Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].[OH-].[NH4+]>C(O)(C)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(-n3ccnc3)cc12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncnc3ccc(-n4ccnc4)cc23)cc1Cl
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
A mixture of 4-chloro-6-(1-imidazolyl)quinazoline (3.8 g) and 3-chloro-4-fluoroaniline (2.64 g) in isopropanol (50 ml) was heated to reflux for 3 hours. The solid product so obtained was filtered off, washed with isopropanol and with diethyl ether and dried. The solid so obtained was suspended in water (40 ml) and an aqueous ammonium hydroxide solution (15 ml) was added. The mixture was stirred for 10 minutes. the solid was filtered off, washed with 20% aqueous ammonium hydroxide solution, with water, with acetone and with diethyl ether and dried to give 4-(3-chloro-4-fluoroanilino)-6-(1-imidazolyl)quinazoline (1.10 g); NMR Spectrum: (CD3SOCD3) 7.22 (s, 1H), 7.49 (t, 1H), 7.84 (m, 1H), 7.88 (s, 1H), 7.96 (d, 1H), 8.19 (t, 1H), 8.24 (m, 1H), 8.40 (s, 1H), 8.68 (s, 1H), 8.74 (d, 1H), 9.90 (s, 1H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]3[CH2:15][CH:14](O)[CH:13]=[C:12]([S:17][CH3:18])[C:8]=3[CH:9]=[CH:10][S:11][C:5]=2[CH:4]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:15]1[C:14]2[CH:13]=[C:12]([S:17][CH3:18])[CH:8]=[CH:9][C:10]=2[S:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=2[CH2:7]1
Reactant: COc1ccc2c(c1)SC=CC1=C2CC(O)C=C1SC
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Reaction time: 3 h

Procedure:
15.7 G. of 10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo thiepin-10-ol, 250 ml. of benzene and 6 g. of finely pulverized calcium chloride are saturated with hydrochloric acid gas over a period of 21/2 hours at 15° and subsequently stirred for an additional 3 hours. After the addition of 0.8 g. of activated charcoal, the mixture is filtered and washed with benzene. The benzene phase is evaporated under reduced pressure, whereby there is obtained 10-chloro-10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo [b,f]thiepin, having a melting point of 120°-123°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C@@H:20]([CH2:27][C:28]3[N:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[S:31][CH:32]=3)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][C:14]=2[O:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C@@H:20]([CH2:27][C:28]3[N:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])[S:31][CH:32]=3)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CCOC(=O)C[C@H](Cc1csc(CCCCO)n1)c1ccc2c(c1)OCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](Cc1csc(CCCC=O)n1)c1ccc2c(c1)OCO2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Dimethyl sulfoxide (1.47 mL, 3.15 mmol) was cooled in 5 mL CH2Cl2 to −70° C. for 10 min. The oxalyl chloride (2.0M in CH2Cl2, 4.9 mL, 9.85 mmol) was added, and the reaction was allowed to stir at −70° C. for 1 hr. A solution of (3S)-Ethyl 3-(1,3-benzodioxol-5-yl)-4-[2-(4-hydroxybutyl)-1,3-thiazol-4-yl]butanoate (2.57 g, 6.56 mmol) in CH2Cl2 (5 mL) was added to the reaction and stirred at −70° C. for 1 hr. Add triethylamine (5.96 mL, 6.52 mmol) and allow to warm to room temperature. Dilute with ethyl acetate, wash with water, 1 N HCl, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and purified via silica gel chromatography (eluent: 3:1 Hexane:Ethyl Acetate) to give the product as a colorless oil. Yield: 1.95g (76%) 1H NMR (DMSO-d6) δ9.68–9.65 (m, 1H), 6.98–6.95 (m, 1H), 6.75–6.71 (m, 1H), 6.63–6.58 (m, 1H), 5.94 (s, 2H), 3.96–3.88 (q, 2H), 3.47–3.38 (m, 1H), 3.00–2.85 (m, 4H), 2.68–2.48 (m, 4H), 1.97–1.88 (m, 2H), 1.08–1.01 (t, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:18][S:19]([C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:14]=2)=[CH:26][N:27]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a solution of 4-(5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (19.5 g) and 6-(methylsulfonyl)pyridin-3-ol (14 g) in N,N-dimethylformamide (250 mL) was added potassium carbonate (22.3 g), and the mixture was stirred at 110° C. for 4 hr. 1N HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (26.4 g, yield 83%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: BrCCCCCCCCCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCCCCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,−) cis 7-Benzyloxy-4-[4-(bromodecyloxy)-phenyl]-3-phenylchroman (300 mg, 0.48 mmol) and morpholine (208 mg, 2.4 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].[CH3:19][O:20][NH2:21]>>[CH3:19][O:20][NH:21][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CON
Product: CONC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-methoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.42 mmol of O-methyl-hydroxylamine. LC/MS [8.75 min; 404 (M+1)]
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1.B(F)(F)F.CCOCC>C(OCC)C>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH2:2][CH:3]=[O:1])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: c1cc2c(cc1C1CO1)OCCO2
Agent: FB(F)F
Solvent: CCOCC
Product: O=CCc1ccc2c(c1)OCCO2
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A solution of crude 6-oxiranyl-2,3-dihydro-benzo[1,4]dioxine (200 mg, 1.12 mmol) in diethyl ether (20 ml) was cooled at −10° C. A 10% solution of boron trifluoride diethyl etherate in diethyl ether (0.16 ml) was then added and the mixture was stirred for 10 minutes at −10° C. The reaction was quenched at this temperature by addition of a saturated aqueous solution of sodium bicarbonate (10 ml). The mixture was extracted twice with diethyl ether. The combined organic phases were washed with water, brine, then dried over magnesium sulfate and evaporated to give crude (2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetaldehyde (191 mg, 95%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:19]([O-:21])=O)([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pt]>[OH:21][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([S:15](=[O:17])(=[O:16])[NH2:18])[CH:11]=2)[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: NS(=O)(=O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 59.1 %

Procedure:
A suspension of 4-ethoxalylamino-3-nitrobenzenesulfonamide (1.59 g, 5 mmol) in 300 ml of 96% ethanol was hydrogenated at atmospheric pressure and room temperature for 30 min. in the presence of 50 mg of 5% platinum on carbon. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was washed with ethanol and dissolved in 25 ml of saturated aqueous ammonium hydroxide. An undissolved orange residue was removed by filtration, and most of the ammonia was removed from the filtrate under reduced pressure. After treatment with decolourising carbon the filtrate was acidified with conc. hydrochloric acid to give 0.76 g (59%) of the title compound as an off-white precipitate. M.p.>250° C. decomp. (DSC); NMR (DMSO-d6): 7.07-7.93 (m, 3H, ArH), 7.33 (broad s, 2H, NH2), ca. 11.9 (very broad s, 1H, NH or OH), 12.3 (broad s, 1H, OH or NH); IR (KBr): 3300-2100, 1690 cm -1 ; MS (m/e): 257 (10%, M+).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>>[C:1]1([S:7]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1CCCN1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To 7.06 g of benzenesulfonyl chloride (0.04 mole) was added 6.9 g of N-trimethylsilyl-2-pyrrolidone (0.044 mole), and the mixture was stirred at the reflux temperature for 30 minutes. The reaction mixture was subjected to chromatography on a column (D 40 mm×L 250 mm) of 150 g of silica gel (Wako Gel C-200). Elution with a mixed solvent of hexane-ethyl acetate (3:2) gave a crystalline product, which was recrystallized from a mixed solvent of chloroform-ether to give 3.34 g of N-benzenesulfonyl-2-pyrrolidone as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:38]=[CH:37][C:31]4[O:32][C:33]([F:36])([F:35])[O:34][C:30]=4[CH:29]=3)[CH:25]=[C:24]([C:39](=[O:41])[CH3:40])[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+].Cl>C(O)C.O>[C:39]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]2[CH:38]=[CH:37][C:31]3[O:32][C:33]([F:35])([F:36])[O:34][C:30]=3[CH:29]=2)[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])(=[O:41])[CH3:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OC(F)(F)O3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a solution of 4-[3-{6-[3-acetyl-5-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (300 mg) in ethanol (5 mL) was added a solution of NaOH (176 mg) in water (2 mL) and the resulting mixture was stirred at room temperature for 5 h. Then the reaction mixture was diluted with water, acidified with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a reverse-phase HPLC to yield 137 mg of the title compound (50% yield). HRMS calcd for C34H36O9F2 [M+Na]+ 649.2219, observed 649.2222.
Reaction SMILES: [CH3:1][N:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:3]1[C:8]([CH:9](O)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][CH:9]([C:8]1[C:3]([N:2]([CH3:1])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(c1cccnc1)c1ncccc1C(O)C(c1cccnc1)c1cccnc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN(c1cccnc1)c1ncccc1C(F)C(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of 1-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-2,2-dipyridin-3-ylethanol (31 mg) in 1.5 mL of CH2Cl2 was added DAST (20 mg). After 2 h stirring at room temperature, then reaction was cooled to 0 C and quenched with saturated aqueous sodium bicarbonate. then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and purified by reverse phase HPLC to give 6 mg of 3-(1-fluoro-2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine. 1H NMR (CDCl3) δ 8.48 (2H, t, J=4.9 Hz), 8.45 (1H, dd, J=4.9, 2.0 Hz), 8.33 (2H, d, 20.5 Hz), 8.22 (1H, d, J=3.9 Hz), 8.12 (1H, s), 7.55 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=8.1 Hz), 7.46 (1H, dd, J=8.1, 1.7 Hz), 7.23-7.11 (4H, m), 7.02-7.00 (1H, m), 6.10 (1H, dd, J=46.4, 4.1 Hz), 4.32 (1H, dd, J=26.4, 5.1 Hz), 3.28 (3H, s).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)N3CCOCC3)C2=O)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-(2-chloroacetyl)morpholine, to give the desired product as a white foam (10%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([O:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C.[Pd]>[F:1][C:2]([F:22])([F:23])[CH:3]([O:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(OC(=O)c1ccc(N)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
The reaction liquid was poured into water, and extracted with methylene chloride. The methylene chloride layer was washed with a diluted hydrochloric acid and water in this order. The organic layer thus recovered was distilled under a reduced pressure to remove the solvent, and subjected to purification by a silica gel chromatography (n-hexane:ethyl acetate=10:2) to obtain 1.9 g of p-nitrobenzoic acid 1,1,1-trifluoro-2-octyl ester. The ester was dissolved in 30 ml of ethanol, to which 0.19 g of 5% Pd-C catalyst was added. After the solution was stirred overnight under hydrogen atmosphere, the Pd-C catalyst was separated by filtration, and the ethanol was distilled off under a reduced pressure to obtain 1.8 g of p-aminobenzoic acid 1,1,1-trifluoro-2-octyl ester which was the desired compound of the reaction 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH:14]C(=O)OC(C)(C)C)[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(NC(=O)OC(C)(C)C)cnn1C
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1c(N)cnn1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate (774 mg, 2.29 mmol, 1 eq) was added hydrogen chloride (6.0 mL of a 4.0M solution in 1,4-dioxane, 24 mmol, 10 eq). The reaction mixture was stirred at room temperature for 4 hours and then evaporated to dryness. The solid residue was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous portion was extracted once more with dichloromethane, and the combined organic extracts dried over magnesium sulfate and concentrated to give 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=238.3; 1H NMR (400 MHz, CDCl3) δ: 7.35 (d, 1H), 7.22 (overlapping s and s, 2H), 6.94 (d, 1H), 3.83 (s, 3H), 3.70 (d, 2H), 3.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Fc1cccc(Oc2cncc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 61 %

Procedure:
Using Method EE with 2-chloro-6-(3-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (200 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 3.44 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom 2′+6′), 7.02-7.09 (m, 2H, Harom 4+6), 7.16 (d, 1H, Harom 2, JF=8.8 Hz), 7.43 (q, 1H, Harom 5, J=8.5 Hz), 7.78 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.61 (s, 1H, NH). m/z: 372.1 [(M+H)+, calcd for C19H18FN3O4 371.1].
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](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][CH2:73][NH2:74]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[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]([NH:74][CH2:73][CH2:72][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][N:66]=5)=[O:27])=[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: NCCc1ccccn1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCc2ccccn2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 79.8 %

Procedure:
A mixture of 0.045 g (0.1 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-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.12 mmole) 2-pyridin-2-yl-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.044 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-(2-pyridin-2-yl-ethyl)-benzamide (I-116) as a white solid.
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH:5]=[CH:4][NH:3][C:2]1=[O:8].[C:9](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:9][N:3]1[CH:4]=[CH:5][C:6](=[O:7])[O:1][C:2]1=[O:8]
Reactant: O=c1cc[nH]c(=O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ccc(=O)oc1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
At room temperature, 1.50 g of 2H-1,3-oxazine-2,6(3H)-dione, 2.19 g of potassium carbonate and 3.77 g of methyl iodide were sequentially added to 30 ml of acetone, and the mixture was stirred for 10 hours under heat refluxing condition. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting solid was dried to obtain 1.46 g of 3-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH:8]=2)[CH:4]=[N:3][CH:2]=1>C(O)C>[N:3]1[CH:4]=[C:5]([CH:7]2[CH:12]3[CH2:11][CH2:10][N:9]([CH2:14][CH2:13]3)[CH2:8]2)[CH:6]=[N:1][CH:2]=1
Reactant: C1=C(c2cncnc2)C2CCN1CC2
Solvent: CCO
Product: c1ncc(C2CN3CCC2CC3)cn1
Yield: 54.1 %

Procedure:
Thionyl chloride (0.35 ml. 4.8 mmol) was added to a rapidly stirred solution of 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2] octan-3-ol (0.5 g, 2.4 mmol) in dichloromethane (15 ml), at 0° C. The solution was warmed to room temperature and stirred for 1 h before adding a second portion of thionyl chloride (0.2 ml) and refluxing for 0.25 h. The mixture was cooled to 10° C., water (10 ml) added and basified to pH >10 with potassium carbonate. Extraction into dichloromethane (3×50 ml). drying (Na2SO4) and evaporation of solvents under reduced pressure gave 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.16 g) as a yellow oil which crystallised on standing at 0° C., m/e 188 (M+H)+ ; δ (360 MHz,D2O) 1.86-1.98 (2H, m,CH2); 2.15-2.26(2H,m,CH2): 3.18-3.30 (2H,m,0.5×CH2 and CH); 3.62-3.72(3H,m,CH2 and 0.5×CH2) 7.23(1H,s,vinyl-H): 9.00(2H,s,pyrimidine-H); 9.15(1H,s,pyrimidine H). A solution of 3-(5-pyrmidinyl)-1-azabicyclo[2.2.2]oct-2-ene (0.31 g 1.66 mmol) in ethanol (40 ml) was hydrogenated over 10% pd/C (0.12 g) in a Parr apparatus. After 4 h the suspension was filtered through hyflo, the solvent removed under vacuum and, the residue chromatographed on alumina using dichloromethane/methanol (95:5) as eluant, to give 3-(5-pyrimidinyl)-1-azabicyclo[2.2.2]octane (0.17 g) as a yellow oil. The hydrochloride salt was made. m.p. 267°-270° C. (dec.); (Found C,56.00; H,6.88, N,17.74. C11H15N3.HCl.0.75H2O requires C,55.69; H,6.58; N,17.71%) m/e 189 (M+ for free base); δ (360 MHz,D2O) 1.89-1.94(2H,m,CH2); 2.13-2.24 (2H,m,CH2); 2.38-2.46 (1H, m, CH-bridgehead); 3.34-3.90(7H,m,3×CH2 --N and CH); 8.85(2H,s,pyrimidine-H); 9.09 (1H,s,pyrimidine-H).