Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].C([Li])CCC.CN(C)[CH:16]=[O:17].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:3][C:4]1[S:5][C:6]([CH:16]=[O:17])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 2-ethoxythiophene (355 mg, 2.77 mmol) in 14 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.22 mL, 2.5 M in hexanes) dropwise over 5 minutes. After stirring at −78° C. for 20 minutes, dimethylformamide (1.07 mL, 13.9 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 60 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (2×75 mL), washed with 1 N hydrochloric acid (2×40 mL), water (40 mL) and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-7% ethyl acetate in hexanes) to give 5-ethoxy-2-thiophenecarbaldehyde (216 mg, 49%). Used without further characterization.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:24][N:25]([CH3:29])[C:26]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:27]
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Reactant: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(NC(=O)C(CSC(=O)N(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 28.7 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in pyridine (2 ml), and thereto is added dimethylaminocarbonyl chloride (0.26 g) with stirring under ice cooling, and the mixture is stirred under ice cooling for 2 hours and further at room temperature for 2 hours. To the reaction mixture is added ethyl acetate (50 ml) and the mixture is washed with saturated aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.23 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([C:20]([O:22]C)=O)[CH:10]=2)=[CH:5][CH:4]=1.[Br:24][CH2:25]Br.C[Li]>C1COCC1>[Br:24][CH2:25][C:20]([C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=1)=[O:22]
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccccn2)n1
Reactant: BrCBr
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(=O)CBr)nn2-c2ccccn2)cc1
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
To a stirred solution of methyl 5-(4-methylthiophenyl)-1-(2-pyridyl)pyrazole-3-carboxylate (prepared as described in Penning, T. D. et al. J. Med. Chem. 1997, 40, 1347–1365.; 0.39 g, 1.2 mmol) and dibromomethane (0.17 mL, 2.4 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added methyllithium (1.6 M in ether, 1.4 mL, 2.2 mmol). After being stirred at the same temperature for 90 minutes, the solution was quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (2:1 EtOAc:hexane) gave the title compound (0.32 g, 69% yield) as a white foam. 1H NMR (300 MHz, CDCl3) δ 8.42–8.40 (m, 1H), 7.83 (m, 1H), 7.55–7.51 (m, 1H), 7.17–7.09 (m, 4H), 7.02 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H); LRMS (API-TIS) m/z 388 and 390 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[C:9]([O:10][CH3:11])=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:11][O:10][C:9]1[C:4]([C:3]([OH:16])=[O:2])=[CH:5][N:6]=[CH:7][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cncc(C(=O)OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cncc(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 5,3 g (23.5 mmol) of methyl-4-methoxy-5-methoxycarbonyl-nicotinate in 150 ml of methanol and 50 m. of water is added a solution of 0.94 g (23,5 mmol) of sodium hydroxide in 10 ml of water. The resulting mixture is stirred at room temperature overnight. The methanol is removed under vacuum, the aqueous solution is made slightly acidic and extracted with ethyl acetate. The combined organic phases are dried and filtered through silica. The filtrate is evaporated to near dryness and diluted with diisopropyl ether. A precipitate is obtained, filtered off and dried. There is obtained 2,83 g (57% yield) of a white solid (M+1=212).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)c2cn[nH]c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 74.5 %

Procedure:
A mixture of 4-bromo-6-methyl-1H-indazole (1.05 g, 5 mmol), DHP (2.1 g, 25 mmol), and TsOH.H2O (96 mg, 0.5 mmol) in THF (50 ml) under nitrogen was heated at reflux overnight. The reaction mixture was concentrated in vacuo and to the residue was added DCM (300 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography by using petroleum ether:EtOAc (100:1) as eluting solvents to afford 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as light yellow oil (1.1 g, 90%) MS (ESI): m/z=295.1 [M+1]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1.[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14](Cl)=[N:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14]([NH:2][CH2:3][C:4]2[O:8][N:7]=[C:6]([CH3:9])[CH:5]=2)=[N:15][CH:16]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reactant: Cc1cc(CN)on1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Temperature: 120 °C
Yield: 30.9 %

Procedure:
A mixture of 5-aminomethyl-3-methylisoxazole hydrochloride (890 mg, 6.0 mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 578 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.0 mmol) in 1-butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool to ambient temperature and volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the titled compound (225 mg, 31%). 1H NMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H), 4.5 (m, 2H), 6.1 (br s, 2H), 7.6 (br s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 366.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([C:13]1[N:17]=[C:16]([CH2:18][CH3:19])[O:15][N:14]=1)[OH:12])[CH2:9][CH3:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:13]1[N:17]=[C:16]([CH2:18][CH3:19])[O:15][N:14]=1)[OH:12]
Reactant: CCc1nc(C(O)[C@H](CC)NC(=O)OC(C)(C)C)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc([C@@H](O)C(N)CC)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of {(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (214 mg, 0.751 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (0.578 mL, 7.504 mmol) and stirred at room temperature for 3 hours. Solvent evaporated under reduced pressure to give (S)-2-amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol trifluoroacetate, a mixture of diastercoisomers, (224 mg) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[C:31]=[O:32].C(O)(=O)C>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:31]([NH:30][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[O:32])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1-c1c[nH]c2ccccc12
Reactant: Cc1ccc(N=C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)n2cc(-c3ccccc3C(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(2-tert-Butylphenyl)-1H-indole (24.1 mg, 0.0967 mmol) in 0.5 mL anhydrous tetrahydrofuran was treated with 1M NaN(TMS)2 in THF (0.2 mL) and stirred for 5 minutes at ambient temperature. 1-Isocyanato-4-methylbenzene (15 μL, 0.116 mmol) in 0.5 mL anhydrous tetrahydrofuran was added and stirred for 5 minutes at ambient temperature. 50 μL acetic acid and 200 μL methanol are added and the reaction mixture charged to a silica gel column and purified by eluting with a gradient of ethyl acetate and hexanes to give 3-(2-tert-butylphenyl)-N-p-tolyl-1H-indole-1-carboxamide which was further purified by reverse phase HPLC to give Example 49 (19.1 mg, 52%) as a colorless solid and 99.5% purity. LC/MS (ESI+) 383.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>CC(O)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 70 °C
Yield: 65 %

Procedure:
A mixture of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 12 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.68 g, 10 mmol), and triethylamine (1.5 g, 15 mmol) in IPA (50 mL) was heated at 70° C. for 15 h. The mixture was cooled to room temperature. The resulting yellow solids were collected by filtration and dried in vacuum to afford 120a as a yellow solid (2.83 g, 65%).MS: [M+H]+ 435.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH2:15]([C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH:23]=1)[OH:22])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([O:24][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:20]=[C:21]([OH:22])[CH:23]=1)[CH3:16]
Reactant: CCc1cc(O)cc(O)c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: CCc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield from 2-methylsulfonylbenzenesulfonyl chloride and 5-ethylresorcinol in a manner analogous to step a of Eg. 1. 1H-NMR (300 MHz, CDCl3) δ8.43 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.87 (t, J=7.8 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 6.56 (s, 2H), 6.52 (s, 1H), 5.59 (br s, 1H), 3.45 (s, 3H), 2.49 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].Cl.[NH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:28].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:28])=[O:6]
Reactant: CCCCCN1C(=O)C(N)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCN1C(=O)C(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Under argon atmosphere and ice cooling, a solution of 2.80 g of 3,4-dichlorobenzoyl chloride in 20 ml of methylene chloride was added dropwise to a mixture of 2.84 g of 3-amino-1-pentyl-2,3-dihydro-1H-indol-2-one hydrochloride, 2.24 g of sodium hydrogen carbonate, 30 ml of chloroform and 30 ml of water. The reaction mixture was stirred under ice cooling for 30 minutes and then at room temperature for 30 minutes, diluted with water and extracted with chloroform. After the chloroform layer was washed and dried, the solvent was removed by evaporation. The residue was recrystallized from ethyl acetate-hexane to afford 4.06 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)benzamide as colorless crystals. Melting point: 125° to 126° C., IR (Nujol) (cm-1): 3280, 1725, 1635, 1610, MS (m/z): 390 (M+), 374, 372, 217 (base).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:21](Cl)=[O:22])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2].[NH3:40]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:21]([NH2:40])=[O:22])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)Cl)C[C@@H]1C
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(N)=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-chlorocarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. (Example 50A) (125 mg) was dissolved in dichloromethane (4 mL), and cooled in an ice water bath as gasous ammonia was condensed into the solution. After stirring overnight at room temperature, the reaction mixture was quenched with 10 mL of 1N HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with 10 mL saturated sodium bicarbonate, 10 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the title product (0.091 g, 76%). MS m/z 563 (M+ +1); 1H NMR (CDCl3) δ 1.18 (Me, d, 3H, J=5.9 Hz), 1.2-1.4 (m, 4H), 2.1-2.2 (m, 1H), 4.1-4.3 (m, 3H), 4.3-4.5 (m, 1H), 4.9 (bs, 2H), 5.0-5.3 (m, 3H), 7.20 (C5, s, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.75 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: CS(CSC)=O.[OH-:7].[K+].[Cl:9][C:10]1[S:11][C:12]([CH:15]=[C:16](S(C)=O)SC)=[CH:13][CH:14]=1.Cl.[CH2:23]([OH:25])[CH3:24]>CO>[Cl:9][C:10]1[S:11][C:12]([CH2:15][C:16]([O:25][CH2:23][CH3:24])=[O:7])=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CSC(=Cc1ccc(Cl)s1)S(C)=O
Reactant: CCO
Agent: CSCS(C)=O
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCOC(=O)Cc1ccc(Cl)s1
Temperature: 25 °C

Procedure:
Methyl methylsulfinylmethyl sulfide (5.53 g) and potassium hydroxide (2 g) were added to a solution of 5-chloro-2-thiophenecarboxyaldehyde (6.21 g) in methanol (70 mL), and the reaction solution was stirred with heating under reflux for 21 hours. After leaving to cool to room temperature, the solvent was evaporated under reduced pressure. Methylene chloride was added to the residue, the insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 5.61 g of a (E)/(Z) mixture of 2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene. A saturated solution of hydrogen chloride in ethanol (10 mL) was added to a solution of the resulting (E)/(Z) mixture of 2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene (5.61 g) in ethanol (80 mL), and the reaction solution was stirred with heating under reflux for 23 hours. After leaving to cool to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 3.31 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:36])=[O:35])[CH2:21]1>>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([N:20]3[CH2:24][CH2:23][CH:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:33][S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)(=[O:35])=[O:36])[CH2:21]3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Reactant: COc1cccc2sc(Cl)nc12
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2sc(N3CCC(COc4ccccc4NS(=O)(=O)c4ccccn4)C3)nc12

Procedure:
Compound 32 is prepared using synthesis method 3 using intermediates 2c and 6b (yield: 51%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2>CN(C)C=O>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(O)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Diisopropylethylamine (DIEA, 0.0115 mL, 0.067 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.06 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.025 g, 0.067 mmol) in 0.5 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in dimethylsulfoxide (DMSO). The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% acetonitrile (ACN)/H2O with 0.05% trifluoroacetic acid (TFA) at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected. Solvent was removed under vacuum and the resulting solid was left overnight in vacuo to give 0.010 g of product in 38% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCCl)ccc3n21
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from (R)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, potassium carbonate and 1-bromo-3-chloropropane, to give the title compound as a light yellow solid (56%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:31])=[C:21]([N:26]4[CH2:30][CH:29]=[CH:28][CH2:27]4)[C:22]=3[O:24][CH3:25])[C:17](=[O:32])[C:16]([C:33]([OH:35])=[O:34])=[CH:15]2)[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C@@H:28]2[CH2:27][N:26]([C:21]3[C:22]([O:24][CH3:25])=[C:23]4[C:18]([C:17](=[O:32])[C:16]([C:33]([OH:35])=[O:34])=[CH:15][N:14]4[CH:11]4[CH2:12][CH2:13]4)=[CH:19][C:20]=3[F:31])[CH2:30][C@@H:29]2[O:1][N:2]=1
Reactant: COc1c(N2CC=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: ON=C(Cl)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1c(N2C[C@@H]3ON=C(c4ccccn4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Chloro oxime 2e (70 mg; 0.44 mmol), olefin 119 (100 mg; 0.29 mmol) and sodium bicarbonate (50 mg) in ethyl acetate (10 mL) were heated at reflux temperature overnight. The solid was filtered and the filtrate evaporated. The residue was triturated with methanol to yield acid 122.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(F)ccc1Cl
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(F)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (0.43 g) was added at room temperature diethyl malonate (0.2 g), and then added little by little 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled, and the solvent was evaporated. The residue was dissolved in water, and the aqueous layer was washed with ethyl acetate and concentrated. To the reside was added 2M sodium hydroxide (0.7 ml), and the mixture was refluxed for 2 hours cooled. To the mixture was added 2.5M sulfuric acid (0.7 ml), and the mixture was refluxed for 15 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(2-chloro-5-fluorophenyl)cyclohexane-1,3-dione (0.17 g) as oil.
Reaction SMILES: [P:1]([O:16]C1C=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CI.P(OC)(OC)O[CH3:27]>>[CH3:27][P:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: COP(OC)OC
Solvent: CI
Product: CP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 210 °C

Procedure:
To a three-necked flask equipped with thermometer, magnetic stirrer, distillation head and nitrogen inlet 163 g (0.52 mol) of triphenyl phosphite and 1.0 mL of methyl iodide were charged. Then, 32.7 g (0.26 mol) of trimethyl phosphite was added drop-wise at 100–110° C. over the course of one hour. The reaction temperature was then raised to 210° C. and an exothermic reaction was observed. The reaction temperature was maintained at 230° C. for two hours, and the reaction mixture was analyzed before it underwent transesterification. Diphenyl methylphosphonate was obtained as a liquid. The 31P NMR (CDCl3) indicated 95% diphenyl methylphosphonate. The impurities included triphenyl phosphate (0.8%, δ=−16.4 ppm), trimethyl phosphate (0.6%, δ=−10.3 ppm), and unknown compounds (δ=19.8, 20.4. 28.4 ppm). The acid number of this crude diphenyl methylphosphonate was 5.4 mg KOH/g