Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(Cc2c(F)cccc2F)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (Intermediate 34) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a light yellow solid (571 mg, 65%); ES+-HRMS m/e calcd for C26H23N5O4F4 [M+H+] 546.1759 found 546.1762. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 6H) 3.39-3.58 (m, 2H) 3.88 (s, 2H) 4.66 (s, 1H) 5.70 (dd, J=9.7, 5.6 Hz, 1H) 5.90 (d, J=2.7 Hz, 1H) 6.47 (d, J=2.1 Hz, 1H) 6.96 (t, J=8.0 Hz, 2H) 7.19-7.34 (m, 1H) 7.34-7.41 (m, 2H) 7.42-7.51 (m, 1H) 7.54 (d, J=2.1 Hz, 1H) 8.20 (d, J=2.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[NH:4][C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl.O>C(OCC)(=O)C>[OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CN(C)CCCCl
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 99.4 %

Procedure:
A mixture of 1.7 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, 0.75 g potassium carbonate and 0.7 g of 3-dimethylaminopropyl chloride in 30 mL of ethyl acetate was stirred and heated at reflux for 2 hours then an additional 0.2 g of 3-dimethylaminopropyl chloride was added four times at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours then to the mixture ethyl acetate and water were added. The organic phase was separated, washed with brine and dried (magnesium sulfate). Removal of the solvent gave 2.1 g (100%) (±)-cis-2,3-dihydro-3-hydroxy-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether, mp 123°-124°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc6[nH]ccc56)c34)n(-c3ccccc3)c(=O)c12
Yield: 84.2 %

Procedure:
(S)—N-(4-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl)methanesulfonamide (87 mg, 0.12 mmol) was treated with trifluoroacetic acid (2.5 ml, 32 mmol) and a solution of ammonia (7N in methanol, 1.25 ml, 17 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 50% dichloromethane-2-propanol) to obtain 60 mg (80% yield) of the title compound. Purity 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14].[N+:16]([O-])([O-:18])=[O:17].[K+]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1c(C(=O)O)ccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: COc1c(C(=O)O)cc([N+](=O)[O-])c2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-methoxy-naphthalene-2-carboxylic acid (20.2 g; 0.1 m) in glacial acetic acid (200 ml) was added a solution of potassium nitrate (10.1 g; 0.1 m) in concentrated sulphuric acid (10 ml). The temperature was maintained below 25° C. by means of a water bath. The reaction was stirred for four hours and poured into ice-water (500 ml). The product was collected by filtration, washed well with water and dried in vacuo at room temperature to give 1-methoxy-4-nitro naphthalene-2-carboxylic acid, m.p. 204°-206° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCc2ccc(Br)cc2F)c1
Yield: 71.5 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 716.7 μl (5.181 mmol) of 2-fluoro-4-bromobenzylbromide, there was added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 1 hour at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, water and aequeous sodium bicarbonate, water and aqueous sodium cholride solution in this sequene and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 50 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 212.4 mg (0.3706 mmol, 72%) of 2-(2-fluoro-4-bromobenzyloxy)-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:11]O>>[C:9]1([OH:11])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1.[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: OO
Reactant: c1ccc2ccccc2c1
Product: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12
Yield: 0.4 %
Yield: 25.3 %

Procedure:
Using convenient anhydrous hydrogen fluoride-pyridine complex as the acidic reaction medium at atmospheric pressure and at ambient temperature, the reaction of naphthalene with a molar excess of hydrogen peroxide at 10° to 20° C. gave 25.3% α-naphthol with 0.4% β-naphthol, 9.5% dihydroxynaphthalenes, and 1.2% higher molecular weight polymeric materials were formed with 47% naphthalene recovered unchanged. The yield of α-naphthol is 47%, with an isomeric purity of 98.4%.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:35]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:34]=1>O.ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:35]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:50][CH2:51]2)[CH:34]=1
Reactant: Clc1ccc(N2CCOCC2)c(CN2CCNCC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2cc(Cl)ccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (168 mg, 1.00 mmol, 1.00 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (417 mg, 3.23 mmol, 3.18 equiv) was added dropwise. The mixture was stirred for 2 hours at room temperature. 4-[4-Chloro-2-(piperazin-1-ylmethyl)phenyl]morpholine (300 mg, 1.01 mmol, 1.00 equiv) was added dropwise. The resulting solution was stirred for 2 hours at room temperature and diluted with water (20 mL). The resulting solution was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The crude product (206 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 91.9 mg (18% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as a white solid. 1HNMR 300 MHz (CDCl3) δ 7.45 (s, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 5.69-5.81 (m, 1H), 3.81-3.84 (m, 4H), 3.56 (br, 6H), 2.88-2.91 (m, 4H), 2.50 (br, 4H). LCMS (ESI, m/z): 490 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:37][CH2:36][CH:32]([C:33]([NH2:35])=[O:34])[CH2:31][CH2:30]1>>[ClH:1].[ClH:1].[CH:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[N:18]=[CH:19][C:14]([C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:29]5[CH2:37][CH2:36][CH:32]([C:33]([NH2:35])=[O:34])[CH2:31][CH2:30]5)=[CH:8][CH:7]=4)[O:13][N:12]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CCl)cc4)n3)cn2)CC1
Reactant: NC(=O)C1CCNCC1
Product: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CN5CCC(C(N)=O)CC5)cc4)n3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 44, starting from 1-(5-(5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropylpiperazine and isonipecotamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]#[C:16][C:17]2[CH:31]=[CH:30][C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CC(N(C)C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:26]2[CH:27]=[CH:28][C:23]([C:21]([C:20]3[CH:30]=[CH:31][C:17]([C:16]#[C:15][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:18][CH:19]=3)=[O:22])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(Oc2ccc(C(=O)c3ccc(C#Cc4ccccc4)cc3)cc2)cc1
Temperature: 150 °C
Yield: 85 %

Procedure:
In a 250 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser were placed 4-aminophenol (5.46 g, 0.05 mol), 4-phenylethynyl-4'-fluorobenzophenone (15.02 g, 0.05 mol), potassium carbonate (7.6 g, 0.055 mol), toluene (20 mL), and DMAc (45 mL). The mixture was heated to 150° C. for 2 h, then cooled to room temperature. The reaction mixture was poured into water and the resulting light yellow powder was collected by filtration. Recrystallization from toluene afforded the desired product in 85% yield: m.p. 151°-153° C. IR (KBr); 3382 and 3314 cm-1 (NH2); 3049, 1599, and 1509 cm-1 (aromatic C--H); 2217 cm-1 (C≡C); and 1645 cm-1 (C=O): Mass Spec. m/e (relative intensity): M+, 389.4 (100); FW=389.44 g/mol.
Reaction SMILES: [CH:1](=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C:4]1([CH:2]([CH3:3])[CH2:1][NH:21][C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(C=O)c1ccccc1
Product: CC(CN[C@H]1CCCc2ccccc21)c1ccccc1

Procedure:
Hydratropaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.N12CCCN[CH:16]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCC.O>C1(C)C=CC=CC=1>[C:21]([O:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC1CC(O)=CC(=O)O1
Reactant: C1=CN2CCCNC2CCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1=CC(=O)OC(C)C1

Procedure:
To a solution of 5.13 g (0.040 mole) of 4-hydroxy-5,6-dihydro-6-methyl-2-pyrone and 6.70 g (0.044 mole) of 1,8-diazabicyclo(5,4,0)-undecene (hereinafter referred to as DBU) in 100 ml of toluene was added dropwise 8.39 g (0.044 mole) of decanoyl chloride with stirring and cooling the reaction mixture in an ice-water bath. After termination of the dropwise addition, the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture and the mixture was extracted with toluene. The extract was washed with 5% HCl and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent in the extract was evaporated under a reduced pressure, and the residue was subjected to silica gel column chromatography to purify the product, 4-dodecanoyloxy-6-methyl-5,6-dehydro-2-pyrone. To a solution of 4-dodecanoyloxy-6-methyl-5,6-dihydro-2-pyrone, thus obtained, in 20 ml of toluene was added 0.06 g of 4-pyrolidinopyridine. The mixture was refluxed for 3 hours and the solvent was removed by evaporation under a reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g (yield: 14%) of 3-decanoyl-6-methyltetrahydropyran-2,4-dione, m.p. 62°-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:18](=O)[CH2:19][CH3:20])[C:14](=[O:17])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:25]O>N1C=CC=CC=1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:25][O:17][C:14]=2[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCC(=O)C(CCCCCCOc1ccc(Br)cc1)C(=O)CC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1CCCCCCOc1ccc(Br)cc1

Procedure:
4-[6-(4-Bromophenoxy)hexyl]-3,5-diethylisoxazole [I; Ar is 4-BrC6H4, Y is O(CH2)6, R is C2H5 ] was prepared from 10.0 g. of 4-[6-(4-bromophenoxy)hexyl]-3,5-heptanedione and 2.0 g. of hydroxylamine hydrochloride in 40 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a pale yellow oil, b.p. 190°-195° C. (0.001 mm.); yield 7.3 g.; MIC=12 μg/ml (herpes 2).
Reaction SMILES: Cl.[CH2:2](NC(N1CCN(C(C2CCCC2)=O)CC1)=O)C.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([NH2:32])[CH:23]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:31][O:30][C:29]1[CH:28]=[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[N:32]=[CH:2][N:27]=[CH:26]2
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CCNC(=O)N1CCN(C(=O)C2CCCC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cncnc2cc1OC
Reaction time: 0.5 h

Procedure:
Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-for-mamidate hydrochloride (0.01 mole) is added to a solution of 4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of N,N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension in mineral oil) is added and the mixture stirred 0.5 hr. at room temperature and then at 100° C. for a period of 12 hr. When the reaction period is complete, water is added providing 4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>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>[Cl:9][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1.[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[N:3]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2cc(N)nc(Cl)n2)cn1
Product: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 50.3 %
Yield: 37.2 %

Procedure:
2,6-Dichloropyrimidin-4-amine (4.00 g, 24.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 14.0 g, 36.6 mmol) and K3PO4 (15.5 g, 73.2 mmol) were suspended in dioxane (120 mL, 24.4 mmol) and H2O (4.39 mL, 244 mmol). After degassing under nitrogen, Pd(PPh3)4 (1.41 g, 1.22 mmol) was added and the reaction sealed and stirred at 50° C. for 15 hours. After cooling, the reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with water, brine, dried with MgSO4, filtered and concentrated under reduced pressure to afford the crude material as a thick yellow orange oil. The crude mixture was purified by silica chromatography using a 20-100% EtOAc/Hexanes gradient to afford 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (4.00 g, 50.3%) and 2-chloro-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (2.96 g, 37.2% yield). MS (apci) m/z=326.1 (M+H). The structure and regioisomer of products were confirmed by observed nOe.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.C=O.[C:23]([BH3-])#[N:24].[Na+].[C:27](=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:27][N:24]([CH3:23])[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Nc1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl (R)-3-(4-aminophenyl)-2-hydroxypropionate (0.26 g) in acetic acid (6 ml) was added paraformaldehyde (0.3 g), and further sodium cyanoborohydride (0.3 g) was added gradually, and stirred for 3 hours at ambient temperature. To sodium bicarbonate solution (25 ml) and ice (25 g) was added reaction mixture gradually and was extracted with ethyl acetate (50 ml×2). The separated ethyl acetate layer was washed with brine,dried over anhydrous sodium sulfate and evaporated in vacuo. The resultant crude product was subjected to column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (7:3 by volume). The fractions containing the desired product were combined and evaporated in vacuo to give benzyl (R)-3-(4-dimethylaminophenyl)-2-hydroxypropionate (0.22 g).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]2[CH2:17][CH2:16][CH2:15][S:14][C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>CN(C)C=O>[CH2:1]([C:8]1[C:9](=[O:19])[N:10]([CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C:11](=[O:18])[N:12]2[CH2:17][CH2:16][CH2:15][S:14][C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: O=c1[nH]c(=O)n2c(c1Cc1ccccc1)SCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.11 g (15 mmol) of 9-benzyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.32 g (24 mmol) of potassium carbonate in 70 ml of N,N-dimethylformamide, 3.46 ml (60 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 4.96 g (90.6%, light yellow oily substance) of the desired product.
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.O.NN>C(OCC)C.C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH2:9][CH:5]([SH:4])[C:6]([OH:8])=[O:7])=[O:18])=[CH:16][CH:15]=1
Reactant: CC(=O)SC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C(CC(S)C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 2.87 g of 2-acetylthio-3-(4-chlorobenzoyl)propionic acid in 50 ml of diethyl ether was added dropwise a solution of 0.95 g of 80% hydrazine hydrate in 5 ml of ethanol under ice-cooling with stirring over a period of 30 minutes. The mixture was stirred for a further 30 minutes. The reaction solution was washed with water and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography using a mixture of hexane and diethyl ether as an eluent and recrystallized from the same mixture to give 1.01 g of 3-(4-chlorobenzoyl)-2-mercaptopropionic acid.