Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])[CH:5]=1.CO[CH:27](OC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]([S:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[O:22][CH3:23])(=[O:13])=[O:14])[C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(OC)c1ccccc1
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCCC
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)C(c1ccccc1)O2
Temperature: 100 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 200 mg, 0.537 mmol), benzaldehyde dimethyl acetal (0.5 mL) and toluene-4 sulfonic acid monohydrate (10 mg, 54 mmol) was stirred at 100° C. for 48 h. After cooling, heptane was added, and the precipitate was collected by filtration to afford 3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (208 mg, 84%). Light yellow solid, MS (ISP)=460.2 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:10][C:11]1[CH:12]=[C:13]([CH:47]=[CH:48][CH:49]=1)[C:14]([NH:16][C:17]1[S:18][C:19]2[CH2:46][CH2:45][CH2:44][CH2:43][C:20]=2[C:21]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:23])=[O:15])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7].S(Cl)(Cl)=O.[NH:54]1[CH2:64][CH2:63][CH:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:56][CH2:55]1>>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33]([CH2:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:21]3[C:20]4[CH2:43][CH2:44][CH2:45][CH2:46][C:19]=4[S:18][C:17]=3[NH:16][C:14]([C:13]3[CH:12]=[C:11]([CH:49]=[CH:48][CH:47]=3)[CH2:10][N:4]([CH:5]([CH2:6][CH3:7])[CH2:8][CH3:9])[CH2:3][CH2:2][N:54]3[CH2:55][CH2:56][CH:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:63][CH2:64]3)=[O:15])=[O:23])=[CH:30][CH:29]=2)=[CH:34][CH:35]=1)=[O:38]
Reactant: CCC(CC)N(CCO)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(CCN(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C(CC)CC)CC1
Yield: 86.8 %

Procedure:
By a method similar to Preparation Example 37, 197 mg of methyl 4-(2-{4-[({2-[(3-{[(2-hydroxyethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate was reacted with 0.10 mL of thionyl chloride, and then the resultant was reacted with 325 mg of ethyl isonipecotate, thereby obtaining 206 mg of ethyl 1-(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)piperidine-4-carboxylate.
Reaction SMILES: N1CCCCC1.[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:27]([NH:29][C:30]3[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=3[C:32]([OH:34])=[O:33])=[O:28])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC1CCCC1
Yield: 63.3 %

Procedure:
Piperidine (0.63 mL, 5.8 mmol) was added to a suspension of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.4 g, 6.4 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.3 g, 5.8 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(3-cyclopentyloxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.4 g, 67%) as a yellow crystalline solid; mp 211-217° C.; δH (400 MHz, DMSO-d6) 1.57 (m, 2H, CH2), 1.70-1.72 (m, 4H, CH2), 1.91 (m, 2H, CH2), 3.78 (s, 3H, OCH3), 4.90 (t, J=5.6 Hz, 1H, OCH), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.4 Hz, 1H, Fe), 7.31 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.60 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.6, 32.2, 55.6, 79.5, 112.0, 113.6, 116.7, 119.9, 120.4, 122.2, 122.7, 127.2, 131.1, 134.0, 141.0, 141.6, 147.1, 151.5, 164.2, 169.4; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 751, 1254, 1504, 1583, 1661, 2948, 3516 cm−1.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[ClH:1].[NH:2]([C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[C:17]([CH3:18])=[O:19]
Reactant: CCN(CC)Cc1cc(C)cc(Br)c1N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CCN(CC)Cc1cc(C)cc(Br)c1NC(C)=O

Procedure:
1.53 gm of 2-amino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride were dissolved in 50 ml of acetic acid anhydride at 75°C. The solution was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol, yielding 2-acetamino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride, m.p. 170°-172°C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1>>[OH:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:7][CH2:8]1
Reactant: OCC1CCNCC1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from propionyl chloride and piperidin-4-ylmethanol as a colorless oil (40%). MS 172 (MH+).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26]C(CCCC)CCC)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1[CH2:40][CH2:39][CH2:38][CH2:37]1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:37][CH2:38][CH2:39][CH2:40][CH2:6][CH2:7][CH2:9][CH3:10])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C1CCOC1
Reactant: CCCCC(CCC)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCCCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-4-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.0 g.), conc. hydrochloric acid (6.23 g.), tetrahydrofuran (15 ml.) and methanol (120 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.95 g.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1cccc(OCc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(COc2cccc(CC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of methyl 2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate (1.35 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and water and dilute hydrochloric acid were added to acidify the residue. The precipitated solid was collected by filtration to give crystals (1.25 g, 95%) of 2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[C:5]([C:14]([O:16]C)=[O:15])[CH:4]=[CH:3]1.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
After 750 mg (3.27 mmol) of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in 9 mL of methanol and 3 mL of water, 235 mg (9.81 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50° C. for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by addition of aqueous HCl to titrate a pH of the reaction product to pH 2. After filtration of the resulting solid compound (Actual yield: 470 mg, Percent yield: 67%), the resulting compound was used without purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[O:30]>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[NH:28][C:29](=[O:30])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-N′-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine (536.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 1 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue recrystallized from CH2Cl2/CH3OH. The solid residue is dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([Cl:20])=[O:13])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(SC(C)(C)CC(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(SC(C)(C)CC(=O)Cl)cc1

Procedure:
To a solution of 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (Compound 216, 20.0 g, 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g, 124.8 mmol) in 10 mL of benzene over 30 minutes. After 4 hours the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give a clear yellow oil. This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ: 7.45 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.84 (3H, s), 3.12 (2H, s), 1.41 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1.[Cl-].[NH4+]>[O:12]([C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]=[O:27])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nccc(Oc3ccccc3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(Oc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To a solution of 6-bromo-4-phenoxy-quinoline (1.12 g, 3.73 mmol) in THF (15 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (1.64 mL, 4.10 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned into brown and this solution was stirred for 20 min at this temperature. Then, a neat dimethylformamide (0.576 mL, 7.46 mmol) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.250 g (27% yield) of 4-phenoxy-quinoline-6-carbaldehyde as a white solid: mp 112-115° C.; EI-HRMS m/e calcd for C16H11NO2 (M+) 249.0790, found 249.0787.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])=[O:22]
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(OC(=O)C(C)(C)C)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a mixture of 2-chloro-4-methylphenol (100 g), triethylamine (92.3 g) and anhydrous tetrahydrofuran (1 liter) was added dropwise pivalic chloride (93.0 g) at 5° to 10° C. under stirring over 1 hour. Then, after stirring at the same temperature for 3 hours, the reaction mixture was poured into ice water, which was extracted with diethyl ether. The organic layer was washed with 3% aqueous hydrochloric acid solution and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was distilled under reduced pressure, which afforded 155.3 g of 2-chloro-4-methylphenyl 2,2-dimethylpropanoate as a colorless clear liquid. Yield, 97.7%.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=2)[C:10](=O)[C:9]([C:27]#[N:28])=[CH:8]1.[Cl-:34].[Li+]>O=P(Cl)(Cl)Cl>[Cl:34][C:10]1[C:9]([C:27]#[N:28])=[CH:8][N:7]=[CH:12][C:11]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1
Reactant: [Cl-]
Reactant: COCCOc1cc(-c2cn(Cc3ccc(OC)c(OC)c3)cc(C#N)c2=O)ccc1OC
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOc1cc(-c2cncc(C#N)c2Cl)ccc1OC
Yield: 78.2 %

Procedure:
A solution of 1-(3,4-dimethoxybenzyl)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-4-oxo-1,4-dihydro-pyridine-3-carbonitrile (300 mg, 0.666 mmol) and lithium chloride (LiCl, 254 mg, 6 mmol) in 2.5 mL of POCl3 was heated at reflux for 2.5 h. The excess POCl3 was removed by evaporating in vacuo and then was co-evaporated with toluene. The residue was dissolved in 100 mL ethyl acetate and washed with ice-cold 1 N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo, and the resulting solid was triturated with isopropyl alcohol to yield 166 mg (78% yield) of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@@H:9]2[CH2:11][O:10]2)[CH:2]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1>>[OH:10][C@H:9]([CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1
Reactant: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: c1cncc(OC[C@@H]2CO2)c1
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)COc2cccnc2)cc1)c1ccccc1

Procedure:
In a manner analogous to that of Example 7, the title compound was prepared from the epoxide from Example 162 and N-[4-(2-aminoethyl)phenyl]benzenesulfonamide (Example 6). Purification by preparative thin layer chromatography on silica gel (eluant 90:10:2 methylen chloride/methanol/30% ammonium hydroxide) gave the title compound. 1H NMR (400 MHz, CD3OD) δ8.23 (d, 1H, J=4Hz), 8.12 (dd, 1H, J=2.4Hz), 7.71(d, 2H, J=8Hz), 7.52 (m, 1H), 7.40-7.48 (m, H), 7.35 (m, 1H), 7.09 (d, 2H, J=10Hz), 7.00 (d, 2H, J=10Hz), 3.95-4.08 (m, 3H), 2.69-2.90 (m, 6H).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([NH:25][CH3:26])=[O:24])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1.Br[CH2:34][CH2:35][O:36][CH3:37]>>[Cl:31][C:30]1[C:21]([NH:20][C:18]2[C:17]([Cl:32])=[CH:16][N:15]=[C:14]([NH:13][C:4]3[CH:5]=[CH:6][C:7]4[CH2:8][CH:9]5[N:12]([CH2:34][CH2:35][O:36][CH3:37])[CH:1]([CH2:11][CH2:10]5)[C:2]=4[CH:3]=3)[N:19]=2)=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Reactant: COCCBr
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2CCOC)ncc1Cl
Yield: 33.5 %

Procedure:
Following a procedure analogous to 68a, 2-[2-(12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-chloro-N-methyl-benzamide (60 mg, 0.13 mmol), 1-bromo-2-methoxy-ethane (120 mg, 0.48 mmol) were converted to the title compound as a yellow solid (23 mg, 34%). 1HNMR (400 MHz, DMSO-d6) δ 9.2 (bs, 1H), 9.0 (bs, 1H), 8.3 (m, 1H), 8.1 (s, 1H), 7.7 (d, 1H, J=7.6 Hz), 7.6 (d, 1H, J=7.3 Hz), 7.4 (t, 1H, J=8.1 Hz), 7.1 (s, 1H), 7.0 (m, 1H), 6.7 (m, 1H), 3.6-3.4 (m, 4H), 3.2 (s, 3H), 2.9 (m, 1H), 2.7 (d, 3H, J=4.3 Hz), 2.5-2.4 (m, 2H), 2.2 (m, 1H), 2.1-2.0 (m, 2H), 1.5-1.4 (m, 2H); MS (m/e) 527 (M+1); mp 240-244° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8](=[O:15])[C:7]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:6]2[OH:27])#[N:2].C(O)(C(F)(F)F)=O>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8](=[O:15])[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:6]2[OH:27])#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C#N)ccc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(C#N)ccc21
Yield: 38.9 %

Procedure:
1,1-Dimethylethyl N-((6-cyano-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (124 mg, 335 μmol) was stirred in TFA (1 mL, 13462 μmol) at room temperature for 15 minutes. Water was added. The resulting precipitate was filtered. The green solid was dissolved in saturated NaHCO3 and washed with DCM. The aqueous layer was separated and acidified with 10% HCl. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (41 mg). MS (m/e)=315.1 (M+H)+. Calculated for C16H14N2O5 314.09.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[CH3:12][O-:13].[Na+]>CO>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
200 g (1.11mol) of 4-(trifluoromethyl)chlorobenzene, 179 g (3.31 mol) of sodium methoxide, and 600 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150° C. under tight sealing. The resulting reaction mixture was filtered to remove precipitates. Water was added to the obtained filtrate, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 112 g (0.636 mol) of 4-(trifluoromethyl)anisole (yield: 57%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29])[CH3:32]
Reactant: CCNCC
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Product: CCN(CC)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 68 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and diethylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:10][C:11]([NH2:13])=[S:12])#[N:9].CN1CCOCC1>C(O)C>[C:8]([C:10](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:11]([NH2:13])=[S:12])#[N:9]
Reactant: O=Cc1cccs1
Reactant: N#CCC(N)=S
Solvent: CCO
Solvent: CN1CCOCC1
Product: N#CC(=Cc1cccs1)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of 2-thiophencarbaldehyde (22.4 g, 0.2 mol) and 2-cyanothioacetamide (22 g, 0.22 mol) in 250 ml of ethanol was added N-methylmorpholine (30.3 g, 0.3 mol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solid was filtered and washed with ethanol to give 28.2 g (72%) of product as a yellow solid after drying in vacuo. 1H-NMR (300 MHz, DMSO-d6): δ 10.0 (brs, 1H), 9.45 (brs, 1H), 8.37 (s, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.32 (dd, J=3.3, 4.8 Hz, 1H). ES MS m/z 195 (M+H)+, 193(M−H)−.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reaction time: 4 h

Procedure:
To a solution, being ice cooled, of N-tert-butoxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (1.0 g) in chloroform (10 ml), trifluoroacetic acid (5%, 0.5 g) was added, followed by stirring at the same temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off to yield (L)-isoleucyl-(L)-tryptophanol as an oily substance. This oily substance was dissolved in chloroform (20 ml), and p-toluenesulfonyl chloride (0.52 g) was added and then triethylamine (1.4 ml) was added at 0° C. After stirring at room temperature for 2 days, the reaction mixture was poured over water and extracted with chloroform. After the chloroform layer was dried (MgSO4), the solvent was distilled off, and the oily residue was recrystallized from ethyl acetate to yield N-(p-toluenesulfonyl)-(L)-isoleucyl-(L)-tryptophanol (0.32 g, 28%).