prepared previously was added dropwise, and the resultant mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a cooled 10% aqueous solution of citric acid to conduct extraction with ethyl acetate. After the extract was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9-2:1) to obtain the title compound (4.25 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([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.C=O.[C:51](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:51])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([C:14]([CH3:16])([CH3:15])[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](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.157 g, 0.225 mmol) in 5 mL DCE was added formaldehyde (0.067 mL, 37 wt % in water, 0.901 mmol) followed by sodium triacetoxyborohydride (0.052 g, 0.248 mmol). The resulting suspension was stirred vigorously at room temperature overnight, then treated with saturated Na2CO3 solution (30 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) to afford the desired product as a bright yellow foam, 0.119 g, 74%.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][NH:32]2)[CH2:29]1)=[O:27].ClC1N=C(C)C=CN=1>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][N:32]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[CH:11][N:10]=2)[CH2:29]1)=[O:27]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1ccccc1Br)N1CC2CNC2C1
Agent: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4Br)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 23 and 2-chloro-4-methylpyrimidine. MS (ESI) mass calcd. for C17H17BrN4O, 373.26; m/z found, 373.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([NH:10][CH:11]=[O:12])([CH3:9])[CH:5](O)[CH:6]=[CH2:7].S(Br)(Br)=O.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]([NH:10][CH:11]=[O:12])([CH3:9])/[CH:5]=[CH:6]/[CH2:7][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25]
Reactant: C=CC(O)C(C)(NC=O)C(=O)OC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Product: CCOP(=O)(C/C=C/C(C)(NC=O)C(=O)OC)OCC

Procedure:
A solution of 14.1 g of 2-isocyanopropionic acid methyl ester and 8.5 g of freshly distilled acrolein in 50 ml of tetrahydrofuran is added within a period of 20 minutes at 0°-5° under nitrogen to a solution of 17 g of anhydrous zinc chloride in 75 ml of tetrahydrofuran, and the whole is stirred for 45 hours at 0°-5°. The whole is poured onto 500 ml of 10% sodium hydrogen carbonate solution and extracted with 200 ml of dichloromethane. The organic phase is dried over sodium sulphateand concentrated by evaporation. Filtration of the residue over silica gel (ethyl acetate as eluant) yields 4-methyl-5-vinyl-2-oxazoline-4-carboxylicacid methyl ester. By hydrolysis of the 4-methyl-5-vinyl-2-oxazoline-4-carboxylic acid methyl ester in a manner analogous to that described in Example 1, 2-formylamino-2-methyl-3-hydroxy-4-pentenoic acid methyl ester is obtained. By reaction of the 2-formylamino-3-hydroxy-2-methyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in the manner described in Example 1, E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester is obtained in the form of a yellow oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=O.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:12]([C:11]2[CH:16]=[CH:17][N:18]=[CH:19][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CSC(N)N
Agent: I
Solvent: O
Solvent: c1ccncc1
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Temperature: 140 °C
Yield: 43 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (100 mg, 0.27 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (86 mg, 0.39 mmol, 1.45 eq) in pyridine (2 mL) in a sealed tube was heated at 140° C. for 4 hrs. After cooling the mixture was poured into water, extracted with EtOAc, and the combined organic fractions were dried over anhydrous MgSO4. After filtration and solvent evaporation the resulting residue was subjected to silica gel column chromatography (EtOAC:Hex=1:1) to give the desired product (46 mg). [4.99 min; 397(M+1)]
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=1.O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=3)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1), CuI (0.01 mmol, 2.2) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water (20 mL). The product was extracted with CH2Cl2 (3×10 mL). CH2Cl2 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester. Yield: 48%; 1H NMR (CDCl3) δ 9.36 (br, 1H), 8.37 and 8.25 (s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 (s, 1H), 7.74 (t, J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:18](C(C(OCC)=O)C(OCC)=O)[CH2:19]C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH2:12][CH2:18][CH3:19])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Product: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl propyl-malonate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>ClCCl>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: CSc1ncc(C(=O)Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride prepared above (113 mg, 0.54 mmol) in dichloromethane was added 4-fluoroaniline (56 μL, 0.59 mmol). This was followed by the dropwise addition of DIPEA. The mixture was stirred for 15 min, the mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium bicarbonate and was dried over sodium sulfate. Filtration and concentration afforded a residue that was purified by trituration from ethyl acetate with hexanes. The resulting off-white solid (122 mg, 0.41 mmol, 76%) was sufficiently pure to use without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.86 (s, 1H), 7.69 (m, 2H), 7.23 (m, 2H), 2.56 (s, 3H); MS (EI) m/z 296.2 (M−H)−.
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25])(=O)C>CO.O>[NH2:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CCc1ccccc1)O2
Temperature: 200 °C
Yield: 51.6 %

Procedure:
Aqueous 6N sodium hydroxide solution (3 ml) was added to a solution of 5-acetylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran (0.7 g, 2.1 mmol) in methanol (3 ml) and the mixture was heated at 200° C. in an autoclave for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1). The crude crystals were recrystallized from hexane to obtain the desired compound (0.32 g, yield: 54.5%), m.p. 45°-46° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Al](CC(C)C)CC(C)C)C(C)C.[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42](OCC)=[O:43])[C:29]([C:38]([F:41])([F:40])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[O:43])[C:29]([C:38]([F:40])([F:41])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Reaction time: 0.33 h
Yield: 72 %

Procedure:
3.22 g of 2-aminothiazole were cooled to +2° C. in 80 ml of methylene chloride, and while maintaining the temperature between +2° and +5° C. 17.9 ml of triisobutyl aluminium in toluene (0.9M) were added and stirred for 20 minutes. 2.5 g of the product of Step D were then introduced all at once into the mixture and the temperature was brought up progressively to reflux and kept there for 24 hours then lowered to the ambient. The mixture was concentrated to dryness under reduced pressure and 50 ml of water and 50 ml of 2N hydrochloric acid were added to the residue. The mixture was triturated and the precipitate was separated and washed abundantly with water. While still humid, the latter was dissolved in tetrahydrofuran and the solution was dried and concentrated under reduced pressure. The 2.6 g of residue were triturated in ether, separated and dried to obtain 2.05 g of product melting at 256° C. After crystallizing from acetonitrile, 1.48 g of the expected product melted at 256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[Cl:34]N1C(=O)CCC1=O>CN(C=O)C>[Cl:34][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of tert-butyl 2-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]propan-2-ylcarbamate (130 mg, 0.27 mmol) and N-chlorosuccinimide (47 mg, 0.35 mmol) in DMF (3 mL) was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with water and the aqueous layer was extracted with methylene chloride/methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (silica, methanol/methylene chloride gradient) to afford the desired product (42 mg, 31%) as a brown solid: ESI MS m/z 500 [C26H27ClN2O4S+H]+.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.C1(P(=[CH:30][C:31]([O:33][CH3:34])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC(C)=CC=1>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:2]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2O1
Solvent: Cc1ccc(C)cc1
Product: COC(=O)Cc1coc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 0.4 mol of coumaranone and 0.48 mol of methyl (triphenylphosphoranylidene)acetate in 1 liter of p-xylene is maintained at reflux for 18 h. After cooling to room temperature, the solvent is evaporated off, the residue is taken up in 1 liter of ether, the precipitate is filtered off and washed with ether, the filtrate is concentrated and the expected product is obtained after chromatography on silica (eluent: CH2Cl2).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:30]([NH:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]>C(O)(=O)C>[CH2:30]([N:33]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 45 h
Yield: 28.5 %

Procedure:
A solution of 3.0 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid prop-2-ynylamide in 180 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 45 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The black-brown solid residue was suspended in 200 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 17 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 1.14 g (29%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as yellowish crystals; m.p. 142-144°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1C2C(=CC=C(O)C=2)N[N:30]=1.N12CCCN=C1CCCCC2>ClCCl>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][P:11]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:1][N:30]=1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 497 mg of 50%-pure methylphenylphosphinic acid 4-nitrophenyl ester in 8 ml of dichloromethane is stirred at ambient temperature. A suspension of 403 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 268 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 12 ml of dichloromethane is added dropwise. The reaction medium is stirred at ambient temperature overnight and then evaporated to dryness under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography on a cartridge of 50 g of silica 15-35 μm. 300 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester are collected and recrystallized from ethyl acetate to obtain 220 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester.