Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:57]=[CH:56][C:53](CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][C:53]2[CH:56]=[CH:57][C:50]([F:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 35.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluorobenzyl alcohol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (43 mg, yield 33%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][N:10]=[N:9]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>ClCCl>[CH2:22]([O:21][C:19]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][N:10]=[N:9]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nnnn1C(=O)OCC
Reaction time: 8 h
Yield: 62.5 %

Procedure:
In a mixture of 20 ml of dichloromethane and 3.4 g (33.6 mmol) of triethylamine was dissolved 1.50 g (10.6 mmol) of ethyl tetrazol-5-carboxylate, and 3.75 g (34.6 mmol) of ethyl chloroformate was added dropwise at 0° C. After stirring overnight at 0° C. to room temperature, water was added to the reaction mixture, followed by phase separation. Then, the dichloromethane layer was successively washed with 5% sodium dihydrogenphosphate solution, 5% sodium hydrogencarbonate solution and water, dried with magnesium sulfate, and concentrated, which afforded 1.42 g of ethyl N-ethoxycarbonyltetrazol-5-carboxylate. Yield, 63%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:33]#[C:32][C:30]([OH:34])([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)[CH3:31])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OCC(O)CO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(O)CO)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol (80 mg, 0.21 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg, 1.06 mol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.22 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred for 5 h at 70° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a frit filter. The filtrate was purified by preparative HPLC to afford 23 mg (24%) of 3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol as a white solid. 1H NMR (300 MHz, DMSO) delta 8.38 (d, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.07-7.05 (m, 3H), 6.46 (s, 1H), 6.38 (s, 1H), 5.19 (d, J=5.4 Hz, 1H), 4.83-4.80 (m, 1H), 4.64 (d, J=3.6 Hz, 1H), 4.52 (d, J=6.3 Hz, 1H), 3.93 (d, J=4.5 Hz, 1H), 3.52-3.49 (m, 3H), 2.40 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>O>[ClH:1].[ClH:1].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: CN(C)CCN
Solvent: O
Product: CN(C)CCNc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Product: Cl

Procedure:
4-Chloro-N(1H-tetrazol-5-yl)quinaldamide (0.3 g), N,N-dimethylethylenediamine (6 ml) and water (2 ml) were heated at 100° for 8 hours. The excess of N,N-dimethylethylenediamine was distilled off under reduced pressure and the residue was treated with aqueous hydrochloric acid to pH 1. The solid, in water (5 ml), was treated with 2N sodium hydroxide to give a solution pH 4. The solid which crystallised from this solution was collected and dried, m.p. 200° (d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 120 °C
Yield: 97.6 %

Procedure:
A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0 g, 5.87 mmol) in methanol (20 mL) was treated with a catalytic amount of sulfuric acid. The reaction was heated at 120° C. for 6 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (1.05 g, 97.6%) as a white solid: mp 34-36° C.: EI-HRMS m/e calcd for C9H9FO3 (M+) 184.0535, found 184.0533.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.CC1C=CC=CC=1[C:28](Cl)=[S:29].O=C1CC(=O)N([C:44]2[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:28][S:29][C:51]1[CH:52]=[CH:44][CH:45]=[CH:46][C:47]=1[C:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:49]
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccccc1C(=S)Cl
Product: CSc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 20 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-methylthiobenzoyl chloride (0.24 mmol), the title compound (22 mg, yield 20%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3]1.[C:12](O)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1])=[O:20]
Reactant: Cn1ccc2c(N)cccc21
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cn1ccc2c(NC(=O)c3ccccc3O)cccc21
Yield: 60.7 %

Procedure:
A solution of 5 g of 1-methyl-1H-indol-4-amine [prepared according to Ley (J. Chem. Soc. Chem. Com. (1982) p. 1356], 4.7 g of salicylic acid and 7 g of dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran was refluxed for 24 hours and 20% of salicylic acid and of dicyclohexylcarbodiimide were added after 5 hours of refluxing. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica (eluant: methylene chloride) to obtain 5.5 g of 2-hydroxy-N-(1-methyl-1H-indol-4-yl)benzamide melting at 211° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6])[CH3:2].[CH3:15][Mg]Br.O>CCOCC>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)([OH:6])[CH3:15])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C(=O)c1cccc(Br)c1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1cccc(Br)c1
Yield: 70 %

Procedure:
To a solution of (3-Bromo-phenyl)-oxo-acetic acid ethyl ester (2.5 g, 9.8 mmol) in ether (20 mL) at 0° C. was added methyl magnesium bromide (10.8 mmol, 3 M in ether, 3.6 mL) with stirring. The reaction was stirred at 0° C. for 15 min. Water was added and the crude partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane to afford 2-(3-bromo-phenyl)-2-hydroxy-propionic acid ethyl ester as a colorless liquid. (1.87 g, 70% yield). MS: m/z 273 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:20][S:21]([O:24]S(C)(=O)=O)(=[O:23])=[O:22]>C(#N)C>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[CH2:16]([N:13]([CH2:14][CH3:15])[C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[O:6][C:5]1[CH:18]=[CH:19][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCN(CC)[C@@H]1CCCC[C@H]1Oc1ccc(N)cc1
Solvent: CC#N
Product: CCN(CC)[C@@H]1CCCC[C@H]1Oc1ccc(NS(C)(=O)=O)cc1
Product: CS(=O)(=O)O

Procedure:
To 3.16 g (12 mmol) of trans-2-(4-aminophenoxy)-N,N-diethylcyclohexanamine in 20 mL of acetonitrile under an N2 atmosphere add 2.10 g (10 mmol) of methanesulfonic acid anhydride. Stir the reaction for 3 h at 50° C. Cool the reaction mixture and remove the solvent in vacuo. Recrystallize the resulting product from acetone/ether to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1(O)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)([O-:3])=[O:2].[O:11]1[CH2:15][CH:12]1[CH2:13][OH:14].C[O-:17].[Na+]>CO>[OH:11][CH2:15][CH:12]([OH:17])[CH2:13][O:14][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: OCC1CO1
Reactant: O=[N+]([O-])C1(O)C=CC=CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCC(O)CO)cc1

Procedure:
1-Nitrophenol (2.6 grams; 19 mmole) is added to a mixture of 2,3-epoxypropanol (1.16 g; 15.6 mmole), anhydrous methanol (10 ml.) and sodium methylate (1.0 g.). After five hours under reflux, the solvent is evaporated and the residue chromatographed on preparative silicic acid plates using chloroform-methanol (9:1) to yield 1,2-dihydroxy-3-(4-nitrophenyloxy)-propane which may be crystallized from chloroform-ethyl acetate. In a similar manner, 1,2-dihydroxy-4-(4-nitrophenyloxy)-butane is prepared.
Reaction SMILES: OP([O-])(O)=O.[K+].[C-:7]#[N:8].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]=[O:23])[N:21]=2)=[CH:13][CH:12]=1>CN(C=O)C.O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]([OH:23])[C:7]#[N:8])[N:21]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Reactant: [C-]#N
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
KH2PO4 (712 mg, 5.23 mmol) and NaCN (251 mg, 5.12 mmol) were added to a solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol) in DMF-H2O (10 mL, 4:6, v/v). The resulting reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (500 mg, yield 87%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.88 (s, 1H), 7.20-7.16 (t, J=8.8 Hz, 2H), 5.62 (s, 1H), 4.38 (br s, 1H). MS (ESI) m/z: Calculated for C11H7FN2O2: 218.05. found: 218.8 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:26](=O)([O:37]N1C(=O)CCC1=O)[O:27][CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:26]([O:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)=[O:37])[CH2:23][CH2:24]2)=[O:25])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Reactant: O=C(OCc1cc(F)cc(Cl)c1)ON1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)OCc3cc(F)cc(Cl)c3)CC2)nn1
Temperature: 25 °C

Procedure:
To a stirred suspension of (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (step 5) (150 mg, 0.387 mmol) and 3-chloro-5-fluorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate (117 mg, 0.387 mmol) in DCM (5 mL) was added NaOH (1.547 mL, 1.547 mmol) with stirring at RT and the mixture was stirred at RT for 18 hrs. A further 5 ml DCM was added followed by 1M NaOH (1 ml). The reaction mixture was diluted with DCM (30 ml) and the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]
Reactant: CN(C)CCO
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%)=450 (M+H 35Cl, 100), 452 (M+H37Cl, 32). 1H NMR (400 MHz. DMSO-d6) δ: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J=9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][C:3]=1[CH3:20].[OH-].[Na+]>CO.O>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C(C)(C)C(=O)OCc2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)(C)C(=O)O)sc1Br

Procedure:
A mixture of the benzyl 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoate and sodium hydroxide (0.33 g, 8.3 mmol) in methanol (10 ml) and water (2.5 ml) was heated under reflux for 1 hour. The solvent was evaporated and the residue triturated with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and then evaporated to leave 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid as a yellow gum which was used in the next step without purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Br)cc43)c(C)c2C1=O
Yield: 67.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 5 (59 mg, yield 67.8%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:15](=[S:18])([OH:17])=[O:16])[C:12]([F:14])=[CH:13][C:8]=3[C:7](=[O:19])[NH:6][C:5]2=[O:20])[CH2:3][CH2:2]1.[H-].[Na+].[N+:23](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:23][N:6]1[C:7](=[O:19])[C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15](=[S:18])([OH:17])=[O:16])=[N:10][C:9]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(S(=O)(O)=S)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 0.47 g (1.57 mmol) of 1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Example 35) in 20 mL of dimethylformamide/dioxane (1:1) is treated portionwise with 0.08 g (2.0 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred at room temperature for 1 hour and 0.32 g (1.6 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 100 mL with ice and water and stirred at 5° C. for 1 hour. The aqueous solution is extracted with ethyl acetate (3×50 mL) with the combined organic layers being washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.4 g of the title compound, mp 167-169° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]=[CH2:36])[N:30]=2)=[C:8]([C:10]2[C:11]([F:28])=[C:12]([NH:16][S:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])[CH3:3].[CH3:37][S:38]([OH:40])=[O:39].[Na].C(O)C>C(O)(=O)C.O>[CH3:4][C:2]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH2:36][S:38]([CH3:37])(=[O:40])=[O:39])[N:30]=2)=[C:8]([C:10]2[C:11]([F:28])=[C:12]([NH:16][S:17]([C:20]3[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=3[F:26])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)([CH3:1])[CH3:3]
Reactant: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reactant: CS(=O)O
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(CCS(C)(=O)=O)n2)s1
Yield: 81 %

Procedure:
N-{3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.283 mmol) and methane sulfinic acid, sodium salt (0.144 g, 1.414 mmol) were stirred in acetic acid (1.5 ml) and ethanol (1.5 ml) at RT in a screw-top vial overnight. The reaction mixture is diluted with water and extracted 2× with EtOAc. The EtOAc is washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtain the title compound (173 mg, 81%). 1H NMR (400 MHz, DMSO-d6) ppm 10.87 (s, 1H), 8.54 (d, J=5.31 Hz, 1H), 7.68 (ddd, J=14.56, 8.42, 6.13 Hz, 1H), 7.43 (t, J=7.32 Hz, 2H), 7.32 (t, J=7.97 Hz, 1H), 7.23 (t, J=9.06 Hz, 2H), 6.75 (d, J=5.31 Hz, 1H), 3.53 (m, 2H), 3.29 (m, 2H), 3.03 (s, 3H), 1.44 (m, 9H); MS (ESI): 611 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].CN(P(=N[P+](N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=[PH2]N(CC[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])CCCCCCCC)(N(C)C)N(C)C)C>P(N(C)C)(N(C)C)N(C)C>[CH2:2]([O:1][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:3]
Reactant: CCCCCCCCN(CCCCCCCC)[PH2]=N[P+](N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C
Reactant: CC[O-]
Agent: CN(C)P(N(C)C)N(C)C
Product: CCOc1ccccc1
Yield: 86 %

Procedure:
The reaction was carried out completely in the same manner as in Example 1, except that tris[tris(dimethylamino)phosphoranylideneamino](dioctylamino)phosphoranylideneamino phosphonium ethoxide: [(Me2N)3P═N]3P+{N═P[N(C8H17)2]}, C2H5O− was used instead of tetrakis[tris(dimethylamino)phosphoranylideneamino]phosphonium methoxide in Example 1. Objective ethoxybenzene was produced in the yield of 86%.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](S(C)(=O)=O)[N:5]=1>CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:2][CH3:1])[N:5]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Methylamine (2M solution, 113 mL, 217 mmol, 2.05 equiv) was charged to a 1 L 3-neck flask fitted with a magnetic stirrer and a thermometer. The mixture was chilled in an ice bath. To this stirred solution was added via addition funnel a solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (25 g, 110 mmol) in EtOAc (250 mL) portionwise over a 25 minutes period. The temp was between 5-10° C. After completion of addition, the ice bath was removed, and the mixture was stirred for 1 hour at ambient temperature. LCMS showed conversion complete. The suspension was filtered, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was partitioned between water (100 mL) and EtOAc (450 mL). The organic was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give white solids, which were triturated in 150 mL of CH2Cl2. These solids were collected by filtration and washing with cold CH2Cl2 (50 mL). Drying under house vacuum at room temperature for 20 hours, and then high vacuum at room temperature for 3 hours gave 9.31 g of the title compound as a solid. LC-MS (ES) m/z=179 [M+H]+.