Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 6.02 g of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 50 ml of DMF there were added 1.24 g of 2-hydrazinopyrimidine and 1.9 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 50 ml of methanol and 5 ml of acetic acid. After then adding 3.4 g of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (3.317 g) as a light yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[CH:18]=2)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:2]3[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=3)=[C:19]([F:26])[CH:18]=2)=[CH:15][CH:16]=1)[CH3:10]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)s3)c(F)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 58.5 g (0.31 mol) of 5-bromothiophene-2-carbaldehyde, 75.5 g (0.31 mol) of 4′-ethyl-3-fluoro-4-biphenylboronic acid, 17.0 g (14.7 mmol) of tetrakis(triphenylphosphine)palladium(0) and 375 ml of 2 N sodium carbonate solution in 935 ml of toluene/ethanol (1:1.5) is heated at 80° C. for 1 h. After cooling, the precipitated product is firstly dissolved by addition of THF. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution, and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is digested in toluene, and the product is filtered off, giving 5-(4′-ethyl-3-fluorobiphenyl-4-yl)thiophene-2-carbaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:8][CH:7]1[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][N:3]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C@H:2]1[CH3:1]
Reactant: C=CCOC(=O)N1CCC(C(=O)OCC)C(=O)[C@@H]1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)N1CCC(C(=O)OCC)C(O)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 1-allyl 4-ethyl (2S)-2-methyl-3-oxo-1,4-piperidinedicarboxylate (1.40 g, 5.2 mmol) in methanol (27 ml) were added acetic acid (0.36 ml, 6.3 mmol) and sodium cyanoborohydride (0.39 g, 6.3 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give 1-allyl 4-ethyl (2S)-3-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.36 g). A solution of this compound in dichloromethane (24 ml) was cooled at −30° C. and to the solution were added methanesulfonyl chloride (0.58 ml, 7.5 mmol), triethylamine (1.4 ml, 10.0 ml) and dimethylaminopyridine (61 mg, 0.50 mmol). The mixture was stirred at 0° C. for 20 minutes and poured into 1N hydrochloric acid and the solution was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was dissolved in toluene (10 ml) and dichloromethane (5 ml). To the solution was added DBU (2.3 ml, 15.4 mmol) and the solution was stirred at room temperature for 5 hours. To the reaction solution was added water and after separating the mixture with a separating funnel the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 1-allyl 4-ethyl (6S)-6-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (825 mg) with an intermediate, a methanesulfonylated compound (409 mg).
Reaction SMILES: C(O)(=O)C.OO.[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.[OH-].[Na+]>O>[NH:7]1[CH:11]=[N:10][C:9]([S:12][S:12][C:9]2[N:10]=[CH:11][NH:7][N:8]=2)=[N:8]1
Reactant: Sc1nc[nH]n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1nc(SSc2nc[nH]n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glacial acetic acid (7.89 g) was added to 18.7 g of a 15% aqueous hydrogen peroxide solution. The resulting solution was added slowly to a solution prepared from 16.5 g 1,2,4-triazole-3-thiol, 160 g of water and 16.3 g 40% NaOH. The reaction temperature was moderated with the use of an ice bath during the addition. After stirring overnight at room temperature, the product was filtered, washed with water and then dried under vacuum at 70 C.
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9](O)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([CH2:9][OH:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a stirred solution of (±) 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid (3.4 g., 0.01 mole) in tetrahydrofuran (50 ml.) at 0° C. is added the borane-tetrahydrofuran complex (25 ml., 0.00625 mole) over a one-half hour period. The reaction solution is stirred one hour at 0° C. and 18 hours at 25° C. The reaction solution is diluted with aqueous sodium bicarbonate (50 ml.) and the water layer is separated and the extracted twice with ether (two 20 ml. portions). The organic layers are combined, washed with brine (two 10 ml. portions), dried over magnesium sulfate and the solvents distilled at reduced pressure. The (±)6,7-dichloro-2,3-dihydro-2-hydroxymethyl-5-(2-thenoyl)benzofuran is purified by column chromatography on silica gel (95% benzene-5% methanol) and melts at 65°-8° C. (yield 21%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>C(#N)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Solvent: CC#N
Product: Nc1ccc(-n2cccn2)cc1

Procedure:
General procedure B (82° C., 42 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 516 mg of 4-bromoaniline (3 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:28]#[N:29])[C:22]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>C(O)(C(F)(F)F)=O>[C:28]([C:21]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:30])#[N:29]
Reactant: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(O)C2=O
Yield: 69 %

Procedure:
Following the procedure of Example 52, 2-benzyloxy-5-cyano-6-(pyrrolidin)-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.33 mmol, from Example B2) and a 1.0 M solution of boron tris(trifluoroacetate) in TFA (2 mL) was reacted to give 0.070 g of the title compound, mp 247-248° C.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15]C)[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([C:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[N:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cc(-n2nc(C3CCCC3)c3cc[nH]c(=O)c32)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 4-(3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxamide (60 mg) in acetonitrile (5 mL) were added sodium iodide (52.5 mg) and chloro(trimethyl)silane (0.111 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% trifluoroacetic acid)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate and THF. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The suspension of the residue in ethanol was stirred at 100° C. for 2 hr, allowed to be cooled to room temperature, and the solid was washed with ethanol to give the title compound (35 mg).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCCCCC.C(OCC)(=O)C>CC(C)=O>[N+:1]([C:4]1[N:5]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
To a mixture of 2 -nitroimidazole (8 g, 70 mmol) and dry K2CO3 (9.7 g, 70 mmol) in acetone (100 mL) was added ethyl bromoacetate (11.6 g, 70 mmol). The suspension was stirred under N2 atmosphere for 48 h. TLC (silica gel, 40% hexane-ethyl acetate) showed a single UV-visible spot with Rf =0.55. The suspension was filtered and solid was washed with acetone (3×50 mL). The filtrate and the washings were combined and evaporated on a rotary evaporator to afford a thick yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=O)[CH3:3].CN1CCOCC1.[NH2:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[NH:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:4]([C:5]([NH:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a flask containing Boc-Valine-OH (652 mg, 3 mmol) in DCM (6 ml) at 0° C. was added NMM (0.35 ml, 3.15 mmol). After stirring for 15 min, A5 (1.065 g, 3 mmol), HOBt (405 mg, 3.0 mmol) and DCC (650 mg, 3.15 mmol) were added in portions. The reaction mixture was allowed to warm to 23° C. and stirred for 14 h. The suspension was diluted with DCM (25 ml) and washed successively with aq KHSO4 (2×10 ml, 10%), aq NaHCO3 (2×10 ml, sat) and brine (10 ml) dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash LC (silica, gradient hex-EtOAc 2:1 to 1:1) to give SVPLA4 (1.48 g, 93%) as a white solid. Rf=0.57 (hex-EtOAc 1:2).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-4 (6.45 g, 19.0 mmol), 4-bromophenol (3.29 g, 19 mmol), and Cs2CO3 (3.10 g, 9.5 mmol) in 50 mL of DMF was stirred at room temperature for 18 hr. The solution was then diluted with 200 mL ethyl acetate and washed with H2O (4×100 mL), then dried over Na2SO4, filtered and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 36-1 as a white solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 83 %

Procedure:
(3S)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 6) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (83%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:25])[CH3:24])[C:14]([C@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:1][C:2]([CH3:26])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]([CH3:24])[CH3:25])[C:14]([C@@H:16]2[CH2:21][CH2:20][C:19]([CH3:22])=[CH:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC1=CC[C@@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1=CC[C@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(C)C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 5 using acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (S) in place of acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R): MS (m/z): 388.0 [M+H]+; HPLC retention time 4.59 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (410 mg, 0.79 mmol) in CH2Cl2 (5 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The organic layer was separated, washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) and gave the desired product (343 mg, 88% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 2H), 3.83 (m, 2H). MS (ES+): m/z 493.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[N:15]([O-])=O.[Na+].CO.ClCCl>C(O)(=O)C.[Zn].O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[NH2:15])[CH:11]=[CH:10][CH:9]=1
Reactant: O=N[O-]
Reactant: COC(=O)CNc1cccc(OC)c1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CN(N)c1cccc(OC)c1
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a cold (0°) solution of N-(3-methoxyphenyl)glycine methyl ester (50 g) in aqueous acetic acid (800 ml) was added dropwise an aqueous solution (200 ml) of sodium nitrite (21.2 g) and the mixture was stirred for 30 min. Methanol (200 ml) was added and the mixture was cooled to -10°. Zinc dust (83.2 g) was added portionwise over 2 h during which time the internal temperature was maintained at -10° to 0° and the mixture was stirred for a further 1 h at 0°. Dichloromethane (800 ml) and water (800 ml) were added and the resulting suspension was filtered. The filtrate was diluted with more water (500 ml) and dichloromethane (500 ml). The phases were separated and the aqueous layer was partitioned with more dichloromethane (2×500 ml). The combined organic extracts were washed with water (3×500 ml) and evaporated in vacuo. The residual oil was treated with 8% sodium bicarbonate (1000 ml) and partitioned with ether (3×700 ml). The combined organic layers were washed with brine (500 ml), dried and evaporated. Purification by FCC eluting with System A (1:1) and then System A (7:3) gave the title compound (8.2 g) as an oil, t.l.c. (System A, 1:1) Rf 0.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Cl.[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].CN(C)C(N(C)C)=N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:19]1[C:20](=[O:22])[CH2:21][O:17][C:18]1=[O:23]
Reactant: O=C1COC(=O)N1
Reactant: Fc1ccc(-c2ccc(CCl)c(Cl)c2)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1Cc1ccc(-c2ccc(F)cc2)cc1Cl

Procedure:
A solution of 0.5 g (1.96 mmol) of 3-chloro-4-(chloromethyl)-4′-fluoro-1,1′-biphenyl, prepared in step 5.3., 0.240 g (2.35 mmol) of 1,3-oxazolidine-2,4-dione and 0.45 g (3.92 mmol) of 1,1,3,3-tetramethylguanidine in 10 ml of tetrahydrofuran is refluxed for 18 hours.
Reaction SMILES: Cl.NO.C([N:7](C(C)C)CC)(C)C.[Br:13][C:14]1[N:19]=[C:18]([NH:20][C:21]([NH:23]C(OCC)=O)=S)[CH:17]=[C:16]([CH3:29])[CH:15]=1>C(O)C.CO>[Br:13][C:14]1[N:19]2[N:7]=[C:21]([NH2:23])[N:20]=[C:18]2[CH:17]=[C:16]([CH3:29])[CH:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cc(C)cc(Br)n1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Cc1cc(Br)n2nc(N)nc2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.65 g, 9.27 mmol) in ethanol/methanol (1:1, 20 ml) was added diisopropylethylamine (0.97 ml, 5.56 mmol) and the mixture was stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-4-methyl-pyridin-2-yl)-3-carboethoxy-thiourea (0.59 g, 1.84 mmol) was added and the mixture slowly heated to reflux. Having refluxed overnight the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of water and filtration. The combined solids were washed successively with water, ethanol/methanol and diethylether, then dried in vacuo to give the desired product. Yield 0.19 g, 45%. LCMS MI: 226.91+228.89, RT: 2.52 min, Method: 2
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:22].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].Cl>C(Cl)Cl.O>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=3)=[O:22])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccnc(CSc2nc3c(F)cccc3[nH]2)c1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccnc(CS(=O)c2nc3c(F)cccc3[nH]2)c1
Reaction time: 0.25 h

Procedure:
4-Fluoro-2[[(4-methoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.31 g, 0.0045 mol) was dissolved in methylene chloride (60 ml). NaHCO3 (0.76 g, 0.0090 mol) dissolved in water (10 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid, 84% (1.64 g, 0.0045 mol) dissolved in methylene chloride (10 ml) was added dropwise with stirring. Stirring was continued at +2° C. for 15 min. After separation the organic layer was extracted with an aqueous 0.20 M NaOH solution (2×25 ml, 0.010 mol). The combined aqueous solutions were neutralized to pH 7-8 with 0.1 M HCl in the presence of methylene chloride [100 ml). After separation the aqueous layer was extracted with methylene chloride and the combined organic solutions were dried over MgSO4. The solutions was evaporated and the title compound was obtained (1.06 g, 77%). NMR data for the final product is given below.