Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O1CCOCC1.[I-].[K+]>[C:18]([CH2:17][CH2:16][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)#[N:19]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(CCC#N)CC2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9.20 g, 40.1 mmol, 1.00 equiv, Aldrich), 3-bromopropionitrile (3.66 mL, 44.1 mmol, 1.10 equiv, Aldrich), potassium carbonate (33.25 g, 240.6 mmol, 6.00 equiv), and potassium iodide (266 mg, 1.60 mmol, 0.04 equiv) in n-butanol (70 mL) and 1,4-dioxane (70 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH-EtOAc 0:1 to 1:19) to afford 8.39 g of white solid (59%), which was characterized spectroscopically.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[C:29](=[C:31]([C:35](O)=[O:36])[CH:32]=[CH:33][CH:34]=3)[N:30]=2)=[CH:22][CH:21]=1)[CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+:38].[OH-].O>ClCCl>[C:35]([C:31]1[C:29]2[N:30]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:18])[C:15](=[O:16])[O:14][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:21][CH:22]=3)[O:27][C:28]=2[CH:34]=[CH:33][CH:32]=1)(=[O:36])[NH2:38]
Reactant: CN(Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1)C(=O)OCc1ccccc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1)C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
Oxalyl chloride (218 mg, 1.72 mmol) is slowly added to a solution of 2-(4-(((benzyloxycarbonyl)(methyl)-amino)methyl)phenyl)benzo[d]oxazole-4-carboxylic acid (0.65 g, 1.57 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture is warmed to 50° C. for 4 h and then cooled to 25° C. The solution is condensed in vacuum and then slowly added to 28% NH4OH (6 mL). The mixture is warmed to 50° C. and stirred for another 2 h. Water (50 mL) is added to the reaction mixture and the slurry is cooled to 25° C. The product is filtered and the cake is washed with water, dried to afford benzyl 4-(4-carbamoylbenzo[d]oxazol-2-yl)benzyl(methyl)carbamate solid. MS (ESI) m/e 416 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:21]=[CH:22][C:13]=1[NH:12][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2cccnc2n1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3cccnc3n2)cc1
Temperature: 4 °C
Yield: 82.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.55 g), N,N'-carbonyldiimidazole (6.55 g) and 2-amino-1,8-naphthyridine (5.2 g). The product produced by precipitation in water (8.35 g; m.p. 85° C., viscous) is filtered and then dissolved in boiling 1-propanol (50 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (2×5 cc) and dried at 35° C. under reduced pressure (0.067 kPa). N-(1,8-naphthyridin-2-yl)-4-methoxybenzamide (6.9 g) is produced, m.p. 150° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:24]([NH:23][C:21](=[O:22])[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]#[C:12][C:9]2[CH:8]=[N:7][C:6]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:11][CH:10]=2)=[CH:19][CH:18]=1)[CH3:26])[CH3:25]
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Reactant: CC(C)N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(NC(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 9.3 mg (0.16 mmol) isopropylamine in 0.5 mL DMSO are added 31 mg (0.10 mmol) 2-[4-(2-chloro-pyrimidin-5-ylethynyl)-phenyl]-N-ethyl-propionamide (XVIII.1) in 1 mL DMSO, followed by 254 (16 mmol) DIPEA. The mixture is stirred at rt for 12 h. After that time, the mixture is directly purified by HPLC (preparative column: Sunfire; eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])=[CH:15][CH:16]=1
Reactant: Oc1ccccn1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Agent: Cl
Product: O=c1ccccn1Cc1c(-c2ccc(Cl)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and pyridin-2-ol. 1H-NMR (CDCl3, 400 MHz, δ) 8.45 (dd, J=2.4, 4.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.58 (dd, J=5.1, 9.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.76 (dd, J=1.9, 6.9 Hz, 1H), 6.59 (d, J=9.1 Hz, 1H), 6.00 (m, 1H), 5.62 (s, 2H) ppm; me/354 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[CH:7]=1.[CH3:11][C:12]1([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:13]1>CC(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[C:7]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:12]1([CH3:11])[CH2:14][CH2:13]1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: CC1(c2cc3ccccc3[nH]2)CC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(c2[nH]c3ccccc3c2C2=C(Cl)C(=O)C=C(Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 2,5-dichloro-1,4-benzoquinone (0.177 g, 1.00 mmol) in AcOH (2 mL) was added 2-(1methyl-cyclopropyl)indole (0.081 g, 0.47 mmol). After the reaction mixture was stirred for 2 h at 50° C. under nitrogen protection, Ag2CO3 on Celite® (50%, 0.500 g, 0.90 mmol) was added. After stirring for 4 h at room temperature, the solution was diluted with ethyl acetate (100 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford 2,5-dichloro-3-[2-(1-methyl-cyclopropyl)-1H-indol-3-yl]-[1,4]benzoquinone (0.148 g, 90%) as blue needles from benzene/hexane. Melting Point 170–171° C. 1H NMR (d6-acetone): 0.53–0.60 (1H, m), 0.64–0.70 (1H, m), 0.70–0.77 (1H, m), 0.92–0.98 (1H, m), 1.48 (3H, s), 7.01 (1H, dt, J=1.2, 7.5 Hz), 7.10 (1H, dt, J=1.2, 7.5 Hz), 7.24 (1H, dd, J=0.6, 7.2 Hz), 7.37 (1H, d, J=7.8 Hz), 7.39 (1H, s), 10.70 (1H, s). 13C NMR (d6-acetone): 13.3, 14.1, 15.1, 24.5, 103.6, 111.4, 119.7, 119.9, 121.9, 126.8, 133.8, 136.0, 140.4, 140.8, 143.9, 144.0, 177.1, 177.9. IR (KBr): 3409, 3059, 3004, 2966, 2927, 1662, 1620, 1567, 1435, 1270, 1241, 1028, 755 cm−1. Anal. Calcd. for C18H13Cl2NO2: C, 62.45; H, 3.78; N, 4.05. Found: C, 62.30; H, 3.77; N, 3.94.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N:24][C:23]=2[CH:35]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[N+:27]([O-:28])=[N:26][C:25]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N+:24]([O-:6])[C:23]=2[CH:35]=1)[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
Hydrogen peroxide (70%, 0.7 mL, ca. 13.9 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (2.0 mL, 13.9 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 18 (385 mg, 1.4 mmol) and trifluoroacetic acid (0.53 mL, 6.9 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (20 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was chromatographed, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 19 (125 mg, 31%) as a red solid, mp (MeOH/EtOAc) 150-152° C.; 1H NMR 8.23 (d, J=9.6 Hz, 1 H, H-8), 7.48 (d, J=2.6 Hz, 1 H, H-5), 7.46 (brs, 1 H, NH), 7.03 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.25 (q, J=7.0 Hz, 2 H, CH2O), 3.64 (br dd, J=6.0, 5.9 Hz, 2 H, CH2N), 2.61 (t, J=6.0 Hz, 2 H, CH2N), 2.30 [s, 6 H, (CH3)2], 1.49 (t, J=7.0 Hz, 3 H, CH3); 13C NMR δ 165.5, 150.2, 140.3, 125.6, 123.5, 120.6, 95.4, 65.4, 57.5, 45.2 (2), 35.9, 14.3; MS (FAB+) m/z 294 (MH+, 100%), 278 (30), 276 (20); HRMS (FAB+) calcd for C13H19N5O3 (MH+) m/z 294.1566, found 294.1568. Anal. Calcd for C13H19N5O3: C, 53.2; H, 6.5; N, 23.9. Found: C, 53.1; H, 6.3; N, 23.6%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC(OC)=CC=4)=[C:20]([O:34][CH3:35])[CH:19]=3)[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([I:1])[CH:3]=[C:4]3[N:10]=[C:9]2[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-34-2) (2.40 g, 4.08 mmol) in dichloromethane (50 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to ˜9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.30 g (70%) of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].NO.[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=O)[CH2:19][CH2:18]2>CO.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=[N:2][OH:3])[CH2:19][CH2:18]2
Reactant: NO
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(O)c2c1CCC2=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 Grams of hydroxylamine hydrochloride and 56 g of potassium carbonate were added in 400 ml of methanol, and the mixture was refluxed by hetting for 30 minutes. After cooling the reaction mixture to a room temperature, the supernatant liquor was collected by separation to prepare a methanol solution of hydroxylamine. To this methanol solution of hydroxylamine was added 16.2 g of 7-hydroxy-4-methyl-1-indanone and refluxed by heating for 5 hours under stirring condition. The reaction mixture was concentrated to dryness under a reduced pressure. To the residue thus obtained was added 200 ml of ethyl acetate, then the insoluble matter was removed by filtration. The filtrate was concentrated to dryness under a reduced pressure, and the residue was recrystallized from methanol to obtain 17.6 g of 7-hydroxy-4-methyl-1-indanone oxime in the form of colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cc(F)cc(F)c2)c1
Temperature: 25 °C

Procedure:
3,5-difluorophenyl-boronic acid (0.138 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the solvent was removed under vacuum from fractions containing product.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1)#[N:13]
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Product: Cc1cnc(C#N)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A round bottom flask was charged with 2-bromo-5-methyl-3-nitropyridine (60.53 g, 278.9 mmol) and CuCN (27.52 g, 307.3 mmol) The flask was evacuated, and back-filled with nitrogen. DMF (150 mL) was added via cannula. The solution was heated to 70° C. for 1.5 h. After cooling to room temperature, the reaction mixture was poured into EtOAc (500 mL) and water (250 mL). Both phases were filtered through a 1 cm bed of celite. The layers were separated, and the organic phase washed with water (2×100 mL) then with a solution of 1:1 sat. aq. NH4Cl/NH4OH (2×100 mL). The combined aqueous layers were extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (36.10 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]12[O:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][O:7]1)[CH2:4][O:3]2.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[C:16]=1[CH3:23]>CS(C)=O>[CH3:22][C:17]1[C:16]([CH3:23])=[C:15]([O:11][CH2:10][C:5]23[CH2:4][O:3][C:2]([CH3:1])([O:7][CH2:6]2)[O:9][CH2:8]3)[CH:20]=[CH:19][N+:18]=1[O-:21]
Reactant: CC12OCC(CO)(CO1)CO2
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC23COC(C)(OC2)OC3)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To a dimethylsulfoxide solution (30 ml) of the (1-methyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol (4.5 g, 28.1 mmol) obtained in the step (24a), sodium hydride, in oil (1.29 g, 29.5 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (3.99 g, 25.3 mmol) was added, which was stirred at 60° C. for 3 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (7.46 g, yield: 81%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), allyl tri-n-butyltin (1.4 mL, 4.4 mmol), lithium chloride (470 mg, 11 mmol), and palladium tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:26][CH3:27])[CH2:5][C:6]#[C:7][CH2:8][NH:9][C:10](=[O:25])[C:11](Cl)([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(=O)(O)[O-:29].[Na+]>O>[CH2:2]([N:4]([CH2:26][CH3:27])[CH2:5][C:6]#[C:7][CH2:8][NH:9][C:10](=[O:25])[C:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3]
Reactant: CCN(CC)CC#CCNC(=O)C(Cl)(c1ccccc1)C1CCCCC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCN(CC)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
N-(4-Diethylamino-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide hydrochloride (100 mg) was dissolved in water (1 ml) and the solution was refluxed for 20 minutes. After being cooled, the solution was made alkaline (pH 10) with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The extract was washed with sodium chloride aqueous solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-(4-diethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (74 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:7]1)#[N:2]
Reactant: COCC(=O)Cl
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: COCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and methoxyacetyl chloride. LCMS (M+H)+: m/z=568.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCOC(=O)c1ccc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(Nc2cc(Cl)nc(SC)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (1 g), ethyl 6-aminonicotinate (0.85 g) and NaHMDS (10.3 mL, 1M in THF) in THF (50 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×150 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4 and concentrated to give ethyl 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinate which was used as was.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20]=O)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]4)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=CCN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21
Reactant: CC(C)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A mixture of (1R,2S) and (1S,2R)-2-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde (0.1 mmol), (1-Isopropyl)piperazine (0.15 mmol) and acetic acid (catalytic amount) in DCM (2 ml) was stirred for 20 minutes at room temperature. The mixture was cooled to 0° C. and NaBH(OAc)3 (2 mmol) was added carefully. The mixture was warmed to room temperature and stirred for 14 hours at room temperature. The mixture was concentrated under reduced pressure and dissolved in DMF. Purification by preparative HPLC gave the title product as colorless oil (35 mg). LC/MS m/e calcd. for C25H30ClN3O: 423, observed (M+H)+: 424.1 1HNMR (400 MHz, MeOD-d4) δppm 1.37 (d, J=6.57 Hz, 6 H) 2.18 (dd, J=8.46, 5.94 Hz, 2 H) 2.46-2.64 (m, 1H) 2.85 (d, J=3.54 Hz, 2 H) 3.22 (s, 2 H) 3.50 (d, J=6.57 Hz, 2 H) 3.90-4.27 (m, 2 H) 6.09 (d, J=7.58 Hz, 1H) 6.76 (s, 1 H) 7.10 (d, J=7.83 Hz, 1 H) 7.16-7.25 (m, 3 H) 7.33 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].Cl>CO.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
Dimethylformamide (485 l), p-pentyloxyacetophenone (30.3 kg) and dimethyl terephthalate (45.6 kg) were charged in 2000-liter reactor and stirred. To this mixture was added potassium tert-butoxide (24.7 kg) in several portions and, after that, a reaction was carried out at the inner temperature of 20 to 25° C. for 3.5 hours. After completion of the reaction, methanol (1210 l) was added to the reaction solution at 20 to 30° C. and then 6N hydrochloric acid (49 l) at 5 to 15° C. The mixture was stirred at room temperature for 1 hour, and the resulting appeared crystals were filtered and washed with methanol (152 l) and then water (152 l). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (49.6 kg).