Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[Cl:8][CH2:9][CH2:10][OH:11]>C(#N)C>[Cl-:8].[OH:11][CH2:10][CH2:9][N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCCCl
Reactant: CN1CCCC1=O
Solvent: CC#N
Product: C[N+]1(CCO)CCCC1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
About 200 mL of acetonitrile (manufactured by Junsei Co., Ltd. in Japan) was mixed with about 52.7 mL (0.5 mol) of methylpyrrolidone (manufactured by Fluka Co., Ltd.) under a nitrogen atmosphere to form a liquid mixture. Subsequently, about 36.5 mL (0.55 mol) of 2-chloroethanol (manufactured by Aldrich Co., Ltd.) was added to the liquid mixture drop by drop to form a mixed solution. Subsequently, the mixed solution was stirred at about 65° C. for about 48 hours under a nitrogen atmosphere, and was then stored at about 4° C. for about 12 hours to form crystals. After a supernatant was removed from the mixed solution, the crystals were dried at a temperature of about 35° C. and a pressure of about 0.2 atm for about 12 hours using a vacuum evaporator to remove a solvent therefrom. Subsequently, in order to remove impurities, the dried crystals were dissolved in about 100 mL of acetone, and then were stirred at a temperature of about 25° C. and a pressure of about 1 atm for about 30 minutes to form a solution. The solution was stored at about 4° C. for about 12 hours to form crystals again. After a supernatant was removed from the solution, the crystals were dried at a temperature of about 35° C. and a pressure of about 0.2 atm for about 12 hours using a vacuum evaporator. These processes were repeatedly conducted three times to obtain N-hydroxyethyl-N-methylpyrrolidinium chloride at a yield of about 75%.
Reaction SMILES: C(OC([N:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=O)C=C.O.CCCC[SnH](CCCC)CCCC>C(Cl)Cl.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>[Si:15]([O:14][CH2:13][C@@H:8]1[CH2:9][C:10](=[CH2:12])[CH2:11][NH:7]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: C=CCOC(=O)N1CC(=C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: C=C1CN[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A catalytic amount of PdCl2(PPh3)2 (92 mg, 0.131 mmol) was added to a solution of the allyl carbamate 7 (1.0 g, 3.22 mmol) and H2O (0.34 mL, 18.9 mmol) in CH2Cl2 (30 mL). After 5 minutes stirring at room temperature, Bu3SnH (0.96 mL, 1.04 g, 3.57 mmol) was added rapidly in one portion. A slightly exothermic reaction with vigorous gas evolution immediately ensued. The mixture was stirred for 16 hours at room temperature under nitrogen at which point TLC (50% EtOAc/Petroleum Ether) revealed the formation of amine. After diluting with CH2Cl2 (30 mL), the organic solution was dried (MgSO4), filtered and evaporated in vacuo to give an orange oil which was purified by flash chromatography (50-100% EtOAc/Petroleum Ether) to afford the amine 8 as a slightly orange oil (0.56 g, 77%): [α]21D=−3.9° (c=5.0, CHCl3); 1H NMR (270 MHz, CDCl3) δ 4.93 (t, 1H, J=2.02 Hz, NCH2C═CH2), 4.90 (t, 1H, J=2.02 Hz, NCH2C═CH2), 3.68-3.46 (m, 4H, NCHCH2OTBDMS and NCH2C═CH2), 3.30-3.21 (m, 1H, NCHCH2OTBDMS), 2.53-2.41 (m, 2H, NCH2C═CH2CH2 and NH), 2.26-2.17 (m, 1H, NCH2C═CH2CH2), 0.90 (s, 9H, SiC(CH3)3), 0.06 (s, 6H, Si(CH3)2); 13C NMR (67.8 MHz, CDCl3) δ 150.0 (NCH2C═CH2), 104.7 (NCH2C═CH2), 64.7 (NCHCH2OTBDMS), 60.5 (NCHCH2OTBDMS), 51.3 (NCH2C═CH2), 34.9 (NCH2C═CH2CH2), 25.9 (SiC(CH3)3), 18.3 (SiC(CH3)3), −5.4 (Si(CH3)2); MS (EI), m/z (relative intensity) 227 (M+, 8), 212 (6), 170 (M-tBu, 36), 96 (8), 82 (M-CH2OTBDMS, 100), 75 (11); IR (Neat) 3550-3100 (br, NH), 3074 (C═CH2), 2929, 2857, 1664 (C═C), 1472, 1424, 1391, 1380, 1361, 1255, 1190, 1101, 1006, 939, 880, 838, 777, 723, 668 cm−1.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]#[CH:29])[CH3:25].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][C:11]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:2]([C:29]#[C:28][CH:27]([O:30][CH2:31][CH3:32])[O:26][CH2:24][CH3:25])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)NC1(CNc2nc(Cl)ncc2Br)CCCC1
Reactant: C#CC(OCC)OCC
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NCC1(NC(=O)OC(C)(C)C)CCCC1)OCC

Procedure:
tert-butyl N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) 453 (M+H).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+](C)([O-])=O.Cl>CCOCC>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
One gram of 2-pivaloylamino-4-hydroxy-6-(4-tert.butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 25 ml of nitromethane saturated with hydrogen chloride gas at 0° C. After stirring at 0° C., the reaction mixture is allowed to reach room temperature and stirred for an additional hour. The suspension is diluted with anhydrous ether and suction filtered. The collected solid is washed with ether, methanol, and ether again, and then dried under reduced pressure to give 0.81 g of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a yellowish powder: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (s, 9H), 7.72 (d, 2H, J=8.02 Hz), 7.98 (d, 2H, J=8.02 Hz), 8.52 (d, 1H, J=2.01 Hz), 9.01 (d, 1H, J=2.01 Hz); IR (KBr) 3420, 3000, 1725, 1680, 1425, 1405, 1360, 1250, 1130, 1020, and 800 cm -1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][C:5]([NH:16][C:17](=[O:19])[CH3:18])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C)C=O>[C:17]([NH:16][C:5]1[C:4]([F:20])=[CH:3][C:2]([Cl:1])=[C:7]([CH:6]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
N-[4-chloro-2-fluoro-5-(2-hydroxyphenoxy)phenyl]acetamide is dissolved in N,N-dimethylformamide, then, potassium carbonate is added and the mixture is stirred at room temperature. Then, ethyl bromoacetate is added at room temperature. The mixture is stirred under the same temperature, poured into water, extracted with ethyl acetate, the organic layer is washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate and concentrated, and the resulted crystal is washed with t-butyl methyl ether to obtain ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH3:24]>CN(C=O)C.O>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(C)c1cc(N)c([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol, 1.00 equiv), triethylamine (1.167 g, 11.53 mmol, 4.00 equiv), and (2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equiv) in DMF (20 mL) was stiffed in a sealed tube at 55° C. behind a blast shield overnight. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 723 mg (crude) of the title compound as a dark red oil.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.Cl.[N:21]([O-])=[O:22].[Na+]>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:21]=[O:22])[C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CCn1c(N)cc(=O)n(CC=C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCn1c(N)c(N=O)c(=O)n(CC=C)c1=O
Reaction time: 4 h
Yield: 86.7 %

Procedure:
1,3-Diallyl-6-aminouracil (5 g) was suspended in 400 ml of water in a one-liter round bottom flask with overhead stirring. Acetic acid (6.7 ml of a 20% solution) was added, followed by intermittent addition of 2 ml of concentrated hydrochloric acid and a sodium nitrite solution (1.53 g in 7 ml water). After 4 hours, this solution was filtered, washed with water, collected and dried in a vacuum oven at 80° C. for 20 hours to yield 4.54 g of 1,3-diallyl-5-nitroso-6-aminouracil as a purple solid, m.p. 170°-180° C. (87% yield).
Reaction SMILES: [NH2:1][C:2](=[N:37]O)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH2:19][C@H:20]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:36])[CH2:10]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.C>C(O)(=O)C.O.[Pd]>[C:21]([OH:23])(=[O:22])[CH3:20].[NH2:37][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH2:19][C@H:20]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:36])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@H](CNC(=O)CN1CCN(c2ccc(C(N)=NO)cc2)CC1=O)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)CN1CCN(c2ccc(C(=N)N)cc2)CC1=O)NS(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 160.1 %

Procedure:
Ethyl (2S) -3-{[2- (4-{4-[amino(hydroxyimino)methyl]phenyl}-2-oxopiperazino)acetyl]amino}-2-[(phenylsulphonyl)amino]propanoate (Example 1) (1.5 g, 2.75 mmol) is dissolved in 50 ml of acetic acid. 600 mg of acetic anhydride (5.6 mmol) and 0.76 g of 10%; palladium-on-charcoal are added. The hydrogenolysis is carried out at room temperature under 50 psi for 3 hours. The catalyst is filtered off and the solution is evaporated to dryness. The solid obtained is dissolved in 150 ml of water and treated with charcoal. The solution is filtered. The filtrate is freeze-dried to give 1.3 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C(=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 165 °C
Yield: 76 %

Procedure:
A mixture of 1,3-dichloro-4-fluorobenzene (Aldrich; 4.21 g), piperazine (Aldrich; 11.0 g), and N,N-dimethylacetamide (Aldrich; 15 mL) is heated at 165° C. for 6.5 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 4.48 g of 1-(2,4-dichlorophenyl) piperazine. 1H NMR (CDCl3) δ3.00, 3.06, 6.96, 7.19, 7.36.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[Br:19]Br>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cc2cc3ccccc3o2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Cc2oc3ccccc3c2Br)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.2 g (5 mmol) of 4-(benzofuran-2-yl)methyl-benzonitrile in 25 ml methylene chloride, a solution of 0.8 g (5 mmol) of bromine in 5 ml carbon tetrachloride is added dropwise at 2° C. The solution is stirred for 90 minutes at 2° C., the precipitate formed is suction filtered, washed with a little methylene chloride and dried.
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH2:25])=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[C:27]=[O:28].O>CC(N(C)C)=O>[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH:25][C:27]([NH:26][C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[O:28])=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)n1nc(N)c2cc(Sc3cc(F)cc(F)c3)cnc21
Reactant: CN1CCN(c2ccc(N=C=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)Nc3nn(C(C)(C)C)c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
0.048 g (1.19 mmol) of sodium hydride is added at 0° C. to 0.200 g (0.598 mmol) of 1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine dissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of 1-(4-isocyanatophenyl)-4-methylpiperazine is then added at 0° C. The mixture is left under stirring for 3 hours at room temperature. The reaction is treated by adding 20 ml of water drop by drop at 0° C. and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0.150 g (yield=45%) of 1-(1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea in the form of a light brown solid.
Reaction SMILES: SCC(OCC)=O.[H-].[Na+].[H][H].[C:12]([C:20]1[C:21]([S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:12]2[C:20]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[S:26][C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CSc1ncccc1C(=O)c1ccccc1
Reactant: [H][H]
Agent: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ncccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-mercaptoacetate (0.6 mL, 5.5 mmol) in dry DMF (10 mL) under nitrogen and cooled with an ice bath was added sodium hydride (220 mg of 60% dispersion in oil, 5.75 mmol). After hydrogen evolution had ceased the cooling bath was removed and the reaction stirred at room temperature for 30 mins. A solution of Intermediate 1 (920 mg, 4.6 mmol) in DMF (5 mL) was added and the reaction stirred at room temperature for 3 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give a mixture of the title compound and uncyclised ethyl 2-(3-benzoylpyridin-2-ylsulfanyl)acetate. This crude mixture was dissolved in EtOH (10 mL) and sodium ethoxide (10 mL of 0.5M solution in EtOH, 5.0 mmol) added. The reaction was stirred at room temperature for 45 mins after which time complete conversion of uncyclised material to title compound was observed. The reaction was diluted with EtOAc (50 mL), washed with water (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (10% EtOAc in isohexane) to give the title compound as a white solid (780 mg, 60%). δH (CDCl3) 8.63 (1H, dd, J 4.5, 1.4 Hz), 7.78 (1H, dd, J 8.2, 1.5 Hz), 7.41 (3H, m), 7.33–7.32 (2H, m), 7.24 (1H, dd, J 8.2, 4.6 Hz), 4.18 (2H, q, J 7.1 Hz), 1.15 (3H, t, J 7.1 Hz) LCMS (ES+) RT 3.90 minutes, 284 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 63.4 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 70%, 0.53 g, 2.1 mmol) in chloroform (10 ml) was added dropwise to a solution of 2-{6-[(4-methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one (0.35 g, 1.0 mmol) in chloroform (50 ml) with stirring. The reaction mixture was stirred at room temperature for 5 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethanol to give the titled compound (0.25 g, 64%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1.CCN(CC)CC.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C1COCC1>[CH2:32]([O:31][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc2c(c1)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc(NC(=O)OCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
To a stirred solution of 4 (50 mg, 0.15 mmol) in THF (5 mL) was added Et3N (0.031 mL, 0.22 mmol) followed by benzyl chloroformate (1.06 mL, 0.18 mmol) at 0° C. under inert atmosphere. The resulting reaction mixture was allowed to warm to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography [eluent: 35% EtOAc/hexane] to afford the title compound 82 (15 mg, 21.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.60 (bs, 1H), 10.00 (bs, 1H), 8.18 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.51-7.28 (m, 9H), 5.18 (s, 2H), 3.49 (s, 2H). MS (ESI): 466 [M+1]+
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1.[C:14]1([S:20]([O-:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:14]1([S:20]([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1nc(-c2ccccc2)no1
Reactant: O=S([O-])c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(Cc1nc(-c2ccccc2)no1)c1ccccc1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a stirred solution of 525 mg (2.7 mmol) of 5-chloromethyl-3-phenyl-[1,2,4]oxadiazole in acetonitrile at RT, 465 mg (2.8 mmol, 1.05 eq) of sodium benzenesulfinate and 143 mg (0.5 mmol, 0.2 eq) of 18-crown-6 were added. Stirring was continued overnight, and an additional 50 mg (0.3 mmol, 0.12 eq) of sodium benzenesulfinate were added and the reaction mixture was allowed to stirr for one further hour. The solvent was evaporated and the resulting oil was taken up in EtOAc, washed with a saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 8:2) yielded 622 mg (77%) of 5-benzenesulfonylmethyl-3-phenyl-[1,2,4]oxadiazole as a white solid, MS: 301 (MH+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH:1]([C:3]1[S:7][C:6]([C:8](=[N:13][OH:14])[O:10][CH3:11])=[CH:5][CH:4]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=NO)c1ccc(C=O)s1
Yield: 72 %

Procedure:
A solution of methyl 5-formyl-2-thiophenecarboxylate, prepared according to Example 10, (6.26 g, 36.78 mmoles), hydroxylamine hydrochloride (3.07 g, 44.14 mmoles) and pyridine (3.49 g, 44.14 mmoles) in 200 ml of ethanol was refluxed for 2 hours. The ethanol was removed in vacuo, the residue dissolved in ether and washed with water. The organic layer was dried (magnesium sulfate) and evaporated to a yellow solid. Trituration with a small amount of ether furnished the title compound as a white solid (4.93 g, 72%), m.p. 164°-7° C. Oxime Z:E ratio:(82:18).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].O>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:39])=[C:21]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2ccc(-c3cccc(C#N)c3)cc21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(-c3cccc(C#N)c3)cc21
Yield: 74 %

Procedure:
Trifluoroacetic acid (4.00 ml, 54 mmol) was added to a suspension of tert-butyl 2-(7-(3-cyanophenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.162 g, 0.37 mmol) in dichloromethane (2.00 ml). After stirring for one hour at room temperature water was added and the solids formed were collected by filtration. The solids were washed with water, ether, dried in a vacuum oven at 50° C. to afford off-white solids in 74% yield.