Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].ClCCl>[C:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cnc2c(c1)COCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)COCCN2
Temperature: 100 °C

Procedure:
A solution of 3-Bromo-5,7,8,9-tetrahydro-6-oxa-1,9-diaza-benzocycloheptene (0.5 g, 2.2 mmol), tert-butyl acrylate (1.6 mL, 10.9 mmol) and (i-Pr)2EtN (1.1 mL, 6.5 mmol) in proprionitrile/DMF (20 mL/5 ml) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (49 mg, 0.22 mmol) and P(o-tol)3 (133 mg, 0.44 mmol) then heated to 100° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with H2O (100 ml) then extracted with dichloromethane (1×75 mL). The combined organic fractions were treated with brine (100 mL), dried Over Na2SO4 and concentrated to give a yellow residue. This was subjected to flash chromatography on silica gel using 1.3% methanol:dichloromethane. The appropriate fractions were collected and concentrated, to give a cream solid. Yield: 0.4 g (67%); 1H NMR (400 MHz, DMSO-d6) δ8.19 (d, J=2.1 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 6.87 (br s, 1H), 6.33 (d, J=16.0 Hz, 1H), 4.50 (s, 2H), 3.75-3.72 (m, 2H), 3.22-3.20 (m, 2H), 1.47 (s, 9H); ESI MS m/z 277 [C15H20N2O3+H]+
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C.CO.ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
To a stirred solution 4-[4-(1-isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile (2.5 g, 7.62 mmol) in dry diethyl ether (15 ml) at 0° C. was added dropwise a solution of LiAlH4 (1.0M solution in Et2O, 22.87 ml, 22.9 mmol). Reaction stirred at 0° C. for 30 min, then warmed up to ambient temperature overnight under a nitrogen atmosphere until complete. The reaction was cooled to 0° C., water (0.9 ml) was added dropwise followed by sodium hydroxide (2.0M, 0.9 ml) and water (2.7 ml). Dichloromethane (25 ml) and methanol (1 ml) were added and the mixture filtered through a short pad of arbocel, eluting with 2% methanol in dichloromethane (200 ml). The organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as an orange oil (2.59 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[CH:37]([N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1)([CH3:39])[CH3:38]
Reactant: CC(C)I
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline (0.075 g) in dimethyl formamide (2 ml) was added cesium carbonate (0.098 g) and 2-iodo propane (0.030 ml) and the reaction mixture heated at 60° C. for 72 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification via Prep TLC eluting with 2% methanol/1% saturated ammonium hydroxide/67% ethyl acetate/30% hexane provided the title compound (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=6.2 Hz, 2 H), 8.16 (d, J=8.7 Hz, 1 H), 8.05 (d, J=9.1 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.65 (d, J=8.7 Hz, 1 H), 7.59 (s, 1H), 7.53 (t, J=7.1 Hz, 1 H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 4.51 (m, 1H), 1.54 (d, J=6.6 Hz, 6H); MS: (M+H m/z=421.2).
Reaction SMILES: Cl.[CH:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)=[CH:3][CH2:4][CH3:5].[OH-].[Na+]>O.[Fe]>[CH:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)=[CH:3][CH2:4][CH3:5]
Reactant: CCC=COc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC=COc1ccc(N)cc1
Reaction time: 4 h

Procedure:
A 200 ml flask equipped with a mechanical stirrer, condenser, thermometer and heating mantle was charged with iron powder (26.0 g, 464 mmol) and 30 ml of water. This mixture was heated on a steam bath for 30 minutes. Concentrated hydrochloric acid (7 ml) and 4-butenyloxynitrobenzene (14.0 g, 72 mmol) were added dropwise simultaneously. After the addition was complete, the reaction mixture was stirred on a steam bath for an additional four hours. The reaction mixture was quenched by slowly adding a solution of sodium hydroxide (7.0 g, 175 mmol) in 15 ml of water and it was filtered hot. The filtrate was washed twice with 100 ml of hot benzene. The organic layers were combined, dried (MgSO4), and filtered. Solvent was removed under reduced pressure and the product was vacuum dried for three hours at 50° C. and 0.8 mm/Hg. Yield=4.0 g (34%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(#N)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:13]([NH:12][C:10](=[O:11])[O:9][CH2:7][CH3:8])=[S:14]
Reactant: Nc1nncs1
Reactant: CCOC(=O)N=C=S
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1nncs1
Temperature: 24 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 19.2 g (190 mM) of 2-amino-1,3,4-thiadiazole in 200 ml of acetonitrile were added in one portion 25 g (190 mM) of ethoxycarbonyl isothiocyanate. The reaction mixture was stirred at 24° C. for sixteen hours. The precipitate was collected by filtration, washed three times with ethyl acetate and dried to provide 35 g (80% yield) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:10]/[C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1cccc(F)c1
Temperature: 65 °C
Yield: 112 %

Procedure:
To a mixture of 3-fluorobenzaldehyde (4.0 ml, 37.7 mmol) and acetone (8.86 ml, 121 mmol) in water (10 ml), was added 0.25 M sodium hydroxide (15.08 ml, 3.77 mmol). The reaction mixture was heated at 65° C. for 2 h. The mixture was poured into ice water and extracted with ethyl acetate (200 ml). The organic layer was dried, filtered, and evaporated to give (E)-4-(3-fluorophenyl)but-3-en-2-one as yellow oil. It was used for the next reaction without purification (6.92 g, 42.1 mmol, 112% yield). 1H NMR (CDCl3/400 MHz): δ (ppm) 7.46 (d, 1H), 7.40-7.34 (m, 1H), 7.33-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.12-7.06 (m, 1H), 6.70 (d, 1H), 2.38 (s, 3H).
Reaction SMILES: [OH:1]O.[C:3]([C:5]1[C:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([O:14][C:15]1[CH:27]=[CH:26][C:18]3[C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][O:21][C:17]=3[CH:16]=1)[CH2:9][CH2:8]2)#[N:4]>FC(F)(F)C(O)C(F)(F)F.C(OCC)(=O)C>[C:3]([C:5]1[C:6]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:36])=[O:1])=[CH:33][CH:34]=2)=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([O:14][C:15]1[CH:27]=[CH:26][C:18]3[C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][O:21][C:17]=3[CH:16]=1)[CH2:9][CH2:8]2)#[N:4]
Reactant: CSc1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Reactant: OO
Solvent: CCOC(C)=O
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CS(=O)c1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous hydrogen peroxide (35%, 5 μL) is added to a solution of {(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (120 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.5 mL) at room temperature. The mixture is stirred at room temperature for 2 h and then diluted with ethyl acetate. The resulting mixture is washed with aqueous Na2S2C3 solution, 1 M aqueous HCl solution, and brine, and dried (Na2SO4). The solvent is evaporated to give the title compound. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:20])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:29]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]#[CH:39])[CH2:30][CH2:31][CH3:32].O.Cl>C(N(CC)CC)C.C1COCC1.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.[Cu]I>[CH2:29]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]#[C:39][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH2:29][CH2:30][CH2:31][CH3:32])[C:7]=2[Cl:20])[C:2]=1[Cl:1])[CH2:30][CH2:31][CH3:32]
Reactant: O=S(=O)(Oc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1Cl)C(F)(F)F
Reactant: C#Cc1sccc1CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccsc1C#Cc1ccc2c(Cl)c(C#Cc3sccc3CCCC)ccc2c1Cl
Yield: 32.7 %

Procedure:
1.46 g (2.96 mmol) of [1,5-dichloro-6-(trifluoromethylsulfonyloxy)-2-naphthyl]trifluoro-methanesulfonate (17) and 1.46 g (8.89 mmol) of 3-butyl-2-ethynylthiophene (18) are dissolved in 1.25 ml of dry triethylamine and 30 ml of dry THF. To the reaction mixture are added 208 mg (0.30 mmol) of Pd(PPh3)2Cl2 and 113 mg (0.59 mmol) of copper(I) iodide. The mixture is heated under reflux for 20 h. 3 ml of water and 3 ml of 1N HCl solution are added thereto, the phases are separated and the aqueous phase is extracted three times with 25 ml of DCM. The combined organic phases are dried over sodium sulfate. After the solvents have been distilled off, the residue is recrystallized from hexane/chloroform to obtain 505 mg (33%) of product. 1H NMR (CDCl3): 8.22 ppm (d, 2H), 7.68 (d, 2H), 7.27 (d, 2H), 6.94 (d, 2H), 2.88 (dd, 4H), 1.70 (m, 4H), 1.42 (qa, 4H), 0.96 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CC#N.CO>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[C:3]=1[Br:36]
Reactant: Nc1cc(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CO
Product: Nc1c(Br)c(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Reaction time: 1 h

Procedure:
To a solution of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (17 mg, 0.033 mmol) in a 2:1 mixture of CH3CN/MeOH (1.0 mL) was added NBS (6.2 mg, 0.033 mmol). The mixture was stirred at it for 1 h then concentrated in vacuo. The residue was purified by prep-LC to afford the title compound. LC/MS RT=3.27 min. Mass calculated for, M+H 453.07, observed 453.07
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)(CC)C>[F:16][C:17]([F:26])([F:27])[O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc2c(Cl)ncnc2c1
Solvent: CCC(C)O
Product: COC(=O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of methyl 4-chloroquinazoline-7-carboxylate (610 mg, 2.75 mmol) in sec-BuOH (5 mL) was added 4-trifluoromethoxyaniline (535.5 mg, 3.02 mmol) at room temperature. The mixture was heated at 100° C. and stirred for 2 h. The solvent was evaporated and the compound was crystallized from CHCl3 and Et2O mixture (3:1). The white crystals were collected by filtration and washed with Et2O. (890 mg, 91% Yield). MS m/z 364.10 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:17]=[CH:16][N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:15]1[CH:16]=[CH:17][C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)=[CH:14]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cc(=O)oc3cc(Br)ccc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2cc[nH]c2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the silyl compound from Step 1 (42 mg, 0.094 mmol) in THF (1 mL) was added Bu4NF 1M in THF (94 (L, 0.094 mmol) and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[C:29]([C:35]([NH:37][CH3:38])=[O:36])=[N:30][C:31](Br)=[CH:32][N:33]=1>>[NH2:27][C:28]1[C:29]([C:35]([NH:37][CH3:38])=[O:36])=[N:30][C:31]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([S:9]([NH:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])[CH:13]=2)=[CH:32][N:33]=1
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)NCc3ccccc3)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)cnc1N
Product: CNC(=O)c1nc(-c2cccc(S(=O)(=O)NCc3ccccc3)c2)cnc1N
Yield: 20 %

Procedure:
3-Amino-N-methyl-6-(3-{[(phenylmethyl)amino]sulfonyl}phenyl)pyrazine-2-carboxamide was synthesized from N-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide as yellow solid. Yield 20%. 1H NMR (400 MHz, d6-DMSO): 8.84 (s, 1H), 8.80 (m, 1H), 8.46 (d, 1H), 8.38 (br s, 1H), 8.20 (t, 1H), 7.78 (d, 1H), 7.66 (t, 1H), 7.26 (m, 4H), 7.18 (m, 1H), 4.02 (d, 2H), 2.82 (d, 3H); MS (EI) for C19H19N5O3S: 398 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:16])[C:12](Br)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+]>[Cu]I.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:16])[C:12]([C:21]([F:26])([F:25])[F:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 1.50 g (4.66 mmol) of 3-benzyloxy-6-bromo-2-nitrotoluene, 6.33 g (46.6 mmol) of sodium trifluoroacetate, 4.43 g (23.3 mmol) of copper (I) iodide and 80 ml of N-methylpyrrolidone was heated at 160° C. for 7 hours while stirring. Next, the solvent was distilled off under reduced pressure and ethyl acetate was added to the resulting residue. Insoluble matters were then filtered off. The filtrate was washed twice with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.70 (48.3%) of 3-benzyloxy-6-trifluoromethyl-2-nitrotoluene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.Cl.[CH3:10][NH:11][O:12][CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of thiophene-2-carboxylic acid (2 g, 15.6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.6 mmol), EDCI (3.1 g, 15.6 mmol), HOBT (2.4 g, 15.6 mmol), Et3N (6.5 mL, 46.8 mmol) in DCM (30 mL) was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified by column to give N-methoxy-N-methylthiophene-2-carboxamide (1.8 g, yield 67%) as an oil.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=[O:26])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[Si]([N:38]=C=O)(C)C.CO>C(OCC)(=O)C>[C:25]([N:22]1[CH2:23][CH2:24][C@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:20]([O:32][CH3:33])[CH2:21]1)(=[O:26])[NH2:38]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (30 ml, 120 mmol) was added to a solution of tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (103a) in ethyl acetate (10 mL). The mixture was stirred for 45 minutes and the solvent was evaporated under reduced pressure. The residue was diluted with dichloromethane, washed with a 1 N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Trimethylsilyl isocyanate (0.86 g, 7.5 mmol) was added to the resulting residue, and the mixture was stirred at room temperature for 15 hours. Methanol (1 mL) was added, followed by stirring for 30 minutes. The precipitated solid was filtered off and washed with dichloromethane to obtain 1.44 g of the title compound as a colorless solid (81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][Cl:20]>CC(=O)CC.CCOC(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:18][CH2:19][Cl:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
To a mixture of 3-nitrophenol (5.0 g, 36 mmol) and K2CO3 (7.45 g, 54 mmol), in 2-butanone at 85° C. was added 1-bromo-2-chloroethane (1.7 mL, 71.9 mmol) and the reaction stirred for 24 h. The mixture was cooled to rt and reduced in vacuo. The crude was diluted with EtOAc (200 mL) and water (200 mL) and separated. The aqueous layer was extracted twice with EtOAc (200 mL), the organics were pooled, dried over MgSO4 and reduced in vacuo onto silica gel. Purification was achieved via column chromatography using a gradient of EtOAc/Hexanes to afford a yellow oil that solidified upon standing to afford 4.22 g (58% yield) of titled product as an off-white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.8 (m, 1H), 7.7 (t, J=2.4 Hz, 1H), 7.6 (t, J=8.2 Hz, 1H) 7.4 (dd, J=8.2, 2.6 Hz, 1H), 4.4 (m, 2H), 4.0 (m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[NH:12][C:13](=[O:18])/[CH:14]=[C:15](\Cl)/[CH3:16])(=[O:8])[CH2:5][CH2:6][CH3:7]>CO>[C:4]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[NH:12][C:13](=[O:18])/[CH:14]=[C:15](\[O:2][CH3:1])/[CH3:16])(=[O:8])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)c1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
5.4 g of sodium methylate were added with stirring to a mixture of 26.5 g of m-butyryl-3-chlorocrotonanilide and 250 ml of methanol and after stirring for 4 hours at 20° C, the mixture was vacuum filtered to remove sodium chloride. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 7-3 mixture of benzene and ethyl acetate yielded 14 g of m-butyryl-3-methoxy-crotonanilide melting at 81° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(Oc3ccccc3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1c[nH]c2ncc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide from Step 3 in dichloromethane (0.7 mL) was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was stirred with THF (1 mL), water (0.5 mL), and Et3N (0.5 mL) for 2 h then concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by SiO2 column chromatography (0% to 80% EtOAc/hexanes) then triturated with Et2O to provide 0.022 g (22%, 2 steps) of 2-phenoxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide as a white solid. MS: (M+H)+=337; mp=255.0-257.0.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(Cl)Cl.CCOCC>[C:22]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C@@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC1CCCCC2CCC(C(=O)O)N2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: O=C(N[C@H]1CCCC[C@H]2CC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 6-amino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 19, (181 mg, 0.8 mmol) in H2O/CH2Cl2 (7 mL) is treated with sodium bicarbonate (0.50 g, 6 mmol) and benzoyl chloride (140 mg, 1.0 mmol). The reaction is stirred for 18 hours then diluted with ether (100 mL). The organic layer is washed twice with 1 N HCl, once with water, and dried over MgSO4, filtered, and concentrated under in vacuo to afford a residue which is purified over silica to afford the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:14]=1C(O)=O>>[Cl:12][C:13]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:14]=1[C:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=2[N:5]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)c(Cl)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 253-255° C.; MS m/e 262 (M+H)+.