Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[C:16]([NH-:18])#[N:17]>C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[NH2:17][C:16]([NH2:4])=[NH:18]
Reactant: N#C[NH-]
Agent: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)N

Procedure:
Referencing scheme 1 below, the synthesis begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, 3-acetylpyridine (3) is first reacted with phenyl chloroformate at nitrogen position and then regioselectively alkylated using Grignard reagents and catalytic amounts of copper (I) iodide to obtain intermediate dihydropyridine. The dihydropyridine was further deprotected to obtain 3-acetyl-4-methyl-pyridine(4) (Tanis et al., 1996). Product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(4-methyl-pyridyl)-2-propene-1-one (5). Nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(4-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-4-methyl-pyridyl)-2-pyrimidine-amine (7). The first WBZ1 synthesis consists of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(4-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords the Gleevec analog WBZ1 (PCT publication WO2004108699).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([C@:22]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl>O>[P:25]([OH:27])([OH:28])([O:24][CH2:23][C@:22]([NH2:30])([C@@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]3)[CH:13]=2)[CH2:18]1)[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)[C@@H]1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@@](C)(N)COP(=O)(O)O)C3)CC1

Procedure:
tert-Butyl (R)-2-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-1-(phosphonooxy)propan-2-ylcarbamate (38.4 mg, 0.0000712 mol) was dissolved in acetic acid (2.2 mL, 0.039 mol) and 10 M hydrogen chloride in water (0.6 mL) was added and the mixture was stirred for Id. Lyophilizing gave (R)-2-amino-2-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)propyl dihydrogen phosphate as a white solid (16.4 mg, 52%). LCMS: Rf=1.57 min 214 nm (440.22, [M+1]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.03 (d, J=8.3 Hz, 1H), 6.70 (d, J=10.9 Hz, 1H), 6.66 (s, 1H), 4.26 (dd, J=5.3, 11.1 Hz, 1H), 4.18-4.09 (m, 1H), 4.06 (dd, J=4.2, 11.0 Hz, 1H), 2.98-2.64 (m, 4H), 2.27-2.14 (m, 3H), 2.05 (d, J=10.2 Hz, 1H), 1.89 (d, J=12.3 Hz, 2H), 1.62-1.42 (m, 1H), 1.32 (s, 3H), 1.32-1.29 (m, 1H), 1.28-1.02 (m, 3H), 0.92 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd]>[N:16]1([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCCC(N3CCOCC3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC(N3CCOCC3)C2)cc1
Yield: 99.5 %

Procedure:
4-[1-(4-Nitro-phenyl)-piperidin-3-yl]-morpholine (1.30 g, 4.46 mmol) was dissolved in Ethanol (35.0 mL, 599 mmol) and the solution was carefully added to 10% Palladium on Carbon (0.500 g, 37.5 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.16 g of 4-(3-Morpholin-4-yl-piperidin-1-yl)-phenylamine without further purification. (M+H)=262.7. 1H NMR (400 MHz, DMSO, d6) δ 6.67 (d, 2H, J=8.72 Hz), 6.47 (d, 2H, J=10.09 Hz), 4.54 (s, 2H), 3.55 (m, 4H), 3.41 (m, 1H), 3.22 (m, 1H), 2.51 (m, 4H), 2.40 (m, 3H), 1.86 (m, 1H), 1.76 (m, 1H), 1.56 (m, 1H), 1.18 (m, 1H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.Br[CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]([S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)[CH2:23][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrC(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SC(Cc3ccccc3)c3ccccc3)nc1-2
Yield: 41 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 1-bromo-1,2-diphenylethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 41%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])([O-:3])=[O:2].B1([O-])O[O:19]1.O.O.O.O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][C:9]=1[C:10]([OH:19])=[O:11])([O-:3])=[O:2]
Reactant: [O-]B1OO1
Reactant: O=Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.3 %

Procedure:
This aldehyde (454 mg, 2.0 mmol) was dissolved in acetic acid (10 ml) and treated with sodium perborate tetrahydrate (385 mg, 2.5 mmol), the mixture was heated to 50° C. for 48 h then cooled, concentrated to a paste and washed with water (2×50 ml). The residue was dried in a desiccator to afford 3-nitrobiphenyl-4-carboxylic acid as a white solid (420 mg, 87%);
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O.CCN(C(C)C)C(C)C>CCCCO>[CH:26]1([C:24]2[N:21]=[C:19]3[CH:18]=[N:17][C:16]4[N:12]([S:2]([C:5]5[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=5)(=[O:3])=[O:4])[CH:13]=[CH:14][C:15]=4[N:20]3[CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Reactant: O=C(CBr)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nc(C4CCCCC4)cn23)cc1
Temperature: 170 °C

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN([CH:10]=[O:11])C.C(Cl)Cl.[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](O)=[O:19]>CO>[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18]([O:11][CH3:10])=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (1 ml) and DMF (5 μl) were added to a CH2Cl2 (1.6 ml) solution containing 2,3-difluoro-5-nitrobenzoic acid (1.61 g) obtained in the 1st step, followed by stirring at room temperature for 15 minutes. The reaction solution was poured into a liquid mixture of MeOH/Py (100 ml/1.28 ml) and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) was thus obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>CO.[Pd]>[CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:23](=[O:24])[CH3:22])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1Cc2ccc(NC(C)=O)cc2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
A solution of isoindole 245 (3.20 g, 16.7 mmol) in MeOH (100 mL) was stirred with Pd/C (5%, 300 mg) under H2 (60 psi) for 16 h. The solution was filtered through Celite, washed with MeOH (3×20 mL) and the solvent evaporated. The residue was dissolved in DCM (130 mL) and Et3N (13 mL, 93 mmol), Ac2O (13 mL, 138 mmol) was added dropwise and the solution stirred at 20° C. for 15 h. The mixture was partitioned between DCM and aqueous Na2CO3 solution. The organic solution was washed with water, dried and the solvent was evaporated to give acetamide 246 (3.00 g, 88%) as a dark oil: 1H NMR δ 7.45 (br s, 1H, H-4), 7.30 (br s, 1H, NH), 7.18 (br d, J=8.0 Hz, 1H, H-6), 7.12 (d, J=8.0 Hz, 1H, H-7), 3.90 (s, 2H, H-1), 3.87 (s, 2H, H-3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.15 (s, 3H, COCH3) 1.19 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H17N2O (MH+) m/z 203.1184, found 203.1188.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:7]=1)=O)C.[CH2:27]([NH2:29])[CH3:28]>CC(N(C)C)=O>[CH2:27]([NH:29][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:7]=1)=[O:3])[CH3:28]
Reactant: CCN
Reactant: CCNC(=O)Nc1nc2cc(-c3cncnc3)cc(C(=O)OCC)n2n1
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cncnc3)cc(C(=O)NCC)n2n1
Temperature: 60 °C

Procedure:
A slurry of the product of Step 1 (0.268 g, 0.754 mmol) in dimethylacetamide (10 mL) was treated with ethylamine (2 mL, 30.6 mmol) then heated to 60° C. in a sealed tube for 16 h. The precipitate was filtered, washed with dimethylacetamide and then water, to give title compound as a solid; m.p. 317-321° C. ACPI-MS Found: [M+H]+=355.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=O>C(O)(=O)C>[CH3:7][C:6]1[CH:5]=[N:4][N:3]2[C:12]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-amino-4-methylpyrazole and 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone in glacial acetic acid is refluxed for 6 hours. The solvent is removed and the residue dissolved in methylene chloride and passed through a column of hydrous magnesium silicate. Concentration of the eluent and addition of hexane gives the product of the example.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[N:23]([C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]=[O:25]>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[CH:34]=[CH:35][CH:36]=[C:26]([NH:23][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=3[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=2)=[O:25])[CH:27]=1)[CH3:33]
Reactant: CCCc1c(OCc2ccc(N)cc2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)OCC)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-[4-(4-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (980 mg, 30% pure by LC-MS) in anhydrous CH2Cl2 (4 mL) is added ethyl 3-isocyanatobenzoate (0.18 mL) at room temperature under Ar gas. The reaction mixture is stirred at room temperature overnight. The resulting white precipitate is filtered to give the title compound (215 mg). LC-MS (m/e): 491 (M+1).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([F:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-aminoazetidine dihydrochloride, and 110 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by-filtration and washed with ethanol and diisopropylether successively to obtain 70 mg of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:22]([CH3:23])[CH2:21][O:20][CH3:19])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Reactant: COCC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-methoxy-1-methyl-ethylamine (0.12 g, 1.32 mmol) and Hunig's base (0.037 g, 0.29 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature and extracted with EtOAc/H2O. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to yield 0.20 g (87%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 356.2 [(M+H)+, 86].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:3]2)([O-:23])=[O:22]
Reactant: CCC(=O)NCC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(=O)NCC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
N-Indan-2-ylmethyl-propionamide (4.00 g, 19.7 mmol) was dissolved in nitromethane (60 mL) and added to a mixture of concentrated H2SO4 (19 mL), concentrated nitric acid (1.4 mL) and water (3.2 mL) cooled to 5° C. After stirring for 45 min, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (4.67 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To 40 ml of tetrahydrofuran were dissolved 1.8 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate, 1.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.92 g of triphenylphosphine. At room temperature, 1.94 g of diethyl azodicarboxylate was added to the above solution, and the resulting mixture was stirred for 18 hours. After distilling off the solvent, the residue thus obtained was dissolved in ethyl acetate, and the solution was washed with water, and then dried. Thereafter, the solvent was distilled-off, and the resulting residue was purified by silica gel column chromatography using a toluene/chloroform mixture as an eluant, thereby obtaining 2.53 g of the title compound as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH3:31][SH:32]>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:31][S:32][C:26]1[CH:25]=[CH:24][C:23]([S+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: CS
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution and 6.71 g of methane thiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 19.8 g of 4-methylthiophenyl diphenylsulfonium trifluoromethane sulfonate.
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:10](Cl)(=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:10]([N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([CH3:1])[C:7]([OH:9])=[O:8])(=[O:12])[CH3:11]
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid (50.0 mg, 0.387 mmol) dissolved in N,N-dimethylacetamide (1.5 mL, 16 mmol) was added a solution of acetyl chloride (31.9 mg, 0.406 mmol) dissolved in N,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (1 mL, 6 mmol) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce the title compound as a light brown oil (30 mg, 40% yield). (m/z): [M+H]+ calcd for C8H11NO3 172.10 found 172.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[Cl:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cccc3Cl)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 284. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 7.64 (td, J=8.3, 6.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.50-7.40 (m, 1H), 4.77 (dd, J=10.9, 3.7 Hz, 1H), 4.38-4.17 (m, 1H), 4.17-4.03 (m, 1H), 4.02-3.83 (m, 1H), 3.78 (s, 3H), 3.23-3.09 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.76 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 468 (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:31]([CH:28]1[CH2:30][CH2:29]1)=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopropanecarbonyl chloride (0.126 mL, 1.39 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.355 g, 98%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.