Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Cl:3])[N:11]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd. ) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 100 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 100 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 9.3 g (0.055 mol) of a white crystal of 2-amino-6-chloropurine (yield 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24][OH:25])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38]>C1COCC1>[CH2:38]([O:25][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1)[CH:37]=[CH2:36]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydro-xyethyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol) in THF (5 mL) was added NaH (30 mg, 1.10 mmol) at 0° C. After stirring for 1 h, allyl bromide (79 mg, 0.66 mmol) was added, and the mixture was stirred at rt overnight. The reaction was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give (S)-6-(2-(allyloxy)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 92%) 1H NMR (CDCl3): 1.47-1.59 (d, 3H), 2.05-2.15 (m, 2H), 2.21-2.38 (m, 3H), 2.88-2.93 (m, 1H), 3.12-3.19 (m, 1H), 3.52-3.59 (m, 1H). 3.62-3.85 (m, 2H), 5.03-5.18 (m, 2H), 5.61-5.69 (m, 1H), 5.71-5.81 (m, 1H), 6.81-6.92 (m, 3H), 6.92-7.01 (m, 2H), 7.13-7.20 (m, 4H), 7.21-7.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[C:24]([C:18](=[CH:17][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:25]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: CCOC=C(C#N)C(=O)OCC
Product: CCOC(=O)C(C#N)=CNc1ccc(-c2ccccc2)cn1
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
A mixture of 2-amino-5-phenylpyridine (1.19 g., 6.99 mmoles) and ethyl ethoxymethylenecyanoacetate (1.18 g., 6.99 mmoles) was fused at an oil bath temperature of 100° for 15 minutes. The product was recrystallized from toluene to give the title compound (1.3 g.), m.p. 126°-134°. An additional crop of product (0.3 g.), m.p. 119°-126° was obtained from the mother liquors. Total yield of product, 1.6 g. (78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[OH:20][C:21]1[C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7](=[O:8])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:20][C:21]2[C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23][CH:24]=[CH:25][N:26]=2)[N:14]=1
Reactant: COC(=O)c1nccnc1O
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1nccnc1OCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 8 h

Procedure:
1-(3-fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate XXIII, 1.0 mmol) and methyl 3-hydroxypyrazine-2-carboxylate (1.0 mmol) were dissolved in N-methylpyrrolidinone (3 ml) and K2CO3 (1.1 eq) was added. The mixture was stirred overnight. 20 ml water was added and the product was extracted three times with dichloromethane. The organic was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography using 0-70% gradient of saturated ammonia/MeOH and dichloromethane. 1H NMR (400 MHz, DMSO-d6): 10.73 (s, 1H), 7.89 (d, 1H), 7.40 (d, 1H), 7.35 (m, 1H), 6.95-7.10 (m, 3H), 6.94 (m, 2H), 5.04 (s, 2H), 4.31 (d, 2H), 3.79 (s, 3H). MS (ES+): M/Z 418 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][OH:10]>C=C1OC(=O)C1.NCCO.C(#N)C>[C:4]([NH:7][CH2:8][CH2:9][OH:10])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCO
Solvent: CC#N
Product: CC(=O)CC(=O)NCCO
Temperature: -2.5 °C
Reaction time: 4 h

Procedure:
Acetonitrile (825 g) and diketene (55.0 g) were introduced into a 5,000 mL four-necked flask, and the mixture was cooled so that the temperature in the flask was lowered to −5 to 0° C. Diketene and 2-aminoethanol were simultaneously added dropwise for 4 hours at a rate of 261.5 g/h and 190 g/h, respectively. In such a case, about 2 hours after the commencement of dropwise addition, the reaction system became uneven, causing stirring difficulty. Therefore, cooled acetonitrile (1,000 g) was further added thereto, and dropwise addition was continued under a suspended state. During the addition, cooling was conducted to maintain the temperature in the flask at −5 to 0° C. Thereafter, 25 g of 2-aminoethanol was added dropwise at a rate of 190 g/h. The resultant was heated to room temperature and aged for 12 hours. Then, while the mixture in the flask was heated to a temperature of 50° C., acetonitrile was removed under reduced pressure, and the resulting mixture was finally kept at a pressure of about 0.001 for 4 hours, to thereby produce about 1,850 g of 2-(acetoacetamido)ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5](Cl)=[CH:4][C:3]=1[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([S:30][C:2]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:4][C:3]=2[CH:11]=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1cc(Cl)c(C=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Sc2ccccc2)c(C=O)cc1Sc1ccccc1
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A 500 ml Schlenk flask is charged under an inert atmosphere with 2,5-Dichloro-benzene-1,4-dicarbaldehyde (30.45 g, 0.15 mol), potassium carbonate (62.1 g, 0.45 mol) and dry DMF (200 ml). The flask is immersed in an oil bath of 80° C., and then without delay thiophenol (33.0 g, 0.3 mol) is added via a dropping funnel within 15 minutes. To the formed brown suspension is added water (ca. 100 ml) and the mixture is stirred for another 5 minutes. Then the contents of the flask are poured as a thin stream into a beaker which containd 2 L of vigorously stirred water. A yellow solid precipitates, and the mixture is stirred for another hour. The solid is then filtered off, washed with water (twice 250 ml), and recrystallised without further drying from THF (ca. 200 ml). The crystals of the product are filtered off, washed with little iso-propanol (ca. 50 ml) and dried to give the product (36.75 g). From the mother liquors most of the THF is removed on the rotavapor which leads to the crystallisation of another crop. This material is also filtered off and washed with little iso-propanol to give another 4.72 g of product. Bright yellow crystals, mp. 163° C. 1H-NMR (CDCl3, 300 MHz) δ 7.39 (phenyl para H); 7.40 (phenyl ortho H)); 7.41 (phenyl meta H); 7.58 (s, aryl CH); 10.27 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 129.18 (phenyl para CH); 130.19 (phenyl ortho CH); 132.47 (phenyl ipso C); 133.20 (phenyl meta CH); 133.75 (aryl CH); 136.79 (CCHO); 139.54 (CS); 190.45 (CHO).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([O-:15])=[O:14].[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>O1CCOCC1>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:34][CH2:33][C:32]([O:36][CH3:37])=[O:35])[CH:20]=[C:19]2[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([O-:15])=[O:14]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])c1ccc2[nH]cc(Cc3cccnc3)c2c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 1.25 h
Yield: 74.5 %

Procedure:
Benzyltrimethylammonium hydroxide (0.8 ml of 40% solution in methanol) was added to a stirred mixture of 5-nitro-3-(3-pyridylmethyl)-1H-indole (7.34 g) and methyl acrylate (3.0 g) in dioxan (140 ml) and the resulting solution was stirred for 75 minutes and then evaporated. The residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from ethyl acetate/hexane to give the title compound (7.33 g), m.p. 101°-102° C. Found: C,63.85; H,4.86; N,12.37. C18H17N3O4 requires: C,63.71; H,5.05; N,12.38%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: COCCC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Product: COCCc1noc(C2CC(c3ccc(C)c(C(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.48 mmol) of the compound from Example 163A and 114 mg (0.72 mmol) of t-hydroxy -3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 2. Yield: 105 mg (44% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19].C(N(CC)CC)C>C1COCC1.O>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:24])[CH3:19]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.71 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (prepared as described in example 10 step A, 4 g, 15.26 mmol) in THF (25 ml) at 0° C. was added chlorocarbonyl-acetic acid ethyl ester followed by triethyl amine (3.2 ml, 22.89 mmol) drop wise under nitrogen, then the reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with water (50 ml), and extracted with EtOAc (3×75 ml). The organic phases were combined and washed with brine (40 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc/hexane) to afford N-[4-chloro-2-(2-chloro-phenylethynyl)-phenyl]-malonamic acid ethyl ester (3.6 g, 62.71%) as an off white solid. LC-MS (ESI): 376 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:13]([CH:36]=1)[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])(=O)C.C(O)(=O)C>CO.O1CCOCC1>[CH2:38]([O:37][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][OH:6])=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)OCCc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.37 mL) was added to a solution mixture of tert-butyl 2-(5-(2-acetoxyethyl)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.38 g) in methanol (1.9 mL) and dioxane (1.9 mL), followed by stirring at room temperature for 2 hours. Acetic acid (0.012 mL) was added to the reaction mixture. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 0.35 g of tert-butyl 2-(2-(benzyloxy)-5-(2-hydroxyethyl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]1[NH:8][CH2:7][CH2:6][N:5]2[CH2:9][C@H:10]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH2:11][CH2:12][C@@H:4]12.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:8]1[CH2:7][CH2:6][N:5]2[CH2:9][C@H:10]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH2:11][CH2:12][C@H:4]2[CH2:3]1
Reactant: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Temperature: 95 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 0.49 g (1.38 mmol) of 1-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one dihydrochloride, 0.157 g (1.37 mmol) of 2-chloropyrimidine and 0.64 g (6.02 mmol) of sodium carbonate in 20 mL of water was stirred at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with chloroform (3×), the combined organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 0.181 g (30%) of the title compound. mp (—HCl) 174-176° C. HRMS calcd for C21H25N5O: 363.2059, found: 363.2032.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:37]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])=[O:38])[CH2:13][CH2:14]2)=[CH:8][CH:7]=1
Reactant: CCCCCCCNCC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-ethoxy-3-[4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-propionic acid methyl ester (54 mg, 0.13 mmol), and 2,4-difluorophenylisocyanate (0.156 mmol, 0.0185 mL) in toluene (2.5 mL) was added N,N-diisopropylethylamine (0.29 mmol, 0.050 mL). The mixture was allowed to stir at room temperature for 18 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (1×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate/hexanes to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear film (50 mg, 73%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C(O)C(N)(CO)CO.C([O-])(=O)C(CC([O-])=O)O.[N+](C1C=C([N+]([O-])=O)C=C(C(O)=O)C=1O)([O-])=O>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NC(CO)(CO)CO
Agent: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 0.17 h
Yield: 0 %

Procedure:
Escherichia coli HB101 (pAX1) (FERM BP-950) and Escherichia coli HB101 (pXP102-3) (FERM BP-951) obtained in Examples 2 and 3, respectively were cultured at 37° C. with shaking in LB broth not containing glucose (containing 10 g of tryptone (Difco), 5 g of yeast extract, 20 μg/ml of ampicillin and 10 g of NaCl in one liter of water and adjusted to pH 7.0). The cell growth (cell weight) was measured by optical density at 660 nm. Penicillinase activity was measured by a modified Sargent's method (Sawai et al: Antimicrob. Agents Chemother. 13, 910 (1978)), wherein the amount of penicillinase hydrolysing one micromole of benzyl penicillin per minute at 30° C. was taken as one unit. Xylanase activity was measured as follows: To 0.05 ml of enzyme solution, there were added 0.1 ml of xylan solution (produced by SEI-KAGAKU KOGYO, Japan) and 0.1 ml of 0.2M Tris malate buffer (pH 8.0) and the reaction was allowed to proceed at 40° C. for 10 minutes. DNS (3.5-dinitrosalicylic acid) (1 ml) was added and reacted at 100° C. for 5 minutes. Water (4 ml) was added and absorbance at 510 nm was measured. The amount of enzyme showing a reducing power producing 1 mg of xylose per minute was taken as one unit of xylanase.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9](Br)[N:8]([CH2:22][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24][CH:25]=[CH2:26])[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2C(C3C=NC4C(C=3)=CC=CC=4)=C3N(C=2N=CN=1)C[C@@H](NC(=O)OC(C)(C)C)CC3>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][N:8]3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=CC[C@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Yield: 73.2 %

Procedure:
In accordance with Example 10, except that the (R)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)penta-4-en-2-yl)carbamate (690 mg) obtained in Reference Example 9 was used in place of the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Example 10, the title compound (429 mg) (yield: 73%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][C:15]([O:17]CC)=O)[CH:7]=[CH:6]2.[NH2:21][NH2:22]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH2:14][C:15](=[O:17])[NH:21][N:22]=1)[CH:7]=[CH:6]2
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc2cc(OC)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2cc(C3=NNC(=O)C3)ccc2c1

Procedure:
Ethyl 3-(6-methoxy-2-naphthyl)-3-oxopropanoate (5.0 g, 18.3 mmol) and anhydrous hydrazine (0.63 ml 20 mmol) were refluxed in HOAc (100 ml) for 3 hours. Solvent was removed under reduced pressure, and the residue was washed with DCM and collected by filtration to give 5-(6-methoxy-2-naphthyl)-2,4-dihydro-3H-pyrazol-3-one as an off-white solid. This compound exists in the enol form in DMSO. NMR (500 MHz, DMSO-d6) δ: 3.87 (s, 3H); 5.95 (s, 1H); 7.17 (dd, J=2.7 Hz, 9.0 Hz, 1H); 7.31 (d, J=2.7 Hz, 1H); 7.74˜7.84 (m, 3H); 8.11 (br s, 1H); 9.66 (br s, 1H); 12 (br, 1H). MS C14H12N2O2 Cald: 240.09, Obsd: (M+1) 241.08.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[OH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:1]=1
Reactant: OCc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(CO)cc1
Yield: 79.7 %

Procedure:
Using as starting materials 1.00 g of p-hydroxybenzyl alcohol and 1.61 g of ethyl 2-bromopropionate, 1.44 g of ethyl 2-[p-(hydroxymethyl)phenoxy]propionate was obtained in a manner similar to Reference Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:41])[CH3:40])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Product: CC(=O)Nc1ccc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and acetic anhydride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]-acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][C:35]([OH:39])([CH3:38])[CH2:36]O.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:34][C:35]([CH3:38])([OH:39])[CH3:36])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)CO
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)O
Temperature: 10 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
N-Benzyloxycarbonyl-L-valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol), and), and dicyclohexylcarbodiimide (2.04 g, 9.9 mmol, in 20 mL CH2Cl2) were added to 2-methyl-1,2-propanediol (12.2 mmol) in 30 mL dry CH2Cl2, with cooling in an ice bath. DMF (5 mL) was added. After stirring for 5 h at 10° C., the reaction mixture was filtered, concentrated, and then redissolved in ethyl acetate. The organic solution was washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated. Flash column chromatography (silica, 2/1 petroleum ether—ethyl acetate) gave 2.3 g of the title compound.