Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[CH2:13]([O:25][C:26](=[O:30])[CH:27]([CH3:29])[NH2:28])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(O)(C)C>[NH2:28][C@H:27]([C:26]([O:25][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:30])[CH3:29]
Reactant: CCCCCCCCCCCCOC(=O)C(C)N
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A 100 ml round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (7.0 g, 0.04 mole) and isopropanol (30 g). The suspension was heated to 60° C. over 15 minutes. A mixture of DL-alanine dodecyl ester ptoluenesulfonate salt (16.9 g, 0.04 mole), triethylamine (4.0 g 0.04 mole) and isopropanol (20 g) were added dropwise over 15 minutes from an addition funnel. The reaction mixture was stirred rapidly for about 6 hrs and then cooled to room temperature. The white product was filtered, washed with chloroform (3×150 ml) and dried under high vacuum at 35° C. giving 12.5 g (73% yield) of N-D-gluconyl dodecyl alaninate with a melting point of 97°-98° C. and 98.8% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH2:10][CH2:11][N:12]=1>C1C=CC=CC=1.O.OO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: Fc1ccccc1C1=NCCO1
Agent: [Ni]
Agent: OO
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccccc1-c1ncco1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
A mixture of 2-fluoro-1-(4,5-dihydrooxazol-2-yl)benzene (4.5 g, 27.3 mmol) and nickel peroxide hydrate (7 g) in 40 mL of benzene was heated at reflux for 24 hours. The mixture was allowed to cool to room temperature, filtered and concentrated by rotary evaporation. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-fluoro-1-oxazol-2-yl-benzene (0.5 g, 3.07 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C:20](=[O:33])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Ce+3].[Cl-].[Cl-]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[C:11]1([C:17]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@:20]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])([OH:33])[CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A suspension of 2-methoxyphenylmagnesium bromide (prepared starting from 75.3 g of 2-bromoanisole and 9.8 g of magnesium) in 100 cm3 of dry tetrahydrofuran is added dropwise while stirring to a suspension of 20 g of (3aS,7aS)-7,7-diphenyl-2-tert-butoxycarbonylperhydroisoindol-4-one and 31.6 g of anhydrous cerium chloride in 250 cm3 of dry tetrahydrofuran at room temperature. The reaction mixture is stirred at room temperature for 24 hours, treatea with 400 cm3 of an aqueous saturated solution of ammonium chloride, diluted with 200 cm3 of ethyl acetate, washed with 300 cm3 of water (twice) and then with 300 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 5.8 cm, height 26.5 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions of 100 cm3. Fractions 9 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 17.82 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2- methoxyphenyl)-2-tert-butoxycarbonylperhydroisoindol-4-ol are obtained in the form of a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=4)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:30]I.O>C1COCC1>[CH3:30][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[CH:22]=[C:14]1[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n(C)c2c1
Reaction time: 2 h

Procedure:
1.40 g (3.8 mmol) of the ester produced in Example 13, are dissolved in 20 ml of dry THF, and treated with 0.14 g (4.6 mmol) of sodium hydride (80% in oil). This mixture is stirred for 1 hour, at which point 0.65 g (4.4 mmol) of methyl iodide is added. The resulting mixture is stirred for 2 hours and then poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The organic phase is dried and the solvent evaporated. The resulting residue is recrystallized in hexane, yielding methyl 1-methyl-2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl)-6-indole carboxylate. (1.30 g, 91%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[C:26]2[CH:27]=[C:28]([C:30](O)=[O:31])[O:29][C:25]=2[CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[O:29][C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:20])[C:26]=2[CH:27]=1)=[O:31]
Reactant: O=C(O)c1cc2c(o1)CCCC2=O
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc2c(o1)CCCC2=O

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-oxo-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid. MS: 422.4 (M+H).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1>CO.C(N)CCC>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: CCCCN
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 78.4 %

Procedure:
A suspension of 1-(6-benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (300 mg) prepared in Example 2 in a mixture of methanol (20 ml) and n-butylamine (10 ml) was boiled under reflux for 1 hour. The mixture was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (7:3). The fractions containing the object compound were combined and the solvent was evaporated to give 1-(6-amino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (200 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH:9](O)[C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CC[O:17]CC1.ClC(OC)=O.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:30]([C:37]([OH:39])=[O:38])=[CH:29]2.C(N(CC)CC)C.Cl[Si](C)(C)C.N1C[C@H](O)C[C@H]1C(O)=O>ClCCl>[C:1]([N:4]1[CH2:11][CH:10]([OH:17])[CH2:9][CH:5]1[C:6]([NH:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:30]([C:37]([OH:39])=[O:38])=[CH:29]2)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)[C@H]1C(=O)O
Reactant: CN1CCOCC1
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(O)CC1C(=O)Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
A mixture of 5.20 g (30 mmol) of N-acetyl-3-hydroxy-L-proline and 75 ml of dichloromethane is cooled to -15° and 3.3 ml (30 mmol) of N-methyl morpholine and 2.33 ml (30 mmol) methyl chloroformate is added and stirring is continued for 20 minutes at -10° to -20°. A mixture of 3.06 g (15 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 120 ml of dichloromethane, 6.3 ml (45 mmol) of triethylamine, and 5.7 ml (45 mmol) of chlorotrimethylsilane is stirred at room temperature for 1/2 hour. The silylation mixture is cooled to -20 and the cold mixed anhydride of hydroxyproline is added and stirred for 4 hours with cooling and overnight at room temperature. The reaction mixture is evaporated to an oil which is treated with acetic acid and ethanol to yield 3.92 g of 6-[[(1-acetyl-4-hydroxy- 2-pyrrolidinyl)carbonyl]amino]-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:35])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][S:25][CH2:24]1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 170 mg of 3-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide and 0.3 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 1 hour. The solution was diluted with diethyl ether and the precipitated solid was rapidly filtered off, washed with diethyl ether anddissolved in water. The solution was made alkaline by the addition of potassium carbonate and extracted with three portions of chloroform. The combined chloroform extracts were dried over anhydrous sodium sulphate, filtered and evaporated to give 110 mg of 3-[3 (S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide: MS: m/e 466 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C1CCNC1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.7 (m, 5H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (dd, J=8.7, 1.5 Hz, 1H), 6.51 (s, 1H), 3.1 (m 2H), 2.95 (m, 2H), 2.65 (m, 4H), 1.9 (m, 4H); MS (DCI) m/z 317 (M+H)+;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:37]CC[N:34]([CH2:38]C(O)=O)[C:33]2=O)=[CH:28][CH:27]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCNC2)=CC=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:49][C:46]1[CH:47]=[CH:48][C:43]([C:32]2([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH2:37][CH2:38][N:34]([C:14](=[O:16])[CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C:9]3=[O:17])[CH2:33]2)=[CH:44][CH:45]=1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.28 (m, 4H), 7.18-7.09 (m, 4H), 7.03-6.93 (m, 8H), 4.11 (dd, J=5.1, 9.1, 4H), 3.61-3.48 (m, 3H), 3.42 (t, J=6.7, 1H), 2.77 (dd, J=6.4, 11.7, 2H), 2.57 (t, J=6.7, 1H), 2.47 (t, J=6.9, 1H); MS (DCI) m/z 573.2 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27]([OH:29])=O)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([NH:35][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1

Procedure:
The compound N-[3-(phenylcarbamoyl)phenyl]-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and aniline as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 413.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[F:17][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c(F)c(O)ccc12
Temperature: 85 °C

Procedure:
To a stirred solution of methyl 6-hydroxy-1-naphthoate (25 g, 123.8 mmol) in anhydrous acetonitrile (130 mL), SelectFluor (45 g, 127.5 mmol) was added and the reaction vessel sealed (sealed tube). The reaction mixture was heated to 85° C. for 3 d. The reaction mixture was allowed to cool to RT, diluted with ethyl acetate and washed with water, then brine, dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using methylene chloride as the eluent. The title compound was obtained as a tan solid.
Reaction SMILES: Br[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[N:27]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Product: COc1ccccc1-c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Yield: 51.2 %

Procedure:
The product was prepared in the same manner as described in example 66 using N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(morpholine-4-carbonyl)-1H-pyrazole-5-carboxamide (200 mg, 461 μmol) and 2-methoxyphenylboronic acid (140 mg, 921 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 10% as eluent affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (109 mg, 51.3%) as a light brown foam. MS: m/z=462.5 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][O:17]2)=[CH:10][CH:9]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.Cl>O.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH2:18][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)([OH:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 110 °C
Yield: 41.6 %

Procedure:
5.3 g (0.05 mole) of sodium carbonate were added to a mixture of 245.2 g (1 mole) of 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane (97.2% pure), 72.5 g (1 mole) of 1,2,4-triazole (95.2% pure) and 380 ml of dimethylsulphoxide at room temperature, while stirring, and the mixture was then heated at 110° C. for 4 hours. Thereafter, the reaction mixture was poured into 1 liter of water and neutralized with dilute aqueous hydrochloric acid. The liquid phase was decanted off from the solid and the residue was dissolved in 1 liter of toluene. The solution was extracted with water, the phases were separated and the organic phase was dried and concentrated by stripping off the diluent under reduced pressure. 128 g (42% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-ylmethyl)-4,4-dimethyl-pentan-3-ol were obtained in this manner in the form of a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:16]
Reactant: CCOCCCCCCl
Reactant: O=C1CCNCC1
Product: CCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Ethoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-ethoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[O:12]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[ClH:1].[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][C:22]3[CH:21]=[CH:20][C:19]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:25][CH:24]=3)[C:3]=2[S:10][CH:9]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: Cc1csc2c(Cl)ncnc12
Solvent: CC(C)O
Product: Cc1csc2c(Nc3ccc(Oc4ccccc4)cc3)ncnc12
Product: Cl
Yield: 80 %

Procedure:
4-Chloro-7-methylthieno[3,2-d]pyrimidine (commercially available from Maybridge Chemical Co. Ltd.) (0.185 g, 1.00 mmol) and 4-phenoxyaniline (0.210 g, 1.1 mmol) were reacted in 2-propanol (5 ml) for 2 hours according to Procedure A. The product was obtained as a yellow solid (0.294 g, 80%), m.p. 243-245° C.; (Found: C, 61.46; H, 4.27, N, 11.32. C19H15N3OS.HCl requires: C, 61.70; H, 4.36; N, 11.36%); δH [2H6]-DMSO 10.85 (1H, br s, NH), 8.78 (1H, s, 2-H), 8.05 (1H, 2, 6-H), 7.69 (2H, d, J 9, 2′-H, 6′-H), 7.42 (2H, t, J 9, 3″-H, 5″-H), 7.00-7.20 (5H, m, 3′-H, 5′-H, 2″-H, 4″-H, 6″-H), 2.43 (3H, s, 7-CH3); m/z (%) 333 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1.S(=O)(=O)(O)O.[CH3:26]O>>[O:1]=[C:2]1[CH:7]([CH2:8][C:9]([O:11][CH3:26])=[O:10])[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O

Procedure:
A mixture of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetic acid (5 g) and concentrated sulfuric acid (3 ml) in methanol (50 ml) was heated to reflux for 5 hours. The solvent was removed and the residue was treated with ice cold water. The resulting solid was collected, rinsed with additional cold water and dried at 50° C. to yield 4.05 g. Recrystallization from water gave methyl (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetate, mp 223°-225° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=[CH:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1=CC=CNC=C1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and azepine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.[NH2:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28]O>>[NH2:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 30 °C

Procedure:
Seed culture (4 ml) of each of Corynebacterium glutamicum ATCC 21854 and Corynebacterium glutamicum SA95 was inoculated into 40 ml of SSM medium containing 100 μg/ml of each of phenylalanine, tyrosine, and serine, and cultured with shaking at 30° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:34]([C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)=[O:35])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CC3CCCCC3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CC3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine (216 mg) prepared in Preparation Example 1A-1 and triethylamine (152 mg) in dichloromethane (3 mL) was added 2-furoyl chloride (0.11 mL) dropwise under ice cooling. The solution was stirred at room temperature for 18 hours. Silica gel (NH silica gel) was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound as a colorless crystal (271 mg).