Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH2:26][C:27]([O:29]CC)=[O:28])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH2:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CSc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(SCC(=O)O)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of ethyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyridin-2-yl)sulfanyl]acetate obtained in Example 21 (390 mg), 1 M sodium hydroxide solution (12 mL), methanol (30 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 3 h. 1 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (336 mg, 99%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[N:6]2.COC1C=C2C(N=CC(=O)N2)=CC=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[CH:8]=[N:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Agent: COc1ccc2ncc(=O)[nH]c2c1
Product: COc1ccc2ncc(Cl)nc2c1
Yield: 44.6 %

Procedure:
A solution of 6-methoxyquinoxalin-2(1H)-one & 7-methoxyquinoxalin-2(1H)-one (3 g, 18.28 mmol) in POCl3 (20 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to afford mixture of regioisomers (3.7 g). 2 g of the above mixture was separated by SFC purification to afford 2-chloro-7-methoxyquinoxaline (0.7 g, 34.7%) and 2-chloro-7-methoxyquinoxaline (0.9 g, 44.6%) as off white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:20])=[C:15]([O:21][CH2:22][C:23]#[N:24])[CH:14]=[CH:13]2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4o3)ccc2c1Cl
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC#N)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 3 of Example 23, 2-{[6-(1-benzofuran-2-yl)-1-chloro-2-naphthyl]oxy}acetonitrile (6.12 g, 18.3 mmol) was acylated with valeryl chloride (2.2 mL, 19 mmol) in presence of tin (IV) chloride (2.2 mL, 19 mmol) in methylene chloride (37 mL). Purification by HPLC using 20% ethyl acetate in hexane as the mobile phase yielded 2-{[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile as a yellow waxy solid (2.55 g), mp 86-89° C. Mass spectrum (+ESI, [M+H]+) m/z 418. 1HNMR (500 MHz, DMSO-d6): δ8.55 (d, 1H, J=1.4 Hz), 8.3 (d, 1H, J=8.9 Hz), 8.25 (d, 1H, J=9.2 Hz), 8.0-8.05 (m, 2H), 7.75-7.8 (m, 2H), 7.4-7.5 (m, 2H), 5.5 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.75 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C12H20ClNO3: Calculated: C, 71.85; H, 4.82; N, 3.35. Found: C, 71.73; H, 4.59; N, 3.15.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3].P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH:2]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: BrP(Br)Br
Reactant: COC(=O)c1cccc(C(C)O)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5 g (27.75 mmol) of methyl 3-(1-hydroxyethyl)benzenecarboxylate (Example 60A) were initially charged in 100 ml of toluene. At 0° C., 0.98 g (36.07 mmol) of phosphorus tribromide were added dropwise, and the mixture was stirred at RT for 45 min. The reaction solution was poured onto ice-water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (mobile phase:cyclohexane:ethyl acetate 50:1→40:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.I[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:30])=[CH:24][N:23]=1
Reactant: CI
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 mmol) was used in Procedure L with excess iodomethane. Purified by silica gel chromatography (0-100% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-methoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.57 (50% ethyl acetate/hexanes); MS (Q1) 423(M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]2[N:15]([CH3:19])[N:16]=[C:17]([CH3:18])[C:3]=12.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)(C)C.Cl.O1CCOCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]2[N:15]([CH3:19])[N:16]=[C:17]([CH3:18])[C:3]2=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1
Reactant: Cc1nn(C)c2nc(-c3ccccc3F)nc(Cl)c12
Reactant: Nc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1nn(C)c2nc(-c3ccccc3F)nc(Nc3ccncc3)c12
Yield: 81 %

Procedure:
4-Chloro-6-(2-fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (84 mg, 0.304 mmole) and 4-aminopyridine (57 mg, 0.608 mmole) were combined in 4 ml isopropanol, added 3 drops 4M HCl/dioxane and heated reaction mixture to 80° C. for 5 hours. Cooled reaction mixture and filtered product to obtain 83 mg after vacuum drying (yield: 81%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C)C=O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
Ethyl 1H-pyrazole-4-carboxylate (20.0 g) was dissolved in N,N-dimethylformamide (200 mL), and sodium hydride (60% in mineral oil, 8.6 g) was added by small portions under cooling in an ice bath. The reaction mixture was stirred at the same temperature for 30 min, and tert-butyl 2-bromoacetate (33 g) was added dropwise. The mixture was stirred at room temperature for 10 min, heated at 50° C. overnight. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-petroleum ether) to give the title compound (17.6 g) as a colorless solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:3]1
Reactant: Cn1nc(I)c2ccccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccccc12
Temperature: -16 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
3-Iodo-1-methyl-1H-indazole (0.15 g, 0.58 mmol) was dissolved in THF (3 ml) and the solution was cooled to −16° C. using a NaCl/ice bath. Isopropylmagnesium chloride (2.0M in THF, 0.32 ml, 0.64 mmol) was added dropwise and the reaction mixture was stirred at −16° C. for 15 min. Tributylchlorostannane (0.18 ml, 0.66 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (0.5% triethylamine, gradient 0-5% EtOAc) to give 224 mg (92%) of 1-methyl-3-tributylstannanyl-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.70 (d, J=8.3 Hz, 1H), 7.32-7.45 (m, 2H), 7.11 (ddd, J=8.0, 6.3, 1.5 Hz, 1H), 1.52-1.69 (m, 6H), 1.19-1.44 (m, 12H), 0.83-0.95 (m, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5].[N:16]1([CH2:21][CH2:22][OH:23])[CH:20]=[CH:19][N:18]=[N:17]1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1ccnn1
Reactant: C=CCOc1ccc(CCl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COCCn2ccnn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
816 mg (32.3 mmol) 95% Sodium hydride were given at −50° C. to a solution of 4.32 g (21.5 mmol) 1-allyloxy-3-fluoro-4-chloromethyl-benzene and 2.51 g (22.2 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 30 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 10 ml water added. The mixture was extracted twice with ethyl acetate, and the combined organic phases dried over Na2SO4. Solvents were removed in vacuum to yield 6.18 g 1-[2-(4-allyloxy-2-fluoro-benzyloxy)-ethyl]-1H-[1,2,3]triazole yellow oil that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[NH2:1][C:2]1[N:3]=[C:4]([CH:26]=[CH2:27])[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2nc(Cc3ccccc3)c(N)nc2Cl)c(C=O)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Temperature: 110 °C
Yield: 55.7 %

Procedure:
Under an argon atmosphere, to a solution of 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.28 g, 6.44 mmol) in deaerated toluene (30 mL) were successively added dichlorobis(triphenylphosphine)palladium(II) (226 mg, 322 μmol), tributyl(vinyl)tin (3.75 mL, 12.8 mmol) and tetra-n-butylammonium chloride (3.50 g, 12.6 mmol) at room temperature. The mixture was heated to reflux for 1.5 hours (oil bath temperature at 110° C.). After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1) followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (silica gel mixed with 10 wt % potassium fluoride, n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (1.24 g, 3.59 mmol, 55.5%) as a reddish brown oily substance. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.15 (s, 2H), 4.50 (s, 2H), 5.39 (dd, 1H, J=2.0, 11.0 Hz), 6.33 (dd, 1H, J=2.0, 17.0 Hz), 6.57 (dd, 1H, J=11.0, 17.0 Hz), 7.20-7.28 (m, 4H), 7.30-7.36 (m, 2H), 7.41 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=3.0 Hz), 9.88 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 41.0, 55.7, 110.6, 120.5, 121.0, 127.2, 128.5 (2C), 129.1 (2C), 132.3, 132.9, 134.4, 136.1, 136.5, 138.7, 140.2, 145.2, 151.5, 159.8, 191.5.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[F:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.O>[F:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([S:20][CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]3)[NH:19][C:15]=2[CH:14]=1
Reactant: Fc1ccc2nc(S)[nH]c2c1
Reactant: O=CN1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: O=CN1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Temperature: 92 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (1.20 g, 7.6 mmol), 5-fluoro-2-mercaptobenzimidazole (1.28 g, 7.6 mmol), and diisopropylethylamine (3.93 g, 30.4 mmol) was dissolved in propionitrile (50 mL), and cyanomethyltrimethylphosphonium iodide (7.39 g, 30.4 mmol) was added to the mixture, followed by stirring for one hour at 92° C. under argon. The reaction mixture was allowed to cool and then poured into water (100 mL), followed by extraction with chloroform (100 mL×3) The resultant organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The crude product was crystallized from acetone-ether, to thereby yield 1-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.87 g, yield 80%) as a brown crystalline powder.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]([CH2:35][N+:36]([O-])=O)([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=1)[CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[O:11][CH2:10]2)=O>C(O)C>[Cl:34][C:28]1[CH:27]=[C:26]([C:3]2([C:2]([F:40])([F:39])[F:1])[CH2:4][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[C:12]3([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:18]3)[O:11][CH2:10]4)=[N:36][CH2:35]2)[CH:31]=[C:30]([Cl:32])[C:29]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12

Procedure:
A solution of tert-butyl 5′-(4,4,4-trifluoro-3-(nitromethyl)-3-(3,4,5-trichlorophenyl)butanoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 3, 5.1 g, 8.97 mmol) in ethanol (51 mL) was purged with nitrogen gas for 30 minutes. To this reaction mixture was added pre-washed Raney Nickel (1.22 g, 50% suspension in water). Reaction mixture was stirred under hydrogen atmosphere using balloon for 16 hours at room temperature. Progress of the reaction was monitored by TLC. After consumption of intermediate-4, reaction mixture was filtered through celite bed, the bed was washed with 10% MeOH in DCM (30 mL). The filtrate was concentrated to get 4 g off white solid as crude mass, crude was purified by column chromatography on silica gel using 230-400 silica mesh. Desired product was eluted in 8% ethyl acetate in n-Hexane to get 1.6 g off white semi-solid as desired product and 1.5 g of starting material was recovered. 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.43 (d, J=17.52 Hz, 1H), 3.76-3.81 (m, 1H), 4.13 (d, J=9.64 Hz, 2H), 4.32 (d, J=9.56 Hz, 2H), 4.42 (d, J=17.12 Hz 1H), 4.87 (d, J=17.12 Hz, 1H), 5.13 (s, 2H), 7.39 (s, 2H), 7.54 (d, J=7.92 Hz, 1H), 7.73 (s, 1H), 7.83 (d, J=7.92 Hz, 1H).
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH2:4][OH:5])#[N:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:14][S:15]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:6])(=[O:17])=[O:16]
Reactant: CC(C#N)(CO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(4-chlorophenyl)propan-1-ol (68 g., 0.3 mole) and methane sulfonyl chloride (37.5 g., 0.33 mole) in 2 liters of benzene is added dropwise at 10° C., 36 g., (0.36 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 63 g. of product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14](O)=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B>C1COCC1>[OH:15][CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Yield: 92.6 %

Procedure:
(S)—N-Boc-2-morpholine carboxylic acid (2.00 g, 8.65 mmol) was dissolved in THF (30 mL) and borane (25.9 mL, 1.0 M in THF, 25.9 mmol) was added dropwise. The reaction mixture was heated at reflux for 2.5 h and quenched with water (10 mL). The reaction mixture was concentrated in vacuo and the residue dissolved in DCM (30 mL), washed with sat aq Na2CO3 (2×20 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.74 g, 92%) as a pale yellow oil. LCMS (ES+): 240.3 [MNa]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1.[Br:14]Br.OS([O-])=O.[Na+].N>C(O)(=O)C.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[C:7]([Br:14])[C:8]=2[CH3:12])[N:3]=1
Reactant: Cc1cc(C)c2ccc(N)nc2n1
Reactant: BrBr
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2nc(N)ccc2c(C)c1Br
Temperature: 60 °C
Yield: 52.4 %

Procedure:
173 g (1 mol) of 2-amino-5,7-dimethyl-1,8-naphthyridine is suspended in 500 ml of glacial acetic acid. At 60° C. and with stirring, 160 g (1 mol) of bromine is dripped in, the solid going into solution. After all has been added, the mixture is stirred overnight at room temperature (20° C.) and then poured into 1 liter of water. Excess bromine is reduced by adding a small amount of NaHSO3. The pH is brought to 4 with concentrated NH3 solution. The mixture is stirred for about 30 minutes and the precipitate is filtered off and dried under reduced pressure to give 132 g of a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCc3cc(Cl)ccc3C2=O)CC1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A room temperature solution of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (0.100 g) in N,N-dimethylformamide (3 mL) was treated with sodium hydride (95% dispersion in mineral oil, 0.028 g) and stirred for 20 minutes. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (0.184 g) was added and the reaction was stirred at 40° C. overnight. The mixture was diluted with diethyl ether and washed sequentially with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=47:3) to obtain the title compound (0.188 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
7-Chloro-2-methyl-4-(piperazin-1-yl)quinoline (0.26 g), 4-fluorophenyl isocyanate (114 μL, 1.0 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc. 1H NMR ([D]6-DMSO), δ 2.58 (s, 3H), 3.17 (m, 4H), 3.71 (m, 4H), 6.94 (s, 1H), 7.06 (t, 2H), 7.46 (m, 3H), 7.87 (d, 1H), 8.01 (d, 1H), 8.68 (br. s, 1H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[C:22]([C:26]([O:29][CH3:30])=[CH:27][N:28]=1)[C:23]([OH:25])=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.CCN(CC)CC>C(Cl)Cl.O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]([O:29][CH3:30])=[CH:27][N:28]=1)[C:23]([NH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:25]
Reactant: NCc1ccc(F)cc1
Reactant: COc1cnc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
T3P (2.4 g, 7.4 mmol) was added to a solution of 2-bromo-5-methoxyisonicotinic acid (1.0 g, 3.7 mmol), (4-fluorophenyl)methanamine (466 mg, 3.7 mmol) and Et3N (1.1 g, 11.1 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at RT for 1 h. Water (50 mL) was added and the mixture was extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=2:1) to give the product of compound 2-bromo-N-(4-fluorobenzyl)-5-methoxyisonicotinamide (1.1 g, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, J=2.8 Hz, 2H), 7.96 (s, 1H), 7.31 (dd, J=5.2, 8.4 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 4.61 (d, J=6.0 Hz, 2H), 4.03 (s, 3H). MS (M+H)+: 339/341.