Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH3:37][O:36][C:34](=[O:35])[C:23]1[CH:22]=[C:21]([C:19]2[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:16]=[N:17][C:18]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:26]=[CH:25][C:24]=1[O:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a solution of 4-[6-butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.754 mmol, 428 mg) in DCM (6 mL) was added 4 N HCl in dioxane (2 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and 5-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride was obtained as yellow solid, which was used for next reaction directly
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH3:12][C:11]1([C:7]2[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][CH:8]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: COCOc1cccc(C(C)=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COCOc1cccc(C2(C)OCCO2)c1
Yield: 60 %

Procedure:
A mixture of 3-(acetyl)phenyl methoxymethyl ether (3.6 g, 20 mmol), ethylene glycol (3.72 g, 60 mmol) and pyridinium tosylate (0.075 g, 0.3 mmol, 3 mol %) in benzene (200 mL) was azeotropically refluxed for 8 h. The reaction was concentrated and the resulting residue was diluted with ethyl ether (150 mL) and washed with saturated aqueous bicarbonate (2×50 mL) and brine (100 mL). The ethyl ether solution was dried (K2 CO3) and concentrated. The residue was suspended in n-hexanes and the by-product was precipitated. The n-hexane solution was then separated and concentrated to obtain the desired product (2.69 g, 61%); TLC Rf: 0.5 (30% EtOAc/n-hexanes).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C)C=O>O>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]([N:4]2[CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]([CH3:8])[CH2:5]2)=[C:10]([C:11]#[N:12])[CH:13]=1)([O-:19])=[O:18]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@@H]1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Then, cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), potassium carbonate (4.9 g) and ethyl bromoacetate (6 g) were added to dimethylformamide (35 ml), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl cis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g) as an oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24])([OH:26])=[O:1]
Reactant: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a magnetically stirred solution of 2-(3-hydroxypropyl)-4-benzyl-8-iodo2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.75 grams, 1.7mmol) in 5 mL dimethylformamide at room temperature was added a solution of pyridinium dichromate (2.58 grams, 6.86mmol) in 5 mL dimethylformamde. The reaction mixture was stirred overnight, diluted with 75 mL water, washed 3×75 mL diethyl ether, made acidic to a pH of 2 with conc. HCl and extracted 3×75 mL diethyl ether. The combined organics were extracted 3×40 mL 1N sodium hydroxide. The combined aqueous layers were acidified to a pH of 2 with canc HCl and extracted 3×50 mL diethyl ether. These ether layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 0.557 grams (73%) of 2-(2-carboxyethyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.07 (1H, d, 4JHH =2 Hz, C9-H), 7.69 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.75 (1H, d, 3JHH =8 Hz, C6-H), 4.75 (1H, m, ArOCH), 3.89 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.69 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.44 (2H, d, 3JHH =3 Hz, CH2Ph), 3.07 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, C3-H), 2.8-2.7 (3H, m, C3-H, CH2CO2), 13C NMR (CDCl3) 176.1 167.6, 164.4, 152.8, 141.7, 139.5, 136.4, 129.4, 129.1, 128.9, 128.8, 127.0, 124.7, 86.7, 84.7, 51.4, 45.0, 38.8, 33.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1.[N:21]1[CH:22]=[CH:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=12>>[OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]3[CH2:28][CH2:29][N:24]4[CH:23]=[CH:22][N:21]=[C:25]4[CH2:26]3)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1
Reactant: O=C(O)c1cn(CCO)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn2c(n1)CNCC2
Product: O=C(O)c1cn(CCO)c2c(F)c(N3CCn4ccnc4C3)c(F)cc2c1=O

Procedure:
Using 1-(2-hydroxyethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:17][CH:15]([CH2:16]2)[O:14][C:13](=[O:18])[NH:12]3)=[CH:7][CH:6]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C(N(CC)CC)C>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:17][CH:15]([CH2:16]4)[O:14][C:13](=[O:18])[NH:12]5)=[CH:7][CH:6]=3)[N:33]=[C:29]2[N:28]=1
Reactant: COc1ccnc(N)n1
Reactant: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C45CC(C4)OC(=O)N5)cc3)nc2n1
Temperature: 100 °C

Procedure:
A mixture of crude 5-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.5 g), 4-methoxypyrimidin-2-amine (1.26 g), triethylamine (0.84 mL) and ethanol (62 mL), under argon, was heated at 100° C. (bath temperature) for 6 hours. On cooling the reaction was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried and concentrated. Purification was achieved by chromatography on silica gel followed by preparative reverse phase HPLC to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1B(O)O.C1(C)C(S(NC2C=C(C3C=CC(C)=CC=3)SC=2C(O)=O)(=O)=O)=CC=CC=1>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>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:26]2[S:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(-c2cc(NS(=O)(=O)c3ccccc3C)c(C(=O)O)s2)cc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)OC(C)(C)C
Yield: 55.6 %

Procedure:
Suzuki coupling of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) and bezothiophene-2-boronic acid (53.4 mg, 0.3 mmol) was carried out using Pd(PPh3)4 and Na2CO3 (as described in example 2) resulted in 5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (27 mg, 55% yield). 1H NMR (CDCl3, 400 MHz) 9.92 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.45-7.24 (m, 7H), 2.7 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C@@H:9]([C:18]([OH:20])=[O:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:23][O:19][C:18](=[O:20])[C@H:9]([CH2:8][C:7]1[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
To suspesion of of 4-nitro-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (226.2 mmol, 70.2 g) and sodium carbonate (1.13 mol, 95 g) in DMF (500 mL) was added methyl iodide (1.13 mol, 70.4 mL) at room temperature. The suspesion was stirred for 15 h at room temperature at this time TLC analysis of the mixture indicated the absence of starting acid and the excess methyl iodide and some DMF were removed under high vacuum. The residue was poured into water (2 L) and stirred at room temperature as a precipitate formed slowly over 72 h. The precipitated solids were collected by filtration and washed with water (2 L). After air and vacuum drying, 72 g (98%) of a light yellow solid, mp 95-96° C. were obtained. 1H-NMR, (DMSO-d6) (400 MHz) δ 8.16 (d, 2H, J=20 Hz), 7.53 (d, 2H, J=20 Hz), 7.39 (d, 1H, J=22 Hz), 4.26-4.28 (m, 1H), 3.6 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). 13C NMR, CDCl3 (100 Mhz) δ 172.04, 155.29, 146.27, 145.96, 130.48, 123.18, 78.36, 54.44, 51.9, 36.1, 27.99. HR MS: Obs. mass, 325.1404. Calcd. mass, 325.1400 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](OC)=[O:20].[H-].[Na+].O>CN(C=O)C>[OH:20][CH:19]=[C:11]([S:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CSc1cccc(-c2ccccc2)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)Sc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 15.4 %

Procedure:
Methyl (3-phenylthiophenoxy)acetate (6.60 g) and methyl formate (30.78 g) were dissolved in DMF (30 ml) and added dropwise at 0° C. to sodium hydride (0.83 g, 50% dispersion in oil) in DMF. The reaction mixture was stirred at 0° C. for 45 minutes and then left at room temperature under nitrogen over the weekend. The reaction mixture was then poured into water (300 ml) and washed with diethyl ether (3×150 ml). The aqueous phase was adjusted to pH 7 with hydrochloric acid and then extracted with diethyl ether (3×100 ml). The combined organic extracts were washed successively with water (3×100 ml) and brine (2×75 ml) and then dried. Filtration and evaporation of the solvent under reduced pressure gave methyl 3-hydroxy-2-(3'-phenylthiophenoxy)propenoate (1.13 g) which was used without further purification.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Cl[C:17]1[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1>O1CCOCC1.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>[CH:1]([C:17]1[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ncc(C(=O)OCC)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of tributyl(vinyl)stannane (1.1 mL, 3.83 mmol) and ethyl 2-chlorooxazole-5-carboxylate (546 mg, 3.11 mmol) in dioxane (37 mL) is added Pd(PPh3)2Cl2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl 2-vinyloxazole-5-carboxylate (470 mg). HPLC retention time=0.39 minutes (condition B); MS (m+1)=168.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.38 (t, J=7.1 Hz, 3H) 4.38 (q, J=7.2 Hz, 2H) 5.88 (d, J=11.4 Hz, 1H) 6.39 (d, J=17.7 Hz, 1H) 6.69 (dd, J=17.6, 11.2 Hz, 1H) 7.83 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](/[CH:23]=[CH:24]/[C:25]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[N:28][N:27]=2)=[N:10][N:11]=[C:12]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=1
Reactant: COc1cc(C(=O)NNC(=O)/C=C/c2nnc(-c3ccc(S(C)(=O)=O)cn3)n2-c2ccccc2Cl)ccn1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cn4)n3-c3ccccc3Cl)o2)ccn1
Reaction time: 2 h

Procedure:
N′-[(E)-3-[4-(2-chlorophenyl)-5-(5-methylsulfonyl-2-pyridyl)-1,2,4-triazol-3-yl]prop-2-enoyl]-2-methoxy-pyridine-4-carbohydrazide 10 was dissolved into dichloromethane (10 mL), and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-(methylsulfonyl)pyridine as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[S:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CN(C)C=O>[Cl:3][CH2:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[S:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(CCSc1scnc1CO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(CCSc1scnc1CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.5 mL) was mixed with N,N-dimethylformamide (15 mL) and stirred at room temperature for 30 min. The resulting solution was then transferred via syringe to a solution of 4-hydroxymethyl-5-(2-phenylsulfonylethyl)thio-1,3-thiazole (1.69 g, 5.36 mmol) in N,N-dimethylformamide (5 mL). After 2 h, the mixture was partitioned between ethyl acetate and water. The organic solution was washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to dryness, affording 1.78 g of the title compound. 1H NMR (CDCl3) δ 3.05 (2H), 3.35 (2H), 4.70 (2H), 7.50-7.85 (5H), 8.82 (s, 1H).
Reaction SMILES: C=C.[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][N+:32]([O-:34])=O)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[C:37]1(N=C=O)C=CC=C[CH:38]=1>C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:31]3[CH2:38][CH2:37][O:34][N:32]=3)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: C=C
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)CC(C2=NOCC2)c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
Ethylene was bubbled into a mixture of 76.3 (235 mg, 0.5 mmol, see Example 76) in benzene (2 mL) for 20 minutes. Phenyl isocyanate (0.22 mL, 2 mmol) and TEA (3 drops) were then added. The mixture was stirred at room temperature for 2 days. The solid was removed by filtration and washed by benzene. The filtrate was concentrated and purified by flash chromatography to give 85.1 (200 mg). MS ESI (pos.) m/e: 476 (M+H). 1HNMR (CDCl3) δ 7.37 (d, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 6.92 (m, 6H), 5.05 (dd, 2H), 4.98 (s, 2H), 4.25 (m, 2H), 4.10 (t, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.24 (dd, 1H), 2.79 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH2:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(C)c1NN
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)NNc1c(C)cccc1C

Procedure:
18 g of 2,6-dimethylphenyl-hydrazine and 14 g of triethylamine were dissolved in 150 ml of ethyl ether. Keeping the temperature at 0° C., 12.5 g of methyl chloroformate were added dropwise to the solution. Precipitation of the chlorohydrate of triethylamine was observed.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>C1COCC1>[CH3:20][O:19][CH2:18][CH2:17][NH:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([B:25]([OH:26])[OH:24])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
n-Butyllithium (2.5M in hexanes, 8.36 mL, 20.89 mmol) was added dropwise to a solution of 4-bromo-N-[2-(methoxy)ethyl]benzenesulfonamide (0.5 g, 1.72 mmol) and triisopropylborate (4.8 mL, 20.89 mmol) in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 3 h and allowed to warm up to ambient temperature, stirred at ambient temperature overnight. The mixture was quenched with water (5 mL) and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 30% 2M NH3 in MeOH/CH2Cl2 to give 400 mg (89%) of [4-({[2-(methoxy)ethyl]amino}sulfonyl)phenyl]boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.06-7.28 (m, 4H), 3.25-3.19 (m, 2H), 3.16-3.06 (m, 3H), 2.88-2.74 (m, 2H); LRMS (ESI), m/z 258 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12])[CH3:20]
Reactant: CCOC(=O)CCBr
Reactant: Nc1ccc2ccccc2c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNc1c(N)ccc2ccccc12

Procedure:
A solution of VII (11.4 g, 58 mmol) and ethyl 3-bromopropionate (7.5 mL, 58 mmol) in DMF (120 mL) was heated to 50° C. for 8 h. The reaction mixture was poured into water and neutralized with NaHCO3. The products were extracted into CH2Cl2 (2×200 mL). The combined organics were washed with water (4×200 mL) and dried over Na2SO4. The solvent was evaporated in vacuo and the products separated by flash chromatography using 27% EtOAc in hexane as the eluant to give the product VIII, 2.60 g (17%) as a brown solid: MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.64 (t, 2H), 3.09 (br t, 2H), 4.05 (br s, 1H), 4.09 (q, 2H), 5.19 (br s, 2H), 7.04 (d, 1H), 7.13 (dd, 1H), 7.33 (dd, 1H), 7.40 (d, 1H), 7.66 (d, 1H) and 7.97 (d, 1H); and the product XII, 2.06 g (13%) as a brown solid: MS m/z 259 (MH+); H NMR (DMSO-d6) d 1.21 (t, 3H), 2.63 (t, 2H), 3.43 (br m, 2H), 4.10 (q, 2H), 4.65 (br s, 1H), 4.97 (br s, 2H), 7.04 (d, 1H), 7.11-7.18 (m, 2H), 7.27 (dd, 1H), 7.62 (d, 1H), and 7.94 (d, 1H)
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:11]3[C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([CH3:1])=[N:3][N:4]=5)[C:7]=4[CH:13]=[C:12]3[CH3:14])=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Reactant: C1CNC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN2CCC2)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using azetidine (0.013 mL, 0.20 mmol, Aldrich) in the displacement, which was performed overnight (8.0 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])(=[O:13])=[O:12])[C:7]([OH:23])=[C:6]([Cl:24])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([Cl:24])[C:7]2[O:23][CH2:28][CH2:27][N:10]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:8]=2[CH:9]=1)=[O:25]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(Cl)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Product: COC(=O)c1cc(Cl)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=534.8 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 50, step 2) and 1,2-dibromoethane, yielding 8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.