Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.Cl.[CH3:13][NH:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]([CH3:15])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cc1Cl
Yield: 101.1 %

Procedure:
A solution of 3-chloro-4-fluoronitrobenzene (3.0 g, 17.1 mmol), dimethylamine hydrochloride (1.53 g, 18.8 mmol) and K2CO3 (4.96 g, 35.9 mmol) in Me2SO (20 mL) was heated in a sealed tube at 105° C. for 18 h. On cooling the reaction mixture was poured into water (200 mL) and extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated to give 3.47 g of 3-chloro-4-(dimethylamino) nitrobenzene as a yellow solid. An aliquot of this (3.4 g, 16.95 mmol) was dissolved in 20 mL of EtOH/AcOH (1:1, v/v) with warming. Iron powder (−325 mesh, 9.5 g, 170 mmol) was added in small portions. The mixture was then heated on a steam bath for 30 min. The mixture was cooled, filtered through a pad of celite and the filtrate was evaporated to give 3.33 g of 3-chloro-4-(dimethylamino)aniline as a dark solid. A solution of this compound in EtOH (10 mL) was treated with HNO3 (69% aq, 2.6 mL, 40.6 mmol) dropwise, followed by cyanamide (50% solution in water, 5.3 mL, 67.78 mmol). After heating for 18 h at reflux the reaction mixture was cooled to room temperature, poured into Et2O (100 ml) and basified with NaOH solution (2 N, 100 mL). The ethereal layer was separated. The aqueous phase was extracted with Et2O. The combined organic phases were washed with brine, dried on MgSO4, filtered, and evaporated to give a black oil, which solidified on standing to afford 1.6 g of the title compound. RP-HPLC: tR=12.7 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (CD3OD) δ: 2.68 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.75 (s, 6H, CH3), 7.05 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=8.8 Hz, pyrimidinyl-H), 7.49 (dd, 1H, J=8.8, 2.4 Hz, Ph-H), 7.94 (d, 1H, J=2.4 Hz, Ph-H), 8.43 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z=393 [M+Na] (C17H18N6O2S requires 370.4).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH:9]=[C:8]([CH2:10][S:11]C(=O)C2C=CC=CC=2)[CH:7]=[N:6]1.[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34](OS(C)(=O)=O)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1>C1COCC1.CN(C=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:43])=[C:34]([S:11][CH2:10][C:8]4[CH:7]=[N:6][N:5]([CH3:4])[CH:9]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reactant: Cn1cc(CSC(=O)c2ccccc2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(CSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(N)n4)[C@H]3SC2)cn1
Temperature: -65 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Under nitrogen atmosphere, 1.35 ml of sodium methoxide (6.5 m mol) was added slowly to a solution of 1.50 g of 1-methyl-4-benzoylthiomethylpyrazole (6.5 m mol) in THF (6 ml) and DMF (18 ml) at 0° C. Stirring was continued for 1 hour. The mixture was cooled to −65° C. with dry ice/ethanol bath, and added to a solution of 4.36 g of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylate (5 m mol) in a mixture of THF (15 ml) and DMF (25 ml) at the same temperature. After stirring for 1 hour, the reaction was quenched with 10% hydrochloric acid, and the mixture was poured into water-ethyl acetate. The organic layer was separated washed with brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford a diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1-methylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (2.15 g).
Reaction SMILES: [H-].[Na+].[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6](=[O:16])[CH:5]=[CH:4]1.[CH3:17]I>CCCCCC.CN(C)C=O>[CH3:17][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[S:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]1=2
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2sccc(=O)c21
Reaction time: 3 h

Procedure:
Sodium hydride (2.3 g of 50% suspension in mineral oil, 0.05 mole) is washed with hexane and suspended in 25 ml of dimethylformamide (DMF). Thiopyrano [3,2-b]indol-4(5H)-one, 10.0 g (0.05 mole) in 130 ml of DMF is added and the mixture stirred for 3 hours. Methyl iodide (14.2 g, 0.1 mole) is added and the mixture stirred for 3 hours and then poured over ice. The white precipitate is filtered, dried and recrystallized from hexane to give 9.3 g of product, mp 113°-114° C.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[Si](C)(C)[O:46][CH2:47][CH2:48]O[Si](C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]2([O:46][CH2:47][CH2:48][O:34]2)[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](COCc2ccccc2)C1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (2.5 mL) was added dropwise to a 0° C. solution of (4R)-4-benzyl-3-({(1R,2R)-2-[(benzyloxy)methyl]-4-oxocyclohexyl}carbonyl)-1,3-oxazolidin-2-one (57.89 g, 138 mmol) and 1,2-bis-(trimethylsilyloxy)ethane (35.4 g, 172 mmol) in CH2Cl2 (400 mL) followed by stirring at rt for 4 h. Triethylamine (3 mL) was then added at 0° C. and the mixture was washed with saturated aqueous NaHCO3 solution and dried over Na2SO4. Concentration in vacuo gave (4R)-4-benzyl-3-({(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}carbonyl)-1,3-oxazolidin-2-one as a thick, tan colored syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36-7.22 (10H, m), 4.48 (1H, m), 4.42 (2H, s), 4.11 (1H, dd, J= 3.1, 8.9 Hz), 3.97 (4H, m), 3.94-3.90 (1H, t, J= 9.0 Hz), 3.67 (1H, m), 3.44-3.38 (2H, m), 3.09 (1H, dd, J= 3.3, 13.5 Hz), 2.92 (1H, dd, J= 8.3, 13.5 Hz), 2.52 (1H, m), 1.97 (1H, m), 1.86-1.76 (3H, m), 1.57-1.50 (1H, m), 1.44 (1H, t, J= 12.8 Hz).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH3:11].II.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>C(OCC)C.C1COCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:26])[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:21][C:20]1=[O:25])[CH3:11]
Reactant: CCOc1ccccc1Br
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 g (1.65 mol) of magnesium chips and 5% of the total amount of the 2-bromo-1-ethoxy benzene were added to 100 ml diethyl ether and after adding a few crystals iodine the mixture was carefully heated to initiate the reaction. To the refluxing mixture the remaining amount of 203 ml (1.65 mol) 2-bromo-1-ethoxy benzene, dissolved in 450 ml diethyl ether, was added slowly to maintain the reaction. Then 75 g (0.41 mol) of 5-methoxyisatine, suspended in 750 ml THF, were added to the cooled reaction mixture. After stirring the reaction mixture for 30 minutes at ambient temperature, the mixture was poured into an ice/aqueous NH4Cl mixture. The aqueous phase was extracted with ethyl acetate several times and the combined organic phase was washed with H2O, dried over magnesium sulfate and the solvent was removed in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].BrCC[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH2:2][CH2:24][C:25]#[N:26])=[CH:9][CH:8]=1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCCCC#N)cc1
Temperature: 80 °C
Yield: 56.7 %

Procedure:
To a solution of Step 1 intermediate, Intermediate 10 (350 mg, 1.355 mmol) in DMF (10 ml) was added 4-bromobutyronitrile (280 mg, 1.897 mmol) at room temperature followed by K2CO3 (560 mg, 4.065 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography to afford 250 mg the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 3.80-3.85 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 4.00 g (0.029 mol) of glycine ethyl ester hydrochloride in 40 mL of chloroform and 7.0 mL of pyridine was added 5.58 g (0.029 mol) of 4-fluorobenzenesulfonyl chloride and the reaction was stirred at room temperature for 15 h. The reaction mixture was then washed with water and 5% HCl solution and the organics were dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether/hexanes (1:1) and dried in vacuo to provide 4.72 g (63%) of the sulfonamide as a white solid. Electrospray Mass Spec 261.8 (M+H)+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(OC(F)(F)F)cc3)(CC1)CC2
Yield: 37.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.3 mg) and 4-trifluoromethoxyaniline (60.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-trifluoromethoxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.2 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].C(N(CC)CC)C>C1COCC1.[Cu]I.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>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cccc(I)c1NC(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C#C[Si](C)(C)C)c1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
To tert-butyl 2-iodo-6-methoxyphenylcarbamate (10.36 g, 29.67 mmol), ethynyltrimethylsilane (3.20 g, 32.63 mmol), copper(I) iodide (0.28 g, 1.48 mmol), and PdCl2(PPh3)2 (1.04 g, 1.48 mmol) in THF (100 mL) was added triethylamine (3.60 g, 35.6 mmol), followed by overnight stirring. The crude reaction was then concentrated and the mixture was flashed through silica gel with 10:1 Hex/EtOAc to give the desired product (98%).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])=O.Cl.S(=O)=O>>[C:1]([Cl:17])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Product: CCCCCCCCCCCC(=O)Cl
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a stirred mass of lauric acid (200 g, 0.999 gmol) and sodium N-lauroyl, N-methyl taurate (0.6 g, 0.0017 gmol) at 25° C. under nitrogen blanket, thionyl chloride (123 g, 1.03 gmol) was added slowly at 25° C. and atmospheric pressure over a period of 2 hours maintaining temperature below 25° C. The hydrochloric acid and sulfur dioxide generated during the process was continuously scrubbed in a gas scrubber containing caustic lye. The reaction mixture was stirred for additional 4 hours at the reaction temperature. The progress of reaction in the last phase was monitored by measuring alkanoyl chloride formation. Nitrogen gas was purged through the reaction mass for 3 hours to remove the residual traces of sulfur dioxide, hydrogen chloride gas and unreacted thionyl chloride. At the end of this procedure lauroyl chloride (212 g, 97%) was obtained as practically colorless product. The detailed analysis is given in the Table 13.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: CCOC(=O)CBr
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-bromoisatin and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained as a yellow solid (68%): 1H NMR (300 MHz, CDCl3) δ 7.39 (t, 1H), 7.27(dd, 1H), 6.71 (dd, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 312 (M+1), 314 (M+1), 334 (M+23) 336 (M+23).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][OH:34])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:38])([F:37])[F:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:30]=2)[NH:25][C:24]=1[C:35]([F:37])([F:36])[F:38])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)c1c(C(F)(F)F)[nH]c2ccc(CCO)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccc2[nH]c(C(F)(F)F)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 1.15 mmol, 1 eq) and triethylamine (0.32 mL, 2.30 mmol, 2 eq) were added to 5-(2-hydroxy-ethyl)-2-trifluoromethyl-1H-indole-3-carboxylic acid benzyl ester (420 mg, 1.15 mmol, 1 eq) obtained from previous step in THF (50 mL) solution in 100-mL round bottom flask at room temperature. The reaction mixture was stirred at room temperature for 3 hours (followed by TLC). After the solvent was removed, the residue was dissolved in ethyl acetate (100 mL), and then washed with sat NaHCO4 and brine respectively. The organic layer was dried over MgSO4, and concentrated to give a pale brown solid. The crude was carried over to the next step.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=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>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1cnc(C)c(Cl)n1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(C)cnc2C)c(OC)c1
Temperature: 75 °C

Procedure:
A mixture of 3-chloro-2,5-dimethyl-pyrazine (283 mg, 2.0 mmol), 2,4-dimethoxyphenylboronic acid (455 mg, 2.5 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in DME (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 75° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, and washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (25% ethyl acetate in hexanes) yields 3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazine as an oil MS: 245.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][S-:24].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:24][CH3:23])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cncc(Br)c2)c(SC)s1

Procedure:
The procedure described in Example 27: step a was followed using 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide (1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried Na2SO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography SiO2 (30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+1) found: 408.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:10]([I:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Clc1cc2ccccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Clc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-pyrazolo[1,5-a]pyridine (0.500 g, 3.28 mmol) in acetonitrile (16.4 mL) was added N-iodosuccinimide (0.885 g, 3.93 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound. LCMS m/z 278.72 [M+H]+, 280.64 [M+2+H]+, 1H NMR (500 MHz, CDCl3) 8.35 (d, J=6.8 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1H), 7.24 (d, J=8.6 Hz, 1 H), 6.84-6.81 (m, 1 H).
Reaction SMILES: C1(N(C[CH2:22][C:23]2[CH:28]=CC=CC=2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCCC1.C(=O)CC(C)C.C1([C@H]2CC[C@H](NCOC)CC2)CC1.[CH3:48][O:49][CH2:50][CH:51]1[CH2:56][CH2:55][CH:54]([N:57]([CH2:71][CH2:72][CH:73]([CH3:75])[CH3:74])[C:58](=[O:70])[NH:59][C:60]2[S:61][C:62]([S:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:63][N:64]=2)[CH2:53][CH2:52]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:48][O:49][CH2:50][C@H:51]2[CH2:56][CH2:55][C@H:54]([N:57]([CH2:71][CH2:72][CH:73]([CH3:75])[CH3:74])[C:58](=[O:70])[NH:59][C:60]3[S:61][C:62]([S:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:63][N:64]=3)[CH2:53][CH2:52]2)[CH2:23][CH2:22]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: COCC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COCN[C@H]1CC[C@H](C2CC2)CC1
Product: CC(C)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](COCC2CC2)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-cyclopropyl-methoxymethyl-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH:1]([N:4]1[C:5](=[O:17])[CH:6]=[CH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:9]1)([CH3:3])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)n1cc(C2CCC(=O)CC2)ccc1=O
Product: CC(C)n1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-isopropyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of aniline (178 mg, 1.9 mmol) in 20 mL CH2Cl2 at room temperature was added NaOH (76.2 mg, 2.9 mmol) in 6 mL water. This mixture was stirred vigorously for 5 minutes after which 3-chlorobenzoyl chloride (500 mg, 2.9 mmol) was added drop-wise while stirring over a period of 30 minutes. This reaction mixture was stirred for an additional 2 hours followed by an acid work-up and extraction with CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4. The product was purified via column chromatography on silica gel and eluted with a CHCl3/MeOH/Et3N (9.8:0.1:0.1) to give white crystals in 81% yield.