Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[N:4]=[N:3][N:2]=1.CC1(C)C(C)(C)OB(C2C=CC([C:41]3[S:42][CH:43]=[CH:44][C:45]=3[NH:46][S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=CC=2)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CN(C=O)C.O.CCOC(C)=O>[N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:41]3[S:42][CH:43]=[CH:44][C:45]=3[NH:46][S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccc(CC3N=NN=N3)cc2)cc1)C(F)(F)F
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(Cc3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
Deoxygenate and heat a mixture of trifluoro-methanesulfonic acid 4′-(5H-tetrazol-5-ylmethyl)-biphenyl-4-yl ester (48mg, 0.2 mmol), propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (95 mg, 0.24 mmol, 1.2 eq.), barium hydroxide octahydrate(189 mg, 0.6 mmol, 3 eq.) and Pd(dffp)(29 mg, 0.04 mmol, 0.2 eq.) in 2 ml DMF and water mixture (4/1, v/v) to 80° C. overnight. Cool the mixture to room temperature and dilute with 30 mL EtOAc. Wash with water (3×10mL) and saturated aq. sodium chloride, dry, and remove solvent. Purification by flash chromatography (Silica gel-CH2Cl2:MeOH(1/50, v/v)) affords the title compound 50 mg(53%). MS (m/e): 441.1(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].C(Cl)(Cl)Cl.[CH3:18][NH2:19]>O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[NH:19][CH3:18])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccsc1C(=O)OC

Procedure:
43.5 G. (0.18 mol) of the obtained 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in 450 ml. of absolute chloroform and dry methylamine is led through the solution at 10° C. until a moistened pH paper shows an alkaline reaction with the solution. The mixture is then allowed to react at room temperature for a further 2 hours, the solution always remaining alkaline. The solution is then shaken out with 500 ml. of water and 500 ml. of a 5% sodium bicarbonate solution [the aqueous phases are back-extracted in each case once with chloroform]. The combined organic phases are dried over sodium sulfate and then evaporated. The crystalline residue is digested with ether for purification. There is obtained 3-methylsulfamoylthiophene-2-carboxylic acid methyl ester of melting point 115°-122° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([O:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc(CO)o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C=O)o1

Procedure:
Prepared by reacting 5-(hydroxymethyl)-2-furan-carboxaldehyde with methanesulfonic acid chloride in the presence of triethylamine in methylene chloride at ambient temperature. The crude product is further reacted without any more purification.
Reaction SMILES: [O:1]1CCN=[CH:2]1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[Li]C(CC)C.CN(C=O)C>C1COCC1>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[CH:2]([OH:1])[O:11][C:10]2=[O:12]
Reactant: C1=NCCO1
Reactant: O=C(O)c1cccc(F)c1
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of the oxazoline derivative (7.8 g, 40.4 mmol), prepared from 3-fluorobenzoic acid in tne usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.4 M solution). After 30 min, DMF (6.3 mL) was added, and the reaction mixture was stirred at -78° C. for 2 hr. Tne reaction was then quenched with water (10 mL), and the mixture was acidified witn HCl and allowed to stir for 12 hr. The layers were separated, the aqueous layer was extracted with EtOAc, and the combined organic layer was concentrated in vacuo. Tnis material was dissolved in 5% KOH (50 mL), and the base layer was washed with Et2O (2×100 mL) to remove neutrals. The resulting base layer was added to 0° C. solution of concentrated HCl (25 mL), and the resulting cold acidic solution was extracted with EtOAc (3×75 mL). Workup and drying gave a tacky yellow solid (4.4 g) which was recrystallized from CHCl3 to give the title compound (1.97 g, 30%), mp 97°-100° C.
Reaction SMILES: [C:1]1([C:7]([NH2:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)C.[CH:13]1([C:16]2[N:20](C)[C:19]([CH:22]=[O:23])=[CH:18]N=2)CC1>>[CH2:16]([N:20]1[C:19]([CH:22]=[O:23])=[CH:18][N:9]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)c1ccccc1
Agent: CCN
Product: CCn1c(C=O)cnc1-c1ccccc1

Procedure:
3-Ethyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzene carboxamide and ethylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnnc(Cl)c1Cl

Procedure:
A stirred solution of 20.0 grams of 4,5-dichloro-3-pyridazone in 150 ml of phosphorus oxychloride is heated under reflux for five hours. The excess phosphorus oxychloride is removed under reduced pressure, and the residue poured into ice water. The mixture is extracted with diethyl ether. The extract is dried with magnesium sulfate, filtered, and the filtrate concentrated to a residue. The residue is distilled under reduced pressure. A fraction, b.p. 117°-118° C./14-15 mm, 20 grams, solidifies on standing. The solid is recrystallized from acetone-water to yield 3,4,5-trichloropyridazine; m.p. 61° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)C>C1COCC1.Cl.[Zn]>[NH2:28][C:13]1[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]=12
Reactant: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
Zinc (414 mg, 0.006 mol) was added to a stirred solution of 1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (500 mg, 0.001 mol) in THF (50 mL) and concentrated HCl (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 400 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([C@@H:24]([CH2:26][CH3:27])[CH3:25])[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1)(=[O:48])=[O:47].BrBr>>[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH:56][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([C@@H:24]([CH2:26][CH3:27])[CH3:25])[CH:20]=2)=[O:30])=[N:53][CH:54]=1)(=[O:48])=[O:47]
Reactant: CC[C@@H](C)n1cc(C(=O)O)c(=O)c(Br)c1C
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: CC[C@@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)c(Br)c1C

Procedure:
Preparation 19 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 11b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum: [M+H]+=456 (bromine isotope pattern); Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: Br[C:2]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH2:6][NH:5][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:3]1.[Cl:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([F:33])=[C:30]([CH:32]=1)[NH2:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:31][C:30]1[C:29]([F:33])=[C:28]([C:6]2[N:5]=[C:4]([CH:7]3[CH2:9][CH2:8]3)[NH:3][C:2]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH:27]=[C:26]([Cl:25])[CH:32]=1
Reactant: COC(=O)N[C@@H](C)CNc1nccc(C2(Br)CNC(C3CC3)=N2)n1
Reactant: CC1(C)OB(c2cc(Cl)cc(N)c2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCOC
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(Cl)cc(N)c2F)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1b, 0.59 g, 1.5 mmol) in DME (15 mL) was added a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-5, (˜12 mL, 0.25 M solution in dioxane; 3.0 mmol) and aqueous Na2CO3 solution (6 mL, 2.0 M, 12.0 mL). The resulting mixture was sparged with nitrogen, and Pd(PPh3)4 (87 mg, 0.075 mmol) was added. The reaction mixture was sealed and subjected to microwave irradiation at 120° C. for about 20 minutes. The reaction was allowed to cool to room temperature and partitioned upon standing. The layers were separated and the organic portion was concentrated, dissolved in EtOAc (150 mL), washed with water (50 mL), followed by extraction with aqueous 0.01 M HCl solution (2×100 mL) and aqueous 0.02 M HCl solution (2×100 mL). The combined acidic aqueous portions were neutralized with saturated aqueous NaHCO3 solution, and extracted with EtOAc (2×225 mL). The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to yield (S)-methyl 1-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (530 mg) which was carried forward without further purification. LCMS (m/z) 460.2 (MH+), tR=0.57 minute.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:4]([Cl:14])[N:3]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH2:41])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.O>[CH3:26][O:27][C:28](=[O:42])[C@@H:29]([NH:41][C:11](=[O:13])[CH2:10][CH2:9][S:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35]
Reactant: COC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C
Reactant: Nc1nc(Cl)cc(SCCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
3-(2-Amino-6-chloropyrimidin-4-ylsulfanyl)propionic acid (211 mg, 0.903 mmol) obtained in Step 1 of Example 2-8 was dissolved in a mixture of dichloromethane (5.0 ml) and N,N-dimethylformamide (2.0 ml), and then 1-hydroxybenzotriazole monohydrate (139 mg, 0.887 mmol), (S)-2-amino-5-tert-butoxycarbonylaminopentanoic acid methyl ester (202 mg, 0.822 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (173 mg, 0.902 mmol), and diisopropylethylamine (0.157 ml, 0.901 mmol) were added thereto. After the resulting mixture was stirred at room temperature for four hours, water (30 ml) was added to the reaction solution. The mixture was extracted three times with ethyl acetate (30 ml). The organic layers were combined together and then sequentially washed with a saturated aqueous sodium chloride solution (20 ml), a saturated aqueous sodium bicarbonate solution (20 ml), and a saturated aqueous sodium chloride solution (20 ml). The washed organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=30:1) to yield (S)-2-[3-(2-amino-6-chloropyrimidin-4-ylsulfanyl)propionylamino]-5-tert-butoxycarbonylamino pentanoic acid methyl ester (359 mg) as a white amorphous material.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>C1COCC1>[CH:19]1([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:27]=[CH:28][C:3]([CH2:2][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])=[CH:4][CH:5]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4CCCCC4)c3s2)cc1
Temperature: 70 °C
Yield: 80.9 %

Procedure:
To a solution of 0.095 g (0.23 mMol) 4-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-benzamide in 1 ml THF were added 0.16 g (1.83 mMol) N-(2-methoxyethyl)-methyl amine. The reaction mixture was heated to 70° C. for 2 h. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (dichloro methane/methanol 19:1) to yield (0.087 g (81%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzamide as a light yellow foam. ES-MS m/e (%): 468 ([M+H]+, 100).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[F:16].[Cl-].[NH4+]>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([OH:14])[CH3:13])=[CH:6][C:5]=1[F:16]
Reactant: CC(=O)CC(O)c1ccc(Cl)c(F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
Sodium borohydride (112 mg, 2.95 mmol) was added in three portions to a solution of 4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2-one (160 mg, 0.73 mmol) in methanol (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then treated with saturated ammonium chloride. After removal of methanol, the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried and concentrated to give 1-(4-chloro-3-fluorophenyl)butane-1,3-diol (130 mg, 81% yield) as a solid. 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 1H), 7.17 (m, 1H), 7.04 (m, 1H), 5.07 (m, 1H), 3.48 (br s, 1H), 2.13 (m, 1H), 1.56 (m, 1H), 1.30 (d, J=6.0 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC

Procedure:
A mixture of 5.32 g (0.017 mol) of N-(2-bromoethyl)phthalimide and 2.74 g (0.017 mol) of triethyl phosphite is heated gently to initiate reaction. After the reaction subsides, heating is continued for 1 hour with distillation of ethyl bromide. Chloroform is added to the cooled mixture and the solution is washed with water. The organic phase is dried and concentrated to give diethyl phthalimidoethylphosphonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11][C:12](=[O:14])[CH3:13].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:20])([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:15][OH:16]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 47 h
Yield: 95.8 %

Procedure:
A 10 l reaction vessel was charged with 110 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol, 11 g of Lipase made by SEIKAGAKU CORPORATION, (derived from Rhizopu delemar, Enzyme No. 3), 2.8 l of 50 mM acetate buffer (pH 5) and 2.8 l of cyclohexane. The resulting mixture was stirred at 30° C. for 47 hours. The obtained reaction mixture was extracted twice with 3 l of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 90 g of (R)-2-(2,4-difluorophenyl)-3-acetoxy-1,2-propanediol.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[N+](=[CH2:16])=[N-].[B]1OC2C(=CC=CC=2)O1.B(O)O.C(O)[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-].[Na+]>>[C:1]([O:13][CH3:16])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: C=[N+]=[N-]
Reactant: C#CCCCCCCCCC(=O)O
Agent: O=C1O[C@H]([C@H](O)CO)C([O-])=C1O
Agent: OBO
Agent: [B]1Oc2ccccc2O1
Product: C#CCCCCCCCCC(=O)OC

Procedure:
Methyl 10-undecynoate was prepared via the reaction of 10-undecynoic acid (Farchan) with diazomethane. The ester (1.6 g, 8 mmole) was hydroborated with catecholborane. The yield of the boronic acid was 1.7 g (87%); mp 48.5-50; mass spectrum, 316.9 (calcd. m/e316.1); NMR (CDCl3) 1.3 δ(broad s, 12H, alkane), 2.35 (broad envelope, 4H, --CH2CH=,--CH2CO2), 3.6 (s, 3H, --OCH3), 5.38 (d, 1H, --C=CHB, J=17 Hz), 6.4 (m, 1H, --CH=CHB).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:40])[N:17]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[NH:19][C:18](=[O:40])[N:17]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-3-ethoxycarbonylmethyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (89 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (2 ml), sodium hydride (7 mg) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 60 mg of the title compound from the elution fraction of hexane-ethyl acetate (1:2).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:19]=2)=[O:15])[NH:5]1.[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37](O)=[O:38])[C:33](=[O:40])[NH:32]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37]([N:27]2[CH2:26][CH2:25][N:24]([C:20]3[CH:19]=[C:18]([CH2:17][NH:16][C:14]([C:6]4[NH:5][C:4](=[O:3])[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:15])[CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:28]2)=[O:38])[C:33](=[O:40])[NH:32]1
Reactant: O=C(NCc1cccc(N2CCNCC2)c1)c1nc2ccccc2c(=O)[nH]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(CC(=O)N2CCN(c3cccc(CNC(=O)c4nc5ccccc5c(=O)[nH]4)c3)CC2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of 4-oxo-N-[(3-piperazin-1-ylphenyl)methyl]-3,4-dihydroquinazoline-2-carboxamide dihydrochloride obtained in Reference Example 116 (0.109 g, 0.250 mmol), (2,5-dioxoimidazolidin-4-yl)acetic acid (0.047 g, 0.300 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole (0.068 g, 0.500 mmol) in DMF (5 mL) was stirred at room temperature for 1 hr. Triethylamine (0.139 mL, 1.00 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from methanol-diethyl ether to give the title compound as a pale-yellow powder (0.078 g, 62%).