Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(O)cc1Cl
Product: O=C(O)c1ccc(OC2CCCC2)cc1Cl

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and cyclopentyl bromide, 2-chloro-4-cyclopentyloxybenzoic acid was obtained in the same manner as in Example 277b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[CH:16]([O-])([O-])OCC>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH:16]=[N:15][N:14]=2)[N:13]=1
Reactant: NNc1ncc(-c2ccccc2F)nn1
Reactant: CCOC([O-])[O-]
Solvent: CCCCCC
Product: Fc1ccccc1-c1cnc2nncn2n1

Procedure:
A mixture of 3.8 g. of 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 40 ml. of ethyl orthoformate is refluxed for 4 hours, cooled and poured into hexane. The solid is separated and washed with ethanol, giving the desired product as a yellow solid, m.p. 193°-196° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=CC=1CC(=O)C>CS(C)=O.CCOC(C)=O.O.[Cu]Br>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([O:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:3]=1)=[O:15]
Reactant: Oc1ccncc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Cu]Br
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Oc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Reaction time: 0.02 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.15 g, 0.401 mmol), 4-pyridinol (0.057 g, 0.602 mmol), cesium carbonate (0.261 g, 0.802 mmol), and 1-(2-pyridinyl)-2-propanone (10.85 mg, 0.080 mmol) were sequentially dissolved in DMSO (4.0 mL). Next added copper(I) bromide (5.76 mg, 0.040 mmol) and the suspension was stirred under nitrogen (degassed) for 1 min. The sealed reaction mixture was stirred with heating at 110° C. (heating block) for 20 h, and then allowed to cool to room temperature overnight. The reaction mixture was diluted with EtOAc (25 mL) and water. The contents were vigorously stirred and then filtered through Celite, washing the filter pad with 20% THF/EtOAc. The layers were separated and the aq. layer extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to a dark residue that was dried under hi-vacuum overnight. The crude product was purified by silica gel chromatography (eluent: gradient of 5-95% Dichloromethane/Chloroform containing 2M Ammonia (in methanol). The collected product was washed with MTBE, filtered, and dried in a vacuum oven at 45° C. for 5 hr. The final product was collected as 0.075 g (42%). LCMS E-S (M+H)=433.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=5.05 Hz, 2H), 5.18-5.30 (m, 1H), 5.91 (s, 1H), 6.30-6.40 (m, 2H), 7.91 (s, 1H), 8.41 (s, 1H), 8.57-8.65 (m, 2H), 8.92 (t, J=4.93 Hz, 1H), 11.58 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1>O1CCCC1>[F:25][C:24]([F:27])([F:26])[C:20]1[N:19]=[C:18]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (0.88 g, 60% in mineral oil, 22 mmol) in tetrahydrofuran (50. mL) at 0° C. was added tert-butyl 4-hydroxypiperidine-1-carboxylate (4.4 g, 22 mmol, Aldrich). The mixture was stirred at room temperature for one hour. A solution of 2-chloro-6-(trifluoromethyl)pyridine (2.0 g, 11 mmol, Oakwood) in tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 2 days. The mixture was quenched by the addition of water, and the product was extracted with EtOAc. The extract was washed with water, followed by brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 120 g silica gel cartridge, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (3.8 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.75-7.64 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 3.83-3.66 (m, 2H), 3.31 (ddd, J=13.4, 8.5, 3.7 Hz, 2H), 1.99 (ddt, J=13.3, 6.9, 3.7 Hz, 2H), 1.73 (dtd, J=12.3, 8.1, 3.9 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −68.94 (s). LCMS (M-tBu+H)+: 291.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24]C=CN=3)C)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][C:27]1C(CN2CCN(C(OC(C)(C)C)=O)CC2)=C(C)[O:29][N:28]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:20]3[C:27]([CH3:26])=[N:28][O:29][C:25]=3[CH3:24])[CH2:16][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1noc(C)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1noc(C)c1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-((3,5-dimethylisoxazol-4-yl)methyl)piperazine-1-carboxylate (1.1 eq, 0.35 mmol, 104 mg), TFA (1.25 mL) and CH2Cl2 (4 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (81 mg, 0.32 mmol) in iPrOH (3 mL) and DIPEA (1 mL). Filtration and washing as previously described gave the product (105 mg, 72% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.19 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.47 (s, br, 4H, piperazine N(CH2)2), 3.03 (s, br, 4H, piperazine N(CH2)2), 3.30 (s, hidden by DMSO peak, 2H, NCH2), 6.96 (s, br, 2H, NH2), 8.16 (s, 1H, bromopyridine H-6);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccccc1Sc1cccc(O)c1
Product: COC(=O)c1ccccc1Sc1cccc(OCCCCl)c1
Yield: 85 %

Procedure:
It was prepared from methyl 2-(3-hydroxyphenylsulfanyl)-benzoate and 1-bromo-3-chloropropane as an oil in a yield of 85.0%. For C17H17ClO3S (336.8) calculated: 60.62% C, 5.09% H, 10.52% Cl, 9.52% S; found: 60.46% C, 5.09% H, 10.35% Cl, 9.42% S.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[K+].[CH3:36]I.[NH4+].[Cl-]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:36])[CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Reactant: CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D149) (260 mg) in dimethyl sulfoxide (10 mL) was added KOH (247 mg) and MeI (1.03 mL). The reaction solution was stirred at room temperature overnight. Saturated aqueous NH4Cl (10 mL) solution was added, and the resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine and dried over sodium sulphate. The organic solution was concentrated to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D150) (268 mg) as a brown oil. MS (ES): C24H24ClFN4O4 requires 486; found 487.2 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:46]1[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]2[C:42]1=[O:52]
Reactant: OCCCCCCCCCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCCCCCCCCCBr
Yield: 66 %

Procedure:
Following general procedure A, 69.4 mmol (26.2 g) of 20-Bromoeicosan-1-ol, 76.3 mmol (20.0 g) of triphenylphosphine, 76.3 mmol (11.2 g) of phthalimide and 76.3 mmol (15.5 mL) of diisopropyl azo dicarboxylate were reacted in 300 mL of tetrahydrofuran for 1 d and the mixture was processed accordingly. The crude product was purified by column chromatography (toluene). Yield 66%.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.Cl.[OH-:9].[Na+]>>[CH2:2]([C:3]1[C:7](=[O:9])[CH2:6][CH2:5][CH:4]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1cccnc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCCCCC1=CCCC1=O
Temperature: 25 °C
Yield: 80.8 %

Procedure:
In accordance with Example 6, the reaction with dropping addition was carried out by using 7.42 g (0.080 mol) of 3-picoline and 5.54 g (0.053 mol) of a 35% hydrochloric acid. After the dropping addition was finished, the resultant mixture was stirred for 5 hours under heating at the same temperature. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 1. As the result, 65.2 g of 2-pentyl-2-cyclopentenone were obtained (yield: 80.8%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:16]([NH:18][C:19]1([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][S:31][CH3:32])[C:20]1=[O:33])=[O:17]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:16]([NH:18][C:19]1([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:9])[C:20]1=[O:33])=[O:17]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCSC)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCS(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.22 g of m-chloroperbenzoic acid was added to a stirred solution of 2.05 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylthiopropyl)-2-oxo-1H-indol-3-yl]propionate in chloroform (80 ml) under ice cooling. The mixture was stirred at room temperature overnight. After removal of solvent, the residue was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography [ethyl acetate-hexane (1:2) to chloroform-methanol (20:1)] to afford ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylsulfinylpropyl)-2-oxo-1H-indol-3-yl]propionate (a sulfinyl compound, Rf: small) and ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylsulfonylpropyl)-2-oxo-1H-indol-3-yl]propionate (a sulfonyl compound, Rf: large). The sulfinyl compound was recrystallized from ethyl acetate-isopropyl ether to afford 1.07 g of the sulfinyl compound as colorless prism. Melting point: 154° to 159° C., IR (Nujol) (cm-1): 3220, 1720, 1655, 1610, FAB-MS (m/z): 527 & 525 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1>CN(C)C=O.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C2=NCCN2)c1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ncc[nH]2)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 28.8 %

Procedure:
To a solution of the title compound of Example 1, Step A (0.35 g, 1.71 mmol) in dimethylformamide (20 mL) was added activated manganese dioxide (4.46 g, 51.3 mmol) and the mixture was heated at 120° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate, filtered through a pad of Celite® and washed three times with water and once with a saturated solution of sodium chloride. The organic phase was dried (magnesium sulfate), concentrated and purified by flash column chromatography (silica gel, 60% then 80% ethyl ether in hexanes then ethyl ether) to give the title compound of Step A (0.1 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:7]1[C:8]2[C:3](=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]3=[O:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)C(=O)C1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To 5-bromoisoquinoline (0.3 g, 1.442 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (0.289 g, 1.442 mmol) was added DMSO (4 mL), 1,10-phenanthroline (0.026 g, 0.144 mmol), K2CO3 (0.498 g, 3.60 mmol). The mixture was degassed for 10 min. to the above mixture was then added Cut (0.055 g, 0.288 mmol). The reaction was heated in a sealed tube in oil bath at 130° C. After 24 h, the reaction was incomplete. Cooled and degassed with Ar, added more Cut and heating was repeated. After 24 h, the reaction was quenched with dilute NH4OH (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). The product was purified by normal phase chromatography followed by prep. HPLC. After partitioning with saturated NaHCO3 (15 mL) and EtOAc (50 mL), the organic layer was washed with brine and dried (MgSO4) to afford 0.157 g (54%) of Intermediate 18A as a white solid with recovered starting material. MS (ESI) m/z: 328 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([O:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:4]1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=2)[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@@H](Oc2ccc(C#N)cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@@H](Oc2ccc(C#N)cc2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 80 °C
Yield: 51 %

Procedure:
To 4-((1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyloxy)benzonitrile (0.826 g, 1.57 mmol) in 1,4-dioxane (16 mL) was added Na2CO3 (2 N aqueous solution, 16 mL, 31 mmol). The reaction mixture was heated at about 80° C. for about 16 h. The layers were separated and the aqueous portion was extracted with EtOAc (3×40 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified by using General Procedure AA (Table 2, Method 17, Rt=19.2 min, or =negative) to give 4-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)benzonitrile (0.298 g, 51%): LC/MS (Table 1, Method b) Rt=2.07 min; MS m/z: 373 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
In a manner similar to that described in Example 127, to a solution of tert-butyl 4,4-dimethyl-7-{2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylate (250 mg, 0.471 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL) to give the final product. MS m/z: 431.3 (M+H). Calc'd. for C25H31N6O-431.55.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:32][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 73.5 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 3.75 g of p-tert-butylphenol to give 6.6 g of product as an amber oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([N:35](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:35][CH3:33])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.013 g (0.20 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with hexane-ethylactate (gradient, 50:50-0:100) gave 0.062 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-24) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:35]([CH3:34])(=[O:37])=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(C)(=O)=O)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.85 mg, 0.25 mmol) in dichloromethane (6 ml) was added methylsulfonyl chloride (28.20 mg, 0.25 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 28 mg (47%); 1H NMR (DMSO-d6, 300 MHz): δ 9.214 (s, 1H), 7.953-7.984 (d, 1H, J=9.3 Hz), 7.85-7.88 (d, 2H, J=8.4 Hz), 7.72-7.76 (m, 3H), 6.771-6.778 (d, 1H, J=2.1 Hz), 3.3727 (s, 3H), 1.774 (s, 6H); MS: m/z 485 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10]Br)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][N:14]([CH3:15])[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of m-nitro-α-bromotoluene (3.2 g) in dimethylformamide (50 ml) was added dropwise to a solution of dimethylamine hydrochloride (1.45 g) and triethylamine (4.36 ml) in dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 1 h and then its temperature was raised to 50° C., at which it was stirred for 3 h. The reaction mixture was distilled under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 2.56 g of the titled compound (yield, 96%).