Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[I:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26]Br>>[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][N:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:3]([I:2])=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: Ic1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: COC(=O)CCBr
Agent: Cl
Product: COC(=O)CCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Yield: 91 %

Procedure:
The title compound (280 mg, 91%) was prepared from the compound from Example 14 (300 mg, 0.66 mmol) and 3-bromo-propionic acid methyl ester (153 mg, 0.92 mmol) by the procedure described step 1 of Example 1 MS (ESI) m/z 467 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.56 (t, J=7.2 Hz, 2H), 2.64 (t, J=4.8 Hz, 4H), 2.75 (t, J=7.2 Hz, 2H), 3.15 (t, J=4.8 Hz, 4H), 3.69 (s, 3H), 6.70 (dd, J=0.8, 8.8 Hz, 2H), 6.92 (m, 4H), 7.56 (dd, J=0.8, 8.4 Hz, 2H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=[O:4])=[O:3].S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([Cl:17])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1

Procedure:
3-(Chlorosulfonyl)-4-fluorobenzoic acid (1, 2.50 g, 10.5 mmol), thionyl chloride (10 mL) and DMF (1 drop) were heated at 90° C. for 1 hour and then the mixture evaporated to dryness. The material was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].CN(C)C1C=CC=CC=1.[C:32](Cl)(=[O:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:33](=[O:34])[C:32]1=[O:36]
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-amino3-(2,4-dichlorobenzylamino)benzoate (1.53 g) and dimethylaniline (0.71 g) in toluene was added oxalyl dichloride (0.51 ml). After stirring at room temperature for 1.5 hr, ice was added to the reaction mixture. The toluene layer was separated and washed with 6N hydrochloric acid. The toluene layer was concentrated, and the residue was washed with methyl t-butyl ether and dried to give the object compound (1.03 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[C:7](I)[CH:6]=1)=[O:4].[Br-].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([Zn+])=[N:24][CH:25]=1>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[C:7]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[CH:6]=1)=[O:4]
Reactant: Cc1ccc([Zn+])nc1
Reactant: COC(=O)c1cc(I)c2cnn(C(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-iodo-1-isopropyl-1H-indazole-6-carboxylic acid methyl ester (1.13 g, 3.28 mmol) in THF (30 mL) was added Pd(PPh3)4 (0.2 g, 0.164 mmol), followed by 5-methyl-pyridinyl zinc bromide ((19.7 mL of 0.5M solution in THF, 9.86 mmol). The reaction mixture was stirred overnight at room temperature, then quenched by addition of saturated aqueous NH4Cl solution. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave 0.5 g (50%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[N+:16]=[N-:17].C[O-].[Na+]>CO>[NH2:14][C:13]1[N:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[N:16]=[N:17][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1[F:1]
Reactant: N#CCc1ccc(C(F)(F)F)cc1F
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(C(F)(F)F)cc2F)nnn1-c1ccc(S(N)(=O)=O)cc1
Yield: 99 %

Procedure:
To a stirred and ice-cooled solution of 2-fluoro-4-(trifluoromethyl)phenyl acetonitrile (1.066 g, 5.2471 mmol) and 4-azido-benzenesulfonamide (0.800 g, 4.0362 mmol) in methanol (50 ml), sodium methoxide (0.3271 g, 6.0543 mmol) is added portion wise and the mixture is allowed to attain room temperature spontaneously and stirred for additional 24 hours at this temperature. The reaction mixture is concentrated, water (10 ml) is added and extracted with ethyl acetate (3×80 ml). The combined organic layers are washed with brine (15 ml), dried over MgSO4, filtered and concentrated to afford an off-white solid (1.61 g, ˜99% yield, 97.7% pure at HPLC). M.p. 183.8-185.2° C. LC-ESI-HRMS of [M+H]+ shows 402.0638 Da. Calc. 402.064783 Da, dev. −2.4 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[C:8]([CH3:10])=[CH2:9].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: C=C(C)c1nc(N)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)c1nc(N)ccc1F
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from last step, 4.45 mmol) in methanol (13.5 mL) was added 10% palladium on carbon (95 mg) at room temperature. A hydrogen balloon (1 atm) was attached and the mixture was stirred overnight. After 18 h, the mixture was filtered over Celite, concentrated on to silica gel, and chromatographed (10% to 40% EtOAc in hexanes) to give 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 69% over two steps). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.12 (t, J=9.2 Hz, 1H), 6.30 (dd, J=8.5, 3.0 Hz, 1H), 4.31 (br. s, 2H), 4.15 (m, 1H), 1.26 (d, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2](Br)([CH3:17])[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:1][CH:2]([CH3:17])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)CN2CCN(c3ccncc3)CC2)cc1

Procedure:
A stirred mixture of methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (3.15 g), and 1-(4-pyridyl)piperazine (3.26 g) in acetonitrile (200 ml) was heated at reflux temperature for 4 days. The solvent was removed in vacuo and the residue partioned between dichloromethane/water. The organic phase was dried (MgSO4), evaporated and then purified by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane. Further purification by flash chromatography on neutral alumina, eluting with dichloromethane, gave the title compound, 350 mg, as a clear oil: NMR (d6DMSO) δ 8.12 (2H, d), 7.98 (2H, d), 7.Q4 (2H, d), 6.75 (2H, d), 4.92 (2H, s), 3.86 (1H,m), 3.71 (3H, s), 3.19 (4H, t), 2.70 (1H, q), 2.49 (DMSO+4H), 2.36 (1H, q), 1.09 (3H, s), trace of dichloromethane; m/e 398 (M+H)+ ; calculated for C22 H27N3O4.0.1 CH2Cl2 : C, 65.3; H, 6.7; N, 10.3. found: C, 65.1; H, 6.9; N, 10.1%.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=NO)[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11].Cl>O.CO>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=[O:2])[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphite (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ (CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (644 mg, 1.33 mmol, 72%) was obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])=O)(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.CO[C:31](=[O:42])[C@@H:32]([CH3:41])[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([N:33]1[C@H:32]([CH3:41])[C:31](=[O:42])[NH:8][C@@H:9]([CH3:10])[C:11]1=[O:12])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@@H](C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 0.98 g portion of N-tert-butoxycarbonyl-L-alanine was added to 50 ml of 0° C.-cooled dichloromethane solution containing 1.07 g of DCC, and the mixture was stirred for 5 minutes. This solution was mixed with 10 ml of dichloromethane solution containing 1.0 g of N-benzyl-D-alanine methyl ester and stirred at room temperature for 2 days. White precipitate was separated by filtration and washed with diethyl ether and then the filtrate was concentrated. The residue was dried under reduced pressure, dissolved with 30 ml of dichloromethane, cooled to 0° C., mixed with 5 ml of trifluoroacetic acid and then stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was subjected to a silica gel column chromatography and purified with n-hexane-ethyl acetate (1:5, v/v) to obtain 1.0 g of the title compound as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide (0.9 g, 3.6 mmol) in ethanol (23 mL) was added an aq. solution of 20% aq. sodium hydroxide (4.5 mL) and the mixture was heated to reflux for one hour. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvents were evaporated. The reaction mixture was then diluted with water (50 mL), extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulphate and concentrated to dryness to get the title compound as yellow solid (0.67 g, 95.54%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1.[C:23](O)(=[O:26])[CH:24]=[CH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)[CH2:4]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](N)C2)n1
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(NC(=O)OC(C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of 114c (1.39 g, 4.22 mmol), acrylic acid (0.3 mL, 4.5 mmol), HATU (1.7 g, 4.5 mmol) and DIPEA (3.8 mL, 9 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 6-(3-acrylamidopiperidin-1-yl)pyridin-2-ylcarbamate 114d (880 mg, 60%) as brown oil. The material was used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])=[O:5].[C:22](Cl)(=O)[C:23](Cl)=[O:24].NC(N)=O.Cl>ClCCCl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([N:6]1[C:23](=[O:24])[CH2:22][N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:7]1=[O:8])=[O:5]
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: NC(N)=O
Solvent: ClCCCl
Product: O=C1CN(c2ccc(Cl)cc2)C(=O)N1C(=O)c1c(Cl)cccc1Cl

Procedure:
10.3 g of N-(2,6-dichlorobenzoyl)-N'-(p-chlorophenyl)-urea are boiled in 100 ml of dry 1,2-dichloroethane containing 3 ml of oxalylchloride for 24 hours. The urea dissolves with the evolution of hydrochloric acid. After concentration by evaporation and after the addition of 25 ml of ligroin the residue becomes crystalline. The substance mauy be recrystallized from 30 mls of benzene. Melting point 157° C. Yield 8 g.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[C:37]([CH:38]=O)=[CH:36][NH:35][N:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[C:33]([CH3:32])=[N:34][NH:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1n[nH]cc1C=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]nc4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 3-methyl-1H-pyrazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12.C(OC(=O)C)(=[O:21])C>>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][NH:15][C:14](=[O:21])[CH:13]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccc3nccn3c2)cc1
Product: O=c1cc(OCc2ccc3nccn3c2)cc[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
4-(Imidazo[1,2-a]pyridin-6-ylmethoxy)pyridine 1-oxide (1.69 g, 7.04 mmol) was heated at 140° C. in acetic anhydride (20 mL) for 4 h. The mixture was concentrated and heated at 80° C. for 3 h in a mixture of 1:1 MeOH/H2O (50 mL). The resulting solution was concentrated. The residue was partially dissolved in iPrOH (75 mL). Et2O (200 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration, washed with Et2O and dried under reduced pressure. The solids were again subjected to iPrOH and Et2O, and the solids were removed by filtration. The filtrate was concentrated to afford the title compound (0.47 g, 28%) as a dark brown solid: 1H NMR (300 MHz, CD3OD) δ 8.60 (d, J=0.7 Hz, 1H), 7.87 (d, J=0.6 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.57 (s, 1H), 7.40-7.27 (m, 2H), 6.18 (dd, J=7.3, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.13 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: CSc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)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: COCCOC
Solvent: O
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na2CO3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4 (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50° C. to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: CCC[CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\CCCC(O)=O)[C@@H:12](O)[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:25][C:6]1[CH:5]=[CH:4][C:9]([C:10](=[O:24])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.291 ml. of triethylamine, 0.275 ml. of isobutylchloroformate, and 0.594 g. of p-hydroxybenzophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1). The residue obtained by concentration of selected fractions, 0.492 g., is crystallized from ethyl acetate diluted with three volumes of hexane as the title compound, white free-flowing crystals, m.p. 73.8°-75.8° C., having Rf 0.5 (TLC on silica gel in ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][S:8]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>C(#N)C>[CH3:20][N:21]([CH3:26])[S:22]([N:13]1[CH:14]=[N:15][C:11]([S:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:4][CH:5]=2)(=[O:10])=[O:9])=[N:12]1)(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2ccc(C(F)(F)F)cc2)n1
Yield: 86.4 %

Procedure:
1.0 g of 3-(4-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 3 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate anhydride was added, and 0.59 g of dimethylsulfamoyl chloride was gradually added at room temperature while stirring the solution. The solution was then refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.18 g of the titled compound was obtained.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:20])=[O:19])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Orcinol monohydrate (1.42 g, 10 mmol) and 2-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. The reaction mixture was quenched with 50 mL of water and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (2% ethyl acetate in methylene chloride) to give the title compound as a pale-yellow liquid (2.15 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3 H), 5.24 (s, 1 H), 6.43 (s, 1 H), 6.52 (s, 2H), 7.38 (m, 1 H), 7.60 (m, 2 H), and 7.96 (dd, 1 H, J=0.6, 3.9 Hz).