Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1.C(N(CC)CC)C.ClCCl>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:8][C:3]([CH2:2][S:24][C:22]3[N:21]=[C:20]([OH:25])[CH:19]=[C:18]([CH3:17])[N:23]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH3:16]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN1CCN(c2ccc(CBr)cn2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a suspension of 1-[5-(bromomethyl)pyridin-2-yl]-4-ethylpiperazine (3.85 g, 13.54 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.25 g, 8.86 mmol) in anhydrous ethanol at 0° C. was added triethylamine (5.47 g, 54.18 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by column chromatography using 0-15% methanol:dichloromethane to provide (2-({[6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol as a white solid (1.82 g, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.18 (s, 3H), 2.31 (q, 2H), 2.56 (m, 4H), 3.42 (m, 4H), 4.23 (s, 2H), 6.01 (bs, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.14 (s, 1H); LRMS (ES+) m/z 345.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]2[S:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH:39][C:19]([C:11]2[CH:12]=[CH:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:34][O:33]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (377 mg, 0.91 mmol) and diisopropylethylamine (0.47 mL, 2.73 mmol) in DMF (4 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (268 mg, 1.82 mmol), EDCI (349 mg, 1.82 mmol) and HOBt (246 mg, 1.82 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, TBME in cyclohexane) to afford the title compound as a yellow solid (266 mg, 54%). LCMS (method B): RT=4.04 min, [M+H]+=544.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13](C=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][O:50][CH2:51][CH2:52][NH:53][CH3:54].[C:55]([O:58][BH-](OC(=O)C)OC(=O)C)(=[O:57])C.[Na+].O>C(Cl)Cl>[CH:55]([OH:58])=[O:57].[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:54][N:53]([CH2:52][CH2:51][O:50][CH3:49])[CH3:55])=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: CNCCOC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 176b (0.188 mmol) and N-(2-methoxyethyl)methyl amine (32.7 mg, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added and the mixture extracted with DCM. The combined organics were passed through a phase separator and concentrated to dryness. The resulting residue was purified by RP-HPLC (C18, 18 mL/min, 20-85% MeCN in H2O+0.1% HCO2H) and the relevant fractions combined and concentrated to dryness. The title product was isolated as an off white solid (23.9 mg). LCMS (Method 5): Rt 3.68 min, m/z 720.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.74-1.96 (4H, m), 1.98-2.16 (2H, m), 2.17 (3H, s), 2.54 (2H, t, J=6.0 Hz, obscured by solvent), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent), 3.23 (3H, s, obscured by solvent), 3.45 (2H, t, J=6.0 Hz, obscured by solvent), 3.54 (2H, s, obscured by solvent), 4.82 (1H, m), 5.51 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=9.7, 2.2 Hz), 7.24-7.50 (8H, m), 7.64 (1H, d, J=10.0 Hz), 7.69 (1H, d, J=1.5 Hz), 8.09 (1H, s), 8.17 (1H, s).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[C:13](O)(=[O:25])[CH2:14]CCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCC.C(O)CO>ClCCl.OS(O)(=O)=O>[C:1]([O:12][CH2:14][CH2:13][OH:25])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: OCCO
Solvent: ClCCl
Product: CCCCCCCCC(=O)OCCO
Reaction time: 216 h

Procedure:
Decanoic acid (C10 acid), dodecanoic acid (C12 acid), and tetradecanoic acid (C14 acid)--each of 100 mmol of C10, C12 and C14 acids were dissolved in 50 ml dichloromethane, and 300 mmol of ethylene glycol were added to the solutions. Several drops of H2SO4 were added to the mixture. The reaction mixtures were stored at room temperature for 9 days. Isolation of the esters were carried out using the same procedure as that to isolate ethylene glycol monopelargonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].O=[CH:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccncc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
4-Methylpyridin-3-amine (36.0 mg, 0.000333 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) and followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and the mixture was stirred for 24 h. The mixture was poured into pre-cooled water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The product was purified by CombiFlash using CH2Cl2EtOAc (max EtOAc 50%). LC-MS: 392.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]1=[O:34].O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:23]3[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:24]3=[O:34])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: O=C1C(Br)CCN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCN(c3ccccc3)C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g in 1 ml of absolute DMF was mixed with 11 mg (0.23 mmol) of sodium hydride (50%) and stirred at RT for 1 h. Then 55.5 mg (0.23 mmol) of (+/−)-3-bromo-1-phenyl-2-pyrrolidinone were added, and the mixture was stirred at RT for 45 min. The reaction solution was mixed with 1 ml of water and extracted several times with EA. The combined EA extracts were dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by chromatography on silica gel with CH2Cl2/methanol (92:8 to 85:15 in 35 min) as mobile phase afforded 52.2 mg of the title compound.
Reaction SMILES: [SH2:1].[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:5]2[CH2:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:2][N:3]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[N:16][C:17]([C:18](=[S:1])[NH2:19])=[C:5]2[CH2:4]1
Reactant: S
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1Cc2c(C(N)=S)ncn2-c2ccccc2C1=O
Reaction time: 48 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was passed for 1 hr. through a solution of 10.2 g (0.429 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 250 ml of pyridine and 2.5 ml of triethylamine. The green solution was left to stand for 48 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.0 g (87%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. A sample was recrystallized from methanol and gave pale yellow crystals; m.p. 295°-297°.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[CH:31][C:21]=3[C:20]=2[CH:19]=1.[CH2:32]([C:34]([O-:36])=[O:35])[CH3:33]>CN(C)C=O>[C:8]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[CH:31][C:21]=3[C:20]=2[CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:32]([C:34]([O-:36])=[O:35])[CH3:33]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1)c1ccccc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 53.1 %

Procedure:
52 μL (0.37 mmol) of triethylamine and then 24 μL (0.20 mmol) of benzoyl chloride are added to 50 mg (0.18 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The solution is stirred for 2.5 h at 40° C. The solvent is evaporated and the residue obtained is purified by recrystallization from methanol to give 36 mg (52%) of 8-benzoylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: S(O)(O)(=O)=O.[C:6](=[NH:10])([O:8][CH3:9])[NH2:7].C[O-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([C:35](=O)[CH2:36][CH2:37][CH3:38])[C:30](OCC)=[O:31])=[CH:24][CH:23]=1)#[N:15]>CO>[CH3:9][O:8][C:6]1[NH:7][C:30](=[O:31])[C:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:17]3[C:16]([C:14]#[N:15])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)=[C:35]([CH2:36][CH2:37][CH3:38])[N:10]=1
Reactant: COC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 16.1 %

Procedure:
A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide (26 mL) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (15.8 g) in methanol (100 mL) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, washed with water and diethyl ether to give the title compound (2.62 g, 16%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1)=[O:10]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccsc3S(=O)(=O)C2)no1
Temperature: 5 °C
Yield: 56.2 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (3.1 g, 0.012 mole), 3-amino-5-methylisoxazole (1.5 g, 0.015 mole) and xylene (120 ml) is refluxed for 1.5 hrs. in a Soxhlet apparatus, the thimble of which contains 15 g of Linde type 4A molecular sieve. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline precipitate is collected. The filtrate is refluxed for two additional hours and then cooled to give a second crop. The two fractions are combined and recrystallized from CH2Cl2 --CHCl3 mixture to give a off-white crystalline solid (2.2 g, 56%), m.p. 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[C:31]2[O:30][CH:29]=[CH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>>[ClH:1].[ClH:1].[O:30]1[C:31]2[C:23]([NH:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=4[O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[N:5]=[CH:4][N:3]=3)=[CH:24][CH:25]=[CH:26][C:27]=2[CH:28]=[CH:29]1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Reactant: Nc1cccc2ccoc12
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4ccoc34)ncnc2c1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 7-aminobenzofuran to give the title compound, a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 2.15-2.35 (m, 6H), 2.32 (s, 3H), 2.92 (m, 2H), 3.9 (s, 3H), 4.6 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 7.25-7.4 (m, 2H), 7.68 (d, 1H), 8.58 (d, 1H), 8.6 (s, 1H), 10.25 (br s, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
Using the procedure of Step C of Example 16, 2.76 g of the product of Step A, 1.82 g of potassium carbonate, 15 ml of methyl ethyl ketone and 1.6 ml of ethyl bromoacetate were reacted. Extraction was carried out with methyl ethyl ketone and the organic phase was concentrated to dryness to obtain 3.9 g of crude product which was chromatographed on silica (eluant: hexane-ethyl acetate 8-2) to obtain 3.6 g of the expected product melting at 58° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:41]([C:32]2[CH:33]=[CH:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)=[O:42])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc2ccccc2c1

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.5 g, 1.4 mmol) was dissolved in 1,4-dioxane (20 ml) and triethyl amine (0.29 g, 2.9 mmol) and 2-naphthoyl chloride (0.41 g, 2.2 mmol) were added. Solution was heated under reflux for 4 hr and solvent removed under reduced pressure. Product was subjected to column chromatography on silica gel and the title compound was eluted with hexane-ethyl acetate (8:2; 0.3 g).
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.O>[O:26]=[C:20]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1ccccc1COC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: O
Product: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Magnesium (2.67 g, 0.110 mol) and bromoethane (0.20 ml) were added to a solution of 1-bromo-2-(tetrahydropyran-2-yloxymethyl)benzene (27.11 g, 0.100 mol) in tetrahydrofuran (50 ml) under an atmosphere of nitrogen, and the mixture was stirred at room temperature for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a solution of diethyl oxalate (29.23 g, 0.200 mol) in tetrahydrofuran (100 ml) cooled to -78° C. After stirring for 1 hour at -78° C., water (150 ml) was added. The mixture was extracted with ether, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound ethyl 2-oxo-2-[2-(tetrahydropyran-2-yloxymethyl)phenyl]acetate (22.60 g, 77.3%) as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([CH:7]([O:12]C(=O)C(C)=C)[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].[CH3:19][O:20][CH2:21]CO.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:18][C:2]([F:1])([CH:7]([OH:12])[CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([O:5][CH2:6][CH2:19][O:20][CH3:21])=[O:4]
Reactant: COCCO
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 105.2 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][OH:36].[CH3:37][OH:38]>ClCCl>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:37]([O:36][CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)=[O:38]
Reactant: OCc1ccccn1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccn2)c1=O)C(=O)C(F)(F)F

Procedure:
2-(5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide and 2-pyridylcarbinol were subjected to a procedure similar to that described in Example 3.a. Chromatography, with methanol:dichloromethane (gradient, 3:97, 5:95) as the eluent, gave 2-[6-oxo-2-phenyl-5-(2-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a tan solid; 300 MHz NMR (DMSO/D2O): 8.53 (d,1), 8.43 (d,1), 7.80 (t,1), 7.4 (m,7), 5.21 (s,2), 4.57 (d,1), 4.47 (d,1), 4.02 (s,1), 2.20 (m,1), 0.81 (d,3), 0.73 (d,3).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19].[Cl-].[NH4+]>ClCCl>[OH:19][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[OH:11]
Reactant: O=Cc1ccccn1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Oc1ccccc1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of AlCl3 (1.42 g) in dichloromethane (20 mL) at 0° C. is added a solution of phenol (1 g) in dichloromethane (20 mL) and the mixture is stirred at this temperature for 40 minutes. After addition of a solution of pyridine-2-carboxaldehyde (1.21 g) in dichloromethane (10 mL), the mixture is allowed to warm at room temperature for 4 hours, then cooled to 0° C., treated dropwise with aqueous ammonium chloride and stirred at room temperature for 30 minutes. The aqueous phase is extracted twice with dichloromethane and pooled organic extracts dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient heptane/ethyl acetate from 100/0 to 70/30) to afford pure 2-(hydroxy-pyridin-2-yl-methyl)-phenol.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15](OC)(OC)OC.[NH2:22][CH2:23][CH:24]=O>C(COC)OC.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]2[CH:24]=[CH:23][N:22]=[CH:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC=O
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: COC(OC)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COCCOC
Product: c1ccc(Cc2ccccc2-n2ccnc2)cc1

Procedure:
In the manner given in Preparation 21, α-phenyl-o-toluidine is reacted first with trimethyl orthoformate, the resulting product is reacted with aminoacetaldehyde, dimethyl acetal, and the resulting product of this reaction is heated with titanium tetrachloride in monoglyme to give 1-(α-phenyl-o-tolyl)imidazole.