Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.[OH-].[Na+].Cl>CO>[CH3:1][CH:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: CC1CNC(=O)c2cc3ccc(C(=O)[O-])nc3n21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNC(=O)c2cc3ccc(C(=O)O)nc3n21
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a suspension of 9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylate (298 mg, 1.09 mmol) in methanol (0.5 mL) is added a solution of 2M aqueous NaOH (2.2 mL, 4.4 mmol). The mixture is warmed to 60° C. and stirred for 2 h, at which point it is acidified with concentrated HCl. The volume of the mixture is reduced to approximately 5 mL, and it is chilled to 0° C. The resultant suspension is filtered and the solid is washed with H2O and hexanes, to provide the title compound as a light yellow solid (135 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH2:6][CH2:5]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc2c(cc1Br)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc2[nH]ccc2cc1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a solution of 5-bromo-6-nitro-2,3-dihydro-1H-indole (20 g, 82.3 mmol) in 1,4-dioxane (400 mL) was added DDQ (30 g, 0.13 mol). The mixture was stirred at 80° C. for 2 h. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford 5-bromo-6-nitro-1H-indole (7.5 g, 38%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][N:4]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC.[I-].[Na+]>[I:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:8]=1
Reactant: C1COCCN1
Reactant: BrCc1cc(I)ccn1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: Ic1ccnc(CN2CCOCC2)c1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
2-(Bromomethyl)-4-iodopyridine (500 mg, 1.68 mmol) in 1,2-dimethoxyethane (15 ml) was treated with morpholine (1.00 g, 11.48 mmol) and sodium iodide (13 mg, 0.09 mmol) and the resulting solution was heated at 90° C. for 5 h. After cooled to room temperature, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give 4-[(4-iodo-2-pyridinyl)methyl]morpholine as a brown solid (315 mg, 62% yield).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cccc4C#N)cc23)ncn1
Temperature: 150 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile (158 mg, 0.45 mmol), 4-amino-6-methylpyrimidine (55 mg, 0.5 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (26 mg, 0.045 mmol) and cesium carbonate (293 mg, 0.9 mmol) in dioxane (3 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80-90% ethyl acetate in cyclohexane) to afford the title compound as a beige solid (81 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.48 (d, J=2.6 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.38 (s, 1H), 8.23-8.20 (m, 2H), 8.03 (d, J=3.5 Hz, 1H), 7.92 (t, J=8.1 Hz, 1H), 2.46 (s, 3H). LCMS (Method B): RT=3.04 min, m/z: 380 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonyl-amidino)-2-benzofurancarboxylic acid (183 mg, 0.541 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (124 mg, 0.541 mmol) were condensed, and purified by silica gel column chromatography (methylene chloride/methanol=30/1-10/1) to give 251 mg of compound (170) as a colorless solid (84%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 48.5 %

Procedure:
Into a 1-neck round-bottom flask was added 4-fluoro-3-nitrobenzotrifluoride (1.62 mL, 0.012 mol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (4.00 g, 0.017 mol), cesium carbonate (11.3 g, 0.035 mol), and DMF (100 mL). The reaction was allowed to stir and heat at 60° C. overnight. The reaction mixture was allowed to cool to rt and diluted with EtOAc and water. The organic solution was separated, washed with water and brine, and concentrated to yellow oil. The residue was purified by column chromatography to give tert-butyl 4-{2-[2-nitro-4-(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate (2.44 g, 48%) as a brown oil. LCMS: (AA) ES+420.1.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18]Cl)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.Cl>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18][NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: NCc1ccccc1
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCCl)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCNCc2ccccc2)c1=O

Procedure:
A mixture of 5-butyl-7-(2-chloroethyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.6 g, 2 mM) and benzylamine (0.66 ml, 6 mM) in dioxane (20 ml) was refluxed for 20 hours. The reaction solution was concentrated to dryness under reduced pressure to give a syrup, which was poured onto ice-water to give colorless crystals. The crystls were dissolved in 1N-HCl and insoluble material was filtered off, followed by addition of 1N-ammonia water to give crystals. Recrystallization from DMF/methanol/water afforded colorless needles (0.32 g, 43%), m.p. 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH2:17])=[O:4].[F:18][C:19]1[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:20]=1N.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:15][CH2:16]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:20]1[CH:21]=[CH:22][C:23]([S:25][CH3:26])=[CH:24][C:19]=1[F:18])=[O:4]
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(=O)c1c(N)c2cnccc2n1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
In a high-pressure tube was placed 3-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (307.6 mg, 1.33 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (500.0 mg, 2.26 mmol, 1.7 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.5 mg, 0.20 mmol, 1.5 eq), tris(dibenzylideneacetone)di-palladium(0) (91.4 mg, 0.10 mmol, 0.75 eq), and potassium phosphate (564.7 mg, 2.6 mmol, 2.0 eq) in degassed anhydrous toluene (21 mL). The tube was sealed tightly and the reaction mixture was heated to 100° C. for 17 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 ml) and then filtered through a pad of Celite®. The celite pad was rinsed with EtOAc (2×50 mL), and the filtrate was concentrated under reduced pressure. The crude residue was then purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the title compound as an orange glassy solid (339.6 mg, 68.7%). 1H-NMR (500 MHz, MeOD) δ ppm 8.36 (s, 1H), 8.24 (d, J=6.13 Hz, 1H), 7.59 (d, J=6.14 Hz, 1H), 7.14 (d, J=11.72 Hz, 1H), 7.08-6.93 (m, 2H), 3.95 (s, 3H), 3.59-3.47 (m, 1H), 2.47 (s, 3H), 1.25-1.21 (m, 2H), 0.92-0.89 (m, 2H); LC-MS (method C): [M+H]+=371.8, RT=0.80 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:29]\[C@H:30]3[CH2:50][CH2:49][C:32]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:33]4)[CH2:31]3)/[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[ClH:51].Cl.C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[ClH:51].[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:29]\[C@H:30]3[CH2:50][CH2:49][C:32](=[O:33])[CH2:31]3)/[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)O)cn1)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](/C=C(/C(=O)Nc2ccc(C(=O)O)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]prop-2-enoyl}amino)nicotinic acid (194 mg) in 1,4-dioxane (4 mL) was added 4 M hydrochloric acid (4 mL), followed by stirring at 50° C. for 2 hours. After leaving it to be cooled to room temperature, saturated brine was added thereto. After extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was dissolved in ethyl acetate (4 mL), and 4 M hydrogen chloride/ethyl acetate (1 mL) was added thereto. It was stirred at room temperature for 30 minutes and concentrated. The obtained oily substance was solidified with diisopropyl ether and collected by filtration to obtain 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-oxocyclopentyl]prop-2-enoyl}amino)nicotinic acid monohydrochloride (87 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:20])=[CH:14][C:13]([CH3:35])=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[CH2:25][CH2:26][N:21]([C:19](=[O:20])[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:35])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:3][CH:4]=2)[CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Br)cc3)[nH]c3ccc(C)cc23)CC1
Reactant: OB(O)c1ccccc1
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(-c4ccccc4)cc3)[nH]c3ccc(C)cc23)CC1

Procedure:
Prepared from 1-{3-[2-(4-bromophenyl)-5-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 1) and phenylboronic acid according to the method of Example 117. 1H NMR (360 MHz, CDCl3) δ8.05 (1H, br s), 7.71-7.61 (6H, m), 7.48-7.44 (3H, m), 7.39-7.35 (1H, m), 7.29-7.25 (1H, m), 7.06-6.98 (2H, m), 6.90-6.77 (3H, m), 3.82 (3H, s), 3.78 (2H, t, J 5.0 Hz), 3.46 (2H, t, J 5.0 Hz), 3.33 (2H, m), 2.92 (2H, t, J 5.0 Hz), 2.74 (4H, m), and 2.48 (3H, s). m/z (ES+) 530 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5](=O)[O:6][C:7]=1[CH3:8].[NH3:11]>O1CCOCC1>[CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([OH:6])=[N:11][C:7]=1[CH3:8]
Reactant: N
Reactant: Cc1oc(=O)cc(O)c1C
Solvent: C1COCCO1
Product: Cc1nc(O)cc(O)c1C
Temperature: 25 °C

Procedure:
5,6-Dimethyl-4-hydroxy-2-oxo-2H-pyran (J. Chem. Soc. Perkin Trans 1, 1980, 2272) (10 g, 71 mmol) was dissolved in 66 mL of dioxan and 33 mL of 0.88 NH3 solution and the mixture refluxed for 3 h. The resulting suspension was then allowed to cool to room temperature overnight, filtered and the solid collected and dried in vacuo to provide the title compound as a white crystalline solid (6.5 g). The filtrate was concentrated to approximately 10 mL in vacuo, and a second crop of solid collected by filtration (1.0 g). Both crops were combined and used in the next synthetic step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:26]([CH2:27][CH3:28])[N:25]=[N:24][CH:23]=1>>[CH2:27]([N:26]1[C:22]([CH2:21][O:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)=[CH:23][N:24]=[N:25]1)[CH3:28]
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: CCn1nncc1CO
Product: CCn1nncc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl)-1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 34 step b) and 5-hydroxymethyl-1-ethyl-1,2,3-triazole (prepared as described in Example 97 part b), following the procedure given for Example 71 but performing the reaction at −45° C.; 1H NMR (360 MHz, CDCl3) δ 1.62 (3H, t, J=7.2 Hz, CH3), 4.58 (2H, q, J=7.3 Hz, CH2), 5.81 (2H, s, CH2), 7.25 (1H, d, J=1.8 Hz, Ar—H), 7.84 (1H, m, Ar—H), 7.99 (1H, m, Ar—H), 8.08 (1H, s, Ar—H), 8.14 (1H, d, J=7.8 Hz, Ar—H), 8.66 (1H, d, J=1.8 Hz, Ar—H), 8.72 (1H, d, J=7.8 Hz, Ar—H); MS (ES30) m/e 363 [MH]+; Anal. Found. C, 56.47; H, 3.68; N, 30.82. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[NH:11]([CH2:18][CH2:19][OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([OH:8])[CH2:7][N:11]([CH2:18][CH2:19][OH:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Reactant: OCCNc1ccccc1
Product: OCCN(C[C@H](O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
To (R)-4-chloro-styrene oxide (1.55 g, 10.0 mmol), 2-anilinoethanol (1.44 g, 1.05 equivalents) was added; and the mixture was stirred at 60° C. for 15 hours. The mixture was cooled to room temperature to obtain 3.38 of the reaction mixture of the title compound (chemical purity: 52.1 area %, 2-anilinoethanol: 1.5 area %, 28.4 area % of regioisomer was contaminated). The reaction mixture was purified by column chromatography (gel: silica gel, solvent: ethyl acetate/hexane=1/1), and the obtained fractions were concentrated and dried under vacuum, to obtain 1.68 g of the title compound as pale yellow oil (yield: 49%, chemical purity: 91.7 area %; 2-anilinoethanol was not detected; 4.7 area % of regioisomer was contaminated). The retention time in the chemical purity analysis method was 5.6 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Product: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-Chlorosulfonyl-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Keana et al. (J. Org. Chem. 48:3654 (1983)). To 1,4-dihydro-2,3-quinoxalinedione (1.0 g, 6.2 mmol) was added all at once 3.0 mL of chlorosulfonic acid. The mixture was stirred under N2 at 60° C. for 2 h, allowed to come to room temperature and the solution added slowly dropwise to 25 mL of crushed ice. The resulting solid was vacuum filtered and rinsed with ice/H2O. The white solid was further dried at 0.5 torr (25° C.) over CaSO4 to yield 1.1 g (68%). 1H NMR (d6 -DMSO) δ7.07 (d, J7-8 =8.1, 1H, H8), 7.29 (dd, J7-8 =8.1, J6-7 =1.0, 1H, H7), 7.40 (d, J5-7 =1.0, 1H, H5). EIMS m/z 262 (M+2, 15), 260 (M+, 40), 225 (35), 105 (43), 36 (100, bp). EIHRMS calc. for C8H5ClN2O4S 259.9687, found 259.9645.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH2:15][O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH2:22]Cl)=[CH:5][N:4]=1.[SH2:24]>CN(C)C=O>[CH3:2][C:3]1[C:8]([O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH2:15][O:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH2:22][SH:24])=[CH:5][N:4]=1
Reactant: CCOC(=O)OCc1c(CCl)cnc(C)c1OC(=O)OCC
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)OCc1c(CS)cnc(C)c1OC(=O)OCC

Procedure:
A solution of 0.4 moles sodium in absolute dimethylformamide is saturated by passing in hydrogen sulfide for 5 hours. There is then added in portions 0.05 moles of 2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-chloromethylpyridine and the mixture stirred overnight at room temperature with hydrogen sulfide slowly bubbling through the mixture. The reaction mixture is then concentrated in vacuo and taken up between ethyl acetate and water containing acetic acid. The ethyl acetate layer is removed, dried over sodium sulfate and concentrated to give 2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-mercaptomethylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
A mixture of (4-tert-butoxycarbonylaminopiperidin-1-yl)acetic acid (0.50 g; 1.94 mmol), phenylamine (0.18 mL; 1.94 mmol), the coupling reagent TBTU (0.62 g; 1.94 mmol) and DIPEA (0.35 mL; 2.0 mmol) in DMF (5 mL) is stirred at r.t. over night. The solvent is evaporated and the residue is purified by silica gel column chromatography (DCM:MeOH=40:1) to give tert-butyl N-[1-(2-anilino-2-oxo-ethyl)-4-piperidyl]carbamate.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=1)[C:26]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To a solution of m-phenoxybenzyl alcohol (1.89 g) and pyridine (1 ml) in methylene chloride (6 ml) is added a methylene chloride (7 ml) solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride, prepared from the corresponding acid (2.46 g) as illustrated in Example 15. After stirring the reaction mixture overnight, it is washed with water, diluted hydrochloric acid solution, dilute potassium hydroxide solution, water and evaporated to an orange oil. Purification by silica gel chromatography gives the desired ester (2.76 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH3:12]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]([NH2:12])=[O:11]
Reactant: O=C=Nc1cc(F)ccc1F
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)Nc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 2,5-difluorophenyl isocyanate (1 g, 6.45 mmol) in tetrahydrofuran (50 mL) at 0° C. was added a 28% aqueous solution of ammonia (30 mL). The mixture was stirred for 1 h allowing the temperature to warm up to room temperature, then concentrated under reduced pressure, taken into water and filtered. The solid was washed twice with water and with ether, then dried at 65° C. under reduced pressure to give 740 mg (67%) of intermediate 6.