Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([OH:17])[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[Cl:36])[N:29]([CH3:37])[N:28]=1>>[Cl:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH3:37])[N:28]=[C:27]([CH2:26][O:17][C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=3[CH3:16])[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[O:18])[C:35]=12
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide (127.4 mg, 0.487 mmol) and potassium carbonate (77.7 mg, 0.551 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.6 mg, 0.346 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 17) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-N-(4-chloro-phenyl)-4-methyl-benzamide as a white solid. (Yield 25.0 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:4][C:3]1=[O:27]>C(OCC)(=O)C.CCOCC.[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:3]1=[O:27]
Reactant: O=C(CCCCOC1=CC(=O)C(=O)c2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Reaction time: 10 h
Yield: 37 %

Procedure:
Benzyl ester 502 (1.90 g, 5.22 mmol) was hydrogenated at 30 psi with Pd (400 mg) in ethyl acetate (120 mL) for 6 h. The catalyst was removed by filtration through celite, the solvent was evaporated in vacuo and the residue was oxidized with Ag2O (1.45 g, 6.25 mmol) in Et2O by stirring for 10 h. Following filtration and evaporation of the solvent the product was crystallized from benzene to afford 0.53 g of pure material. The mother liquor was purified by flash chromatography (CH2Cl2/MeOH 15:1), the product dissolved in CH2Cl2, extracted with aqueous NaHCO3 solution, acidified to pH 1 with 3% HCl and extracted back with CH2Cl2 to give additional 0.25 g of pure material (total yield 55%), mp 134-136° C.; 1H NMR (CDCl3) 8.12 (d, J=7.0 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H), 7.27 (s, 1H), 4.18 (t, J=5.9 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 1.75-2.15 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:22]([C:21]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=3[Cl:19])=[O:23])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)cc4Cl)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Dichlorobenzoyl chloride (85.9 mg; 0.41 mmol) to obtain 48.1 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br d, 1H), 7.76 (s, 1H), 7.54 (s, 2H), 7.41 (m, 2H), 7.07 (br d, 1H), 6.98 (br d, 1H), 6.83 (t, J=7.6 Hz, 1H), 4.58 (br d, 1H), 3.42 (m, 2H), 3.16 (m, 2H), 2.99 (m, 1H), 2.74 (m, 2H). ESIMS+419.3 m/z
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][CH2:6]2.N.[Li].CO>O1CCCC1.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][CH2:14][OH:15])[C:10]=2[CH2:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCC2CCO
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)(C)O
Product: COC1=CCC2=C(CCCC2CCO)C1
Reaction time: 3 h
Yield: 126 %

Procedure:
A solution of 1 g (4.8 mmole) of the alcohol product from Example 3 in 15 ml of tetrahydrofuran and 15 ml of t-butyl alcohol was cooled to less than 0°, and 45 ml of distilled liquid ammonia was added. This was followed by the addition over a ten-minute period of 600 mg (86 mmole) of lithium. After three hours, methanol was added to the reaction mixture until the blue color disappeared, and the ammonia was then evaporated under a stream of nitrogen. The residue was dissolved in 5 ml of water, extracted with diethyl ether and acidified with 5% hydrochloric acid. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was chromatographed on silica gel to give 1.26 g of the title compound, contaminated with t-butanol. Structure assignment was confirmed by the proton nmr spectrum.
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[Br:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:12]([F:21])[CH:11]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([CH3:37])[C:29]=1[S:30]([CH2:33][N+:34]([O-:36])=[O:35])(=[O:32])=[O:31])[NH2:26]>O1CCCC1.O>[Br:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([S:17]([NH:26][C:25]2[CH:24]=[C:23]([CH3:22])[C:29]([S:30]([CH2:33][N+:34]([O-:36])=[O:35])(=[O:32])=[O:31])=[C:28]([CH3:37])[CH:27]=2)(=[O:19])=[O:18])=[C:12]([F:21])[CH:11]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cc(F)c(Br)cc2F)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
1.3 g (16.4 mmol) of pyridine, dried over potassium hydroxide, and then 3.6 g (12.3 mmol) of 4-bromo-2,5-difluorobenzenesulphonyl chloride are added to a solution, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 7 h 30 min at room temperature and then for 11 h at reflux; after cooling, it is poured into 300 ml of water and extracted 3 times with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 0.24 g (6.2%) of 4-bromo-2,5-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide, containing 5 mol % of ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.C([Li])CCC.CCCCCC.CCOCC.I[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][Cl:40])=[CH:34][CH:33]=1>[Cl-].[Zn+2].[Cl-].O1CCCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][Cl:40])=[CH:34][CH:33]=3)[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: ClCCc1ccc(I)cc1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(-c2ccc(CCCl)cc2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
To a 1 L 3-neck round-bottomed flask equipped with addition funnel and nitrogen inlet were added 10.0 g (40 mmol) 2-bromo-6-(2, 5-dimethylpyrrol-1-yl)pyridine and 200 mL dry tetrahydrofuran. The solution was cooled at −78° C., and a 1.6 M solution of butyl lithium in hexane (25 mL, 40 mmol) was added dropwise over 10 min. The reaction was stirred at −78° C. for 20 min, then a 1.0 M solution of zinc chloride in ether (100 mL, 100 mmol) was added dropwise over 40 min keeping the temperature at −70° C. The reaction was then allowed to warm to room temperature, and 11.0 g (40 mmol) 2-(4-iodophenyl)ethylchloride was added, followed by 200 mg tetrakistriphenylphosphine palladium. The reaction was refluxed for 3 hours, cooled, and filtered through Celite. The filtrate was evaporated, and the residue taken up in ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated. The residue was filtered through silica gel with methylene chloride, concentrated, and chromatographed on silica gel using 1% ethyl acetate in hexane as eluant to afford 7.3 g (59%) of the product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1.[H][H]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2cc([N+](=O)[O-])cn(C)c2=O)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2cc(N)cn(C)c2=O)c(C)c1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a solution containing 0.17 g (0.66 mmol) of 3-(2,4-dimethylphenyl)-1-methyl-5-nitropyridin-2(1H)-one in 50 ml of ethanol was added 0.10 g of 10% palladium on carbon (Degussa type; 50% wet). The flask was fitted with a balloon of hydrogen and allowed to stir for 5 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure to afford 0.063 g (41.9%) of product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[N+](=[CH2:20])=[N-]>O1CCCC1.CCOCC>[CH3:20][O:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CO)C2
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCC1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
To a solution of 2,3,6,7,8,9-hexahydro-2-hydroxymethyl -5-methylfuro-[2,3-f]quinoline-7-one (300 mg) in tetrahydrofuran (100 ml), silica gel (10 g) and a solution of diazomethane in ether (200 ml) were added, and stirred at room temperature for 36 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 280 mg of the target product as a pale yellow powder (88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([NH2:28])[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([NH:28][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: Brc1ccc2cnccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](Nc2ccc3cnccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
124 mg of 6-bromoisoquinoline (3), 488 mg of cesium carbonate and 202 mg (2S,4R)-4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester hydrochloride were dissolved in 6 ml of DMF and degassed. 46 mg Palladium acetate and 132 mg of Xanthphos were added and the mixture was stirred at 100° C. for 5 h. After cooling to rt the mixture was filtrated, evaporated and the residue was purified by chromatography on silica gel (50% ethyl acetate in heptane to 100% ethyl acetate). To obtain (2S,4R)-4-(Isoquinolin-6-ylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colourless oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=[O:29])[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].Cl([O-])=O.[Na+].[OH-].[Na+].[C:37](#N)C>O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][O:29][CH3:37])[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:2])[CH3:3]
Reactant: CC#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=O)cccc21
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: O
Product: COCc1cccc2c1nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-4-carbaldehyde (37 mg, 0.091 mmol) and sodium chlorite (12 mg, 0.11 mmol) in water (1 mL) and acetonitrile (1 mL) was stirred at room temperature for 8 hrs. An additional amount of sodium chlorite (12 mg) was added and stirring was continued overnight. 1M NaOH was added and the mixture was extracted with ethyl acetate (twice). The aqueous phase was acidified with 1M HCl until pH 4. The resulting suspension was extracted with ethyl acetate (2×10 mL) and the combined organic phases washed with water, brine, and dried (MgSO4). The pure title compound (8 mg, 21%) was obtained as a white solid:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O-:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1
Agent: C[C@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1

Procedure:
The salt from Step B was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of EtOAc. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=+21.6 (c=2.55).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][C:9]([CH3:19])([CH3:18])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: C#CC(O)(CCC)CCC
Reactant: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(CC(C)(C)CNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (30) (0.489 g, 1.45 mmol) was coupled with 4-ethynylheptan-4-ol (20) (0.28 g, 2.0 mmol) following the method described in Example 15 and the product was purified by flash chromatography (0 to 50% EtOAc-hexanes gradient) to give 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-2,2-dimethylpropyl)acetamide (31) as a yellow oil. Yield (0.350 g, 61%): 1H NMR (400 MHz, CD3OD) δ 7.20-7.25 (m, 3H), 7.12-7.15 (m, 1H), 3.19 (s, 2H), 2.54 (s, 2H), 1.58-1.71 (m, 8H), 0.98 (t, J=7.2 Hz, 6H), 0.85 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C=O)C>[CH2:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1)[CH3:19]
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc([N+](=O)[O-])c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a DMF (20 mL) solution of 5-bromo-3-methoxy-2-nitropyridine (726 mg) synthesized according to the method described in Acta Chemica Scandinavica vol. 47, p. 805, 1993, ethyl acrylate (0.44 mL), palladium acetate (35 mg), 2-(di-tert-butylphosphino) biphenyl (93 mg) and TEA (0.87 mL) were added, and the reaction solution was agitated at 80° C. for 3 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution to separate an organic layer. After the obtained organic layer was dried over anhydrous magnesium sulfate, solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 787 mg (69%) of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CC(C)=O>[I:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: ClCc1ccncc1
Reactant: Oc1ccccc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1ccccc1OCc1ccncc1
Yield: 53 %

Procedure:
4-Picolyl chloride hydrochloride (4.00 g, 24.4 mmol) was dissolved in acetone (55 mL), potassium carbonate (10.1 g, 73.2 mmol) and o-iodophenol (6.97 g, 31.7 mmol) were added, and the mixture was heated under reflux for 24 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained crystals, and the mixture was suction-filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (4.02 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:20](N)=[NH:21]>C(N)=O>[CH3:18][O:17][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:1]=[CH:20][NH:21][C:4]2=[O:5]
Reactant: COCCOc1cc(N)c(C(=O)OC)cc1OC
Reactant: N=CN
Agent: Cl
Solvent: NC=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 140 °C
Yield: 73.6 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-5-methoxy-4-(2-methoxyethoxyl)benzoate (2.69 g, 10.5 mmol) and formamidine hydrochloride (1.208 g, 15 mmol) in formamide (10 mL) was heated at 140° C. for 8 hours, to afford 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one as a white solid (1.935 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.72 (t, 2H), 3.32 (s, 3H); LC-MS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:13][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cnc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
To a mixture of 6-chloro-5-fluoropyridin-3-ol (2.43 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (3.46 g), triphenylphosphine (6.48 g) and THF (25 mL) was added dropwise a toluene solution (1.9 M, 13.0 mL) of diisopropyl azodicarboxylate at room temperature, and the obtained mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.88 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC(C)C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (224 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (310 mg, 74%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.N1C=CC=CC=1>O1CCCC1>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:27][CH:26]=2)=[O:30])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:18])[CH3:19]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
A suspension in tetrahydrofuran (2.0 ml) containing 100 mg of ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate, 150 mg of α,α,α-trifluoro-p-tolylisocyanate and 35 μl of pyridine was stirred at room temperature for 14 hours. The solvent was removed, and the residue was treated with dichloromethane. After filtering off insoluble substances, the residue was purified by silica gel column chromatography, to give 149 mg of the title compound.
Reaction SMILES: [C:1]([CH:4]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nn12

Procedure:
Analogously to Example 1, 150 mg (0.32 mmol) of 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide (Example 28A) and 250 g (1.61 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetylheptyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.