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.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[S:37])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (82 mg, yield 98%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:36][CH2:37][CH3:38])[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[C:18](=[O:20])[CH:19]=1>O>[CH3:13][C:14]1[N:15]=[C:16]([CH2:36][CH2:37][CH3:38])[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:3][C:4](=[O:7])[O:5][N:35]=3)=[CH:24][CH:23]=2)[C:18](=[O:20])[CH:19]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.35 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 44%).
Reaction SMILES: N[C:2]1[C:7](CO)=C(C2CCCN(C(OC(C)(C)C)=O)C2)[CH:5]=[C:4]([C:23]2C(OCC3C=CC(OC)=CC=3)=CC=CC=2OCC2CC2)[N:3]=1.O1[CH2:48][CH2:47][CH2:46]C1>>[CH:47]([N:3]([CH:4]([CH3:23])[CH3:5])[CH2:2][CH3:7])([CH3:48])[CH3:46]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: C1CCOC1
Product: CCN(C(C)C)C(C)C

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-1-piperidine-carboxylate (5.0 g, 8.478 mmol), which was obtained in the step (2) of Example 17-1, and diisopropylethyl amine (4.12 mL, 25.435 mmol) in tetrahydrofuran (200 mL) under argon atmosphere was added dropwise to a solution of triphosgene (1.258 g, 4.239 mmol) in tetrahydrofuran (100 mL) . The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on Silica-gel (hexane/ethyl acetate=1/1) to give tert-butyl 3-(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1-piperidinecarboxylate as a white form (3.2 g, yield; 61%).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[S:38][CH:39]=1)[C:32](O)=[O:33])[C:27]#[CH:28].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:43])[F:44])[S:38][CH:39]=1)[C:32]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:33])[C:27]#[CH:28]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Yield: 87.1 %

Procedure:
7-Amino-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (1.93 g) and 2-(2-propynyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.61 g) were reacted in the presence of Vilsmeier reagent prepared from dimethylformamide and phosphorus oxychloride to give 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(3.0 g).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)(=[O:18])=[O:17])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])C.[Li+].[BH4-].O.CCOC(C)=O>C1COCC1>[F:25][C:23]1[CH:24]=[C:19]([S:16]([NH:15][CH:5]([CH2:4][OH:3])[CH:6]([C:7]([F:10])([F:8])[F:9])[C:11]([F:13])([F:12])[F:14])(=[O:17])=[O:18])[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CCOC(=O)C(NS(=O)(=O)c1cc(F)cc(F)c1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(3,5-difluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester in anhydrous THF (5 mL) at 0° C. was added 2M LiBH4 solution in THF (0.5 mL). The solution was allowed to warm to 25° C. and stir for 18 h. LC-MS of a reaction aliquot revealed unreacted starting material present. The reaction solution was immersed in an ice bath and 2M lithium borohydride (0.5 mL) was added and the solution allowed to warm to 25° C. and was stirred for 18 h. This procedure was repeated once more and, after 72 h, water was added to quench the reaction. The solvent was removed to give a tan solid which was transferred to a separatory funnel with EtOAc (100 mL) and washed with 1M citric acid solution (100 mL×2). The aqueous washings were combined and extracted with EtOAc (100 mL). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered and evaporated to give a peach colored solid (300 mg). This residue was adsorbed onto silica gel and purified by column chromatography, eluting with a solution of 50% EtOAc in hexanes to afford the alcohol (119 mg, 51%) as a white solid. Mass Spectrum (−ESI): 358.8 [M−H]−
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:34]=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][Mg]Br.[NH4+].[Cl-].CCOCC>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:30][CH3:31])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:34]([OH:35])[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C=O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C(C)O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.7 %

Procedure:
To a solution of0.11 g (0.21 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde in 3 mL of THF were added 0.14 mL (0.42 mmol) of methyl magnesium bromide dropwise at 0° C. under an argon stream. The mixture was stirred at RT for 1.5 h and poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.118 g (quantitative) of crude 1-[1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indol-2-yl]-ethanol, which was dissolved in 2 mL of THF and treated with 0.43 mL (0.43 mmol) of a 1M TBAF-solution in THF, stirred for one hour and then poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.066 g (74%) of 2-[1-benzyl-2-(1-hydroxy-ethyl)-1H-indol-5-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 418 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:25]([O:27][CH3:28])=[O:26])[CH:2]=[CH2:3]>C(Cl)Cl.C(#N)C.[Pd](Cl)Cl>[CH3:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[C:4]([CH:1]=[CH:2][CH3:3])=[C:5]([C:25]([O:27][CH3:28])=[O:26])[CH:6]=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Yield: 74.3 %

Procedure:
To a solution of dimethyl 4-allyl-5-(4-(methylsulfonyl)phenoxy)isophthalate (3.0 g, 8.814 mmol) in CH2Cl2 (25 mL) was added bis(acetonitrile-palladium(II) chloride (229 mg, 0.881 mmol). The mixture was refluxed under N2 for 14 hours. After removal of the solvent, the crude material was introduced into a silica gel column and eluted with EtOAc in hexanes (10/90 to 30/70) to afford the title compound (2.65 g, 88%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (dd, J=6.69, 1.79 Hz, 3 H) 3.04-3.18 (m, 3 H) 3.93 (d, 6 H) 6.00 (none, 1 H) 6.22 (dd, J=16.01, 6.78 Hz, 1 H) 6.62 (dd, J=16.01, 1.70 Hz, 1 H) 6.94-7.09 (m, 2 H) 7.77 (d, J=1.70 Hz, 1 H) 7.85-8.00 (m, 2 H) 8.28 (d, J=1.70 Hz, 1 H); LC-MS(ESI)+ m/z=405.00 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:10](Cl)=[C:9]([CH:12]=[O:13])[C:8]([CH3:14])=[N:7]1)[CH3:2].[OH-].[K+].[C:18](=[S:20])=[S:19].[CH3:21]I>CS(C)=O>[CH:12]([C:9]1[C:8]([CH3:14])=[N:7][N:6]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:18]([S:20][CH3:21])[S:19][C:10]=12)=[O:13]
Reactant: CCOC(=O)Cn1nc(C)c(C=O)c1Cl
Reactant: CI
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(SC)sc2c(C=O)c(C)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of ethyl(5-chloro-4-formyl-3-methyl-1H-pyrazol-1-yl)acetate (560 mg, 2.43 mmol), potassium hydroxide (495 mg, 7.5 mmol) and DMSO (9.72 mL) was added carbon disulfide (194 μL, 3.21 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture, methyl iodide (182 μL, 2.92 mmol) was added, and the mixture was further stirred at room temperature for 8 hours. This reaction mixture was poured into ice water to yield a solid, and the obtained solid was filtered, and then washed with water and dried to obtain the title compound (346.1 mg, 1.22
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH:18](O)[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC.O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccccc2Br)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
Ortho-bromophenol (1.72 g, 9.92 mmol) and racemic Boc-3-hydroxypiperidine (2 g, 9.92 mmol) were placed in THF (60 mL) with triphenylphosphine (3.9 g, 14.9 mmol), and the mixture was cooled to 0° C. DIAD (2.94 mL, 14.9 mmol) was added portion wise over 30 minutes, and the mixture was warmed to r.t. and stirred for about 16 hours. The mixture was diluted with ether (200 mL) and water was added (100 mL). The mixture was washed with 5N NaOH (100 mL), extracted with ether and concentrated. Ethyl acetate/hexanes was added, and the triphenylphosphine oxide was crystallized and filtered away. The residue was chromatographed on silica gel (ethyl acetate/hexanes) to afford the product (1.2 g, 34%) as a clear oil. MS found: 256.0 (M-Boc)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:14]/[O:15][CH2:16][C:17]#[N:18])/[C:8]([O:10]CC=C)=[O:9])[N:6]=1.C(N(CC)CC)C>C(OCC)(=O)C.[Pd](Cl)Cl.P(OCC)(OCC)(OCC)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:14]/[O:15][CH2:16][C:17]#[N:18])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C=CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Agent: Cl[Pd]Cl
Solvent: CCOP(=O)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
2.66 g (0.01 mol) of allyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate in 100 ml of ethyl acetate are treated while stirring with 17.73 mg (0.0001 mol) of palladium chloride and 0.083 ml (0.0005 mol) of triethyl phosphate. After the addition of 1.54 ml (0.011 mol) of triethylamine, the mixture is stirred at room temperature for 24 hours. Crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid triethylamine salt precipitates out. The filtered-off crude salt (2.9 g) is dissolved in 30 ml of methanol. The solution is adjusted to pH 3 with 2N aqueous hydrochloric acid. Crystallization occurs. The crystals obtained are filtered off and washed with methanol and ether. There are obtained 1.24 g (51.2%) of 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid of melting point 140°-142° C. (decomposition).
Reaction SMILES: COC(=O)CCC(C)=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].N1C=CC=CC=1.NC(N)=S.C[OH:42]>C(Cl)Cl>[CH3:19][O:18][C:17]1[C:16]([CH3:20])=[C:15]2[C:11]([C:12](=[O:21])[O:13][CH2:14]2)=[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:9]=1[CH2:8][CH:7]=[O:42]
Reactant: CO
Reactant: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: NC(N)=S
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH2Cl2 (10 mL) and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes, by which time the blue color had disappeared. To this solution, thiourea (75.7 mg, 0.994 mmol) was added in one portion at −70° C., and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction was worked up by filtration to remove solid thiourea S-dioxide, and then partitioned between CH2Cl2 and water. The organic layer was removed. The aqueous layer was washed with CH2Cl2 one more time, and the organic extracts were combined. The organic layer was washed with aqueous 1N HCl, saturated NaHCO3 and brine. The organic extracts were dried in vacuo and the residue was purified to by silica gel chromatography to afford 357 mg (75%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][C:19]=1[O:26][CH3:27].CC1CCCO1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([O:26][CH3:27])[CH:20]=2)=[O:14])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: COc1cc([Mg]Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COc1cc(C(=O)c2nc(Cl)c3ccccc3n2)ccc1F
Temperature: -35 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a stirred mixture of ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in THF (17 mL) at −40° C. was added dropwise 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (2.53 mL, 2.53 mmol). The reaction mixture was stirred at −30 to −40° C. for 3 h. Additional 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (1.05 mL, 1.05 mmol) was added and stirring was continued at −30 to −40° C. for an additional 1.5 h. To the mixture was added saturated aq ammonium chloride (25 mL) and the mixture was allowed to warm to rt. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried to afford (4-chloroquinazolin-2-yl)(4-fluoro-3-methoxyphenyl)methanone as a colorless solid (417 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (s, 3H), 7.42 (dd, J=11.1, 8.7 Hz, 1H), 7.64 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.04 (m, 1H), 8.23-8.25 (m, 2H), 8.43 (d, J=8.4 Hz, 1H); LC-MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 31), 401 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[N:33]=[C:34]([NH:37][CH:38]([CH3:40])[CH3:39])[S:35][CH:36]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:41]([O:43]C(C)(C)C)=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[N:33]=[C:34]([NH:37][CH:38]([CH3:40])[CH3:39])[S:35][CH:36]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:41]([OH:43])=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)O)C(=O)OCC

Procedure:
To a solution of compound 40 (20 mg, 30 umol) in CH2Cl2 (2 mL) was added TFA (2 mL) and Et3SiH (10 μL, 63 umol). After 2 h the volatiles were evaporated and the product was used without any purification. Title compound: 18 mg, quant. as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]=[O:17])[CH:4]=[CH2:5].ClS([N:22]=[C:23]=[O:24])(=O)=O.C(O)(=O)C>C1COCC1.O>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:23]([NH2:22])=[O:24])[CH:11]=[C:10]2[CH:16]=[O:17])[CH:4]=[CH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CCOc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=CCOc1ccc2c(c1)c(C=O)cn2C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of NaH (60% in mineral oil, 352 mg, 8.79 mmol) in THF (12 mL) under nitrogen atmosphere at 5° C. was added a solution of 5-allyloxy-1H-indole-3-carbaldehyde (1.18 g, 5.86 mmol) in THF (28 mL) and the resulting mixture was stirred at 5° C. for 30 min before slow addition of chlorosulfonyl isocyanate (11.02 mL, 11.7 mmol) while maintaining the temperature between 5° C. and 10° C. The solution was further stirred at RT for 4 h, acetic acid (11 mL) was added and the solution was stirred at RT for 1 h. Ice cubes and water (100 mL) were added and the mixture was stirred at RT for 30 min. The solution was extracted twice with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (100% c-hexane to 100% EtOAc) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:2)=0.36; MS (LC/MS): 245.1 [M+H]+, 267.0 [M+Na]+, 200.1 [M−CONH2]−; tR (HPLC conditions a): 2.95 min.