Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=O.[C:19]([O:23][C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:28]([NH2:30])=[S:29])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:28]1[S:29][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:7][CH:6]=2)[N:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCN(C(N)=S)C1CCCC1
Reactant: C[C@H]1CC[C@H](Oc2ccc(C(=O)CBr)cc2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCN(c1nc(-c2ccc(O[C@H]3CC[C@H](C)CC3)cc2)cs1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-bromo-1-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-ethanone (764 mg, 3.44 mmol), 3-(1-cyclopentyl-thioureido)-propionic acid tert-butyl ester (935 mg, 2.46 mmol), NMP (6 mL) were combined as indicated in general procedure B. The reaction was stirred at room temperature overnight. After an aqueous work up, the crude product was purified by silica gel chromatography (gradient, hexane→3% EtOAc-hexane) to afford 3-(cyclopentyl-{4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-propionic acid tert-butyl ester (1.05 g).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=1)(OCC)=O)C.[H-].[Na+].[CH:26]([C:28]1[CH:29]=[C:30]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[C:39]([C:51]([F:54])([F:53])[F:52])[CH:38]=2)[CH:31]=[CH:32][C:33]=1[CH3:34])=O>CN(C=O)C>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]([NH:35][C:36](=[O:55])[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[C:39]([C:51]([F:53])([F:54])[F:52])[CH:38]=2)=[CH:29][C:28]=1/[CH:26]=[CH:9]/[C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:14][CH:15]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C=O
Reactant: CCOP(=O)(Cc1cnc(NC(=O)OC(C)(C)C)cn1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1/C=C/c1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
tert-butyl 5-((diethoxyphosphoryl)methyl)pyrazin-2-ylcarbamate (35 mg, 0.10 mmol) in dried DMF (0.5 mL) was added NaH (5 mg, 0.12 mmol) at 0° C. After 20 minutes, a solution N-(3-formyl-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (44 mg, 0.10 mmol) in dried DMF (0.5 mL) was added slowly into the reaction mixture. The reaction mixture was stirred overnight at room temperature and quenched by adding water. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (3% to 7% MeOH/CH2Cl2) as a solvent to afford title compound (40 mg, 64% yield). MS m/z: 611 [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20](=[O:21])[CH2:19][O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 53.5 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-ol (340 mg, 1.62 mmol) was treated with 60% NaH in oil (130 mg, 3.25 mmol) and tert-butyl bromoacetate (1.2 mL, 8.13 mmol) as above to yield 280 mg of a yellow solid following flash chromatography. ES-MS calcd for C15H21N3O5 (m/e) 323.35, obsd 324.1 (M+H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[C:9]([N:28]2[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]2)=[N:10][CH:11]=[C:12]([CH:27]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].O1CCCCC1[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[N:44]1.C(O)(C(F)(F)F)=O>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:23]([F:25])([F:24])[O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:27]=[C:8]([C:46]3[CH:45]=[N:44][N:43]([CH2:42][CH2:41][OH:40])[CH:47]=3)[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnn(CCO)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2M Na2CO3 (0.375 mL, 0.75 mmol) was added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 116 mg, 0.25 mmol) and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (161 mg, 0.5 mmol) in DME (1.0 mL). under an argon atmosphere. PdCl2(dppf) (9.15 mg, 0.013 mmol) was then added and the RM mixture was stirred at 100° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was dissolved in DCM (1.4 mL) cooled to 0° C., then treated with TFA (0.77 mL, 10 mmol) and stirred at RT for 3 h. The RM was poured into aq. Na2CO3 10% (15 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2% to 10% MeOH) to afford an off-white powder. HPLC (Condition 4) tR=4.33 min, UPLC-MS (Condition 3) tR=0.88 min, m/z=494 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.88 (m, 2H) 2.96 (d, J=11.73 Hz, 0H) 3.24-3.37 (m, 2H) 3.41-3.53 (m, 1H) 3.75 (q, J=5.73 Hz, 2H) 4.04-4.25 (m, 4H) 4.81 (d, J=3.52 Hz, 1H) 4.86-4.94 (m, 1H) 7.31 (d, J=8.21 Hz, 2H) 7.53-7.59 (m, 1H) 7.79-7.89 (m, 3H) 7.93 (d, J=2.35 Hz, 1H) 8.65 (dd, J=2.35, 0.78 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([NH:13][CH2:14][CH2:15][CH2:16]O)=[N:6][CH:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([NH:13][CH2:14][CH2:15][CH2:16][Cl:26])=[N:6][CH:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1C(NCCCO)=NC(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN1C(NCCCCl)=NC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 3.3 g of 6-chloro-1,4-dihydro-2-(γ-hydroxypropylamino)-1-methyl-4-phenylquinazoline, 3.6 g of thionyl chloride and 50 ml of chloroform was stirred at room temperature overnight, and refluxed for an additional 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give 3.5 g of 6-chloro-1,4-dihydro-2-(γ-chloropropylamino)-1-methyl-4-phenylquinazoline as a residue. To the residue were added 100 ml of dry ethanol and 2.8 g of potassium carbonate and the resulting mixture was heated under reflux for 5 hours. After cooling, insoluble material was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed on activated alumina using chloroform as an eluent to give 8-chloro-11-methyl-6-phenyl-3,4,6,11-tetrahydro-2H-pyrimido[2,1-b]quinazoline.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH2:17][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[Cl:1]
Reactant: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1nn(-c2ccccc2)c(Cl)c1CBr
Temperature: -10 °C
Reaction time: 1 h
Yield: 279 %

Procedure:
A solution of 3.0 g (10.9 mmoles) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 60 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.6 g (yield: 95.8%) of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole as white crystals.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[C:12]([Cl:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>O.CO.O1CCCC1>[Cl:3][C:4]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[C:12]([Cl:20])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c(-c2cc(C)no2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2c(Cl)ccc(C(=O)O)c2Cl)on1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
0.35 g (8.8 mmol) of sodium hydroxide in 35 ml of water was added to 2.3 g (8.0 mmol) of methyl 2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoate in a mixture of 50 ml of methanol and 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 12 hours, the solvent was removed and the residue was taken up in ethyl acetate/water. After phase separation, the organic phase was separated off and the aqueous phase was washed with ethyl acetate. The remaining aqueous phase was acidified and then extracted with ethyl acetate; the resulting organic phase was dried and concentrated. 2.1 g (96% of theory) of 2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoic acid were obtained.
Reaction SMILES: C([O:4][C:5]([CH3:31])([C:27]([F:30])([F:29])[F:28])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[C:24](O)=[O:25])=O)(=O)C.C([NH2:34])=O>O>[F:29][C:27]([F:28])([F:30])[C:5]([C:6]1[NH:34][C:24](=[O:25])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH:11]=2)[N:8]=1)([OH:4])[CH3:31]
Reactant: NC=O
Reactant: CC(=O)OC(C)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1C(=O)O)C(F)(F)F
Solvent: O
Product: CC(O)(c1nc2ccc(S(=O)(=O)c3ccccc3)cc2c(=O)[nH]1)C(F)(F)F

Procedure:
2-Acetoxy-N-(2-carboxy-4-phenylsulfonylphenyl)-3,3,3-trifluoro-2-methylpropionamide (100 mg) and formamide (2 mL) were mixed and heated at reflux for 1 hour. The reaction mixture was then cooled, poured into water and extracted with ethyl acetate. The ethyl acetate was washed (water, brine) dried (Na2SO4) and evaporated. The crude solid was treated with charcoal in ethyl acetate, and then crystallized from warm ethyl acetate by addition of hexanes to the cloud point, to give the title compound (69 mg) as white needles; mp 202°-204° C.; NMR: 1.73 (s,3), 7.62-7.73 (m,4), 7.86 (d,1), 8.01 (d,2), 8.27 (d,1), 8.59 (s,1); MS: m/z=399(M+1). Analysis for C17H13F3N2O4S.0.1 C4H8O2 : Calculated: C, 51.33; H, 3.42; N, 6.88; Found: C, 51.70; H, 3.58; N, 6.98.
Reaction SMILES: C(Cl)CCl.[N:5]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][CH:8]([C:11]([O-:13])=O)[CH2:7][CH2:6]1.Cl.[CH3:22][NH:23][O:24][CH3:25].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[C:17]([O:16][C:14]([N:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[N:23]([O:24][CH3:25])[CH3:22])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
EDC (6.29 g, 32.8 mmol) was added in several portions to a stirring solution of piperidine-1,4-dicarboxylic acid, mono tert-butyl ester (5.0 g, 21.8 mmol), DMAP (10 mg), and N,O-dimethylhydroxylamine hydrochloride (3.21 g, 32.8 mmol) in dichloromethane (100 mL). To the resultant solution was added dropwise triethylamine (9.4 mL, 65.6 mmol), and the reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was poured into water, and the aqueous layer was extracted using ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a colorless oil. Purification by column chromatography (silica gel, 0-40% ethyl acetate in heptane) gave tert-butyl-4-[methoxy(methyl)-carbamoyl]-piperidine-1-carboxylate (5.04 g, 85%) as a colorless oil; 1H NMR (CDCl3, 300 MHz) δ 4.16 (m, 2H), 3.70 (s, 3H), 3.17 (s, 3H), 2.72-2.86 (m, 3H), 1.62-1.75 (m, 4H) and 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28](OC)=[O:29])[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=2[O:17][C:16]([CH3:33])([CH3:32])[C:15]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH:37][C@@H:38]1[C@@H:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][N:40]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:39]1)[CH3:36]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([N:37]([CH2:35][CH3:36])[C@@H:38]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:42][CH2:41][N:40]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:39]3)=[O:29])[C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:18]=2[O:17][C:16]([CH3:32])([CH3:33])[C:15]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)OCc1ccccc1
Reactant: CCN[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Product: CCN(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)OCc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1

Procedure:
Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3R,4R)-3-(ethylamino)-4-phenylpiperidine-1-carboxylate, the title compound (60.4 mg) was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH3:12])[NH2:8]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(N)cc1Br
Temperature: 63.5 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Under nitrogen atmosphere, to a solution of 24.0 g of 2-bromo-1-methoxy-4-nitrobenzene in acetic acid (960 ml) was added 57.0 g of iron then the reaction mixture was warmed to an external temperature of 70° C. over 50 minutes (internal temperature: 63.5° C.). After stirring at the same temperature for 8 hours, the solution was cooled to room temperature. The solid was filtered out, and the filtrate was extracted with CHCl3. The organic layer was washed with a saturated aqueous solution of NaHCO3 and with saturated brine, in this order, then, dried over Na2SO4, and then, the drying agent was removed by filtration and the solvent was evaporated under reduced pressure to obtain 13.1 g of the title compound (brown oil).
Reaction SMILES: N[C:2]1[C:3]([C:16]#[N:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:18]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[C:16]([C:3]1[C:2]([I:18])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)#[N:17]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C(F)(F)F
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(C#N)cc1C(F)(F)F
Temperature: 25 °C
Yield: 48 %

Procedure:
Methyl 5-amino-4-cyano-2-(trifluoromethyl)benzoate (250 mg, 1.02 mmol) was dissolved in THF (6 mL), and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (195 mg, 1.02 mmol) and diiodomethane (0.4 mL, 4.95 mmol) were added followed by isoamyl nitrite (0.4 mL, 3.01 mmol), and the mixture was stirred at reflux for 2.5 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, was dried over sodium sulfate, then filtered and concentrated to provide a semi-solid which was purified by column chromatography (silica gel, 20-50% dichloromethane in hexanes) to afford methyl 4-cyano-5-iodo-2-(trifluoromethyl)benzoate (174 mg, 0.49 mmol, 48% yield). 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.93 (s, 1H), 3.98 (s, 3H); GCMS for C10H5F3INO2: 355 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH3:23]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH3:23])[CH3:21])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (2.0 g, 7.11 mmol) and dimethylamine (6.3 ml, 33% in EtOH, 35.0 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.87 g, 86%).
Reaction SMILES: [F:1][C:2]([F:26])([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([C:2]([F:26])([F:1])[C:3]([OH:5])=[O:4])[CH:7]=1)[CH3:28]
Reactant: CCN
Reactant: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: difluoro-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid and ethylamine (2M in THF).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].CC(C)([O-])C.[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: ClCCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCCl)c2ccccc21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
To a solution of isatin (14.7 g) in N,N-dimethylformamide (150 ml) was added potassium tert-butoxide (13.95 g) under cooling at 5° C., and the mixture was stirred vigorously for about 10 minutes. To the mixture was added dropwise a solution of 1-bromo-3-chloropropane (17.35 g) in N,N-dimethylformamide (50 ml) over a period of about 30 minutes at ambient temperature, and the mixture was stirred for 5 hours at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (300 ml) and ice-water (500 ml) containing 50 ml of 10% hydrochloric acid. After separation of the ethyl acetate layer, the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (100 g) using chloroform as an eluent. The fractions containing the object compound were collected, and concentrated to give crystals of 1-(3-chloropropyl)isatin (19.68 g), mp. 72°-76.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C@@H:14]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH2:13][C@@:12]2([CH2:38][CH:39]([CH3:41])[CH3:40])[C:31]([O:33]C(C)(C)C)=[O:32])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C@@H:14]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH2:13][C@@:12]2([CH2:38][CH:39]([CH3:40])[CH3:41])[C:31]([OH:33])=[O:32])=[O:10])=[CH:42][CH:43]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2ccc(N(C)C)cc2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2ccc(N(C)C)cc2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:22]2(=[O:24])=[O:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:22]2(=[O:24])=[O:23])(=[O:9])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of m-chloroperbenzoic acid (2.2 g, 12.8 mmol) and 2-(phenylsulfinylmethyl) saccharin (3.75 g, 11.6 mmol) in MDC (50 ml) was stirred at room temperature for 2 hours. An additional spatula of peracid was added, and stirring was continued for an additional 1 hour. m-Chlorobenzoic acid was removed by filtration and the solid was washed with a small amount of MDC. The filtrate was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. The resultant solid was recrystallized from 50:50 ethanol:acetonitrile to afford 2-(phenylsulfonylmethyl)saccharin as a white solid, mp 169°-171° C. 1H nmr (90 MHz, DMSO-d6, CDCl3):5.15 (2H, s). FDMS: m/e 196 (M+ -PMT).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12][OH:13]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:12][OH:13])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: O
Product: O=[N+]([O-])c1cccc(C=NO)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
151 g (1 mol) of m-nitrobenzaldehyde was added to 1 l of water warmed at 70° C. and then, added with 72.6 g (1.1 mol) of a 50% aqueous solution of hydroxylamine under stirring. The mixture was stirred at the same temperature for one hour and cooled to room temperature and then, crystals deposited were filtered and dried. Thus 160 g of m-nitrobenzaldoxime was obtained. Yield 96%; M.P. 118°-121° C.