Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[Cl:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (1.0 mL, 13 mmol). NaH (5.9 mg, 246 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (67.8 mg, 411 μmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated. 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19 mg, 100% purity). MS in/z: [M+H]+ calcd for C14H19Cl2NO, 288.08. found 288.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:15])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: NC(=O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of (3,5-difluorophenyl)acetic acid in 100 mL of tetrahydrofuran was treated with 9.9 g of carbonyldiimidazole. The mixture was stirred at 25° C. for 3 hours then a vigorous stream of anhydrous ammonia was bubbled through the solution for 1 hour. The mixture was stirred for 2 days and then the solvent was evaporated at reduced pressure. The residue was suspended in 100 mL of distilled water. The mixture was filtered and the filtrant washed with distilled water twice. After drying in a stream of air, the (3,5-difluorophenyl)acetamide was obtained as 8.4 g of an ivory solid. 1H-NMR (DMSO-d6): δ 7.51 (broad s, 1H), 7.15-6.85 (m, 3H), 3.40 (s, 2H). MS (EI): m/z 171. EA Calc'd for C—8H7NO: C, 56.13; H, 4.13; N, 8.18. Found: C, 56.16; H, 4.05; N, 8.07.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[N:1]1([C:26]([C:15]2[N:16]([CH3:25])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=3)[N:14]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)N3CCCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using pyrrolidine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 360 (M+1); Rt=3.12 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:24])[CH3:23]>ClCCl>[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)OCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 84.5 %

Procedure:
4-Chloro-3-nitro[1,5]naphthyridine (4.1 g), dichloromethane (150 mL), triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3 mL, 23.8 mmol) were combined. The reaction mixture was maintained at ambient temperature overnight and then quenched with water (100 mL). The phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g of N4-(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow powder, m.p. 62.5-63.5° C. Analysis: Calculated for C14H18N4O3: %C, 57.92; %H, 6.25; %N, 19.30; Found: %C, 57.96; %H, 6.19; %N, 19.51; {overscore (1H NMR (300 MHz, CDCl3))}: δ10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78 (m, 1H), 8.21 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57 (broad s, 2H), 3.65-3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d, J=6.0 Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc'd for C14H18N4O3).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CO.CCOC(C)=O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1Cn1ccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Cn1ccnc1
Temperature: 70 °C
Yield: 81.5 %

Procedure:
Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 0.07 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (140.0 mg, 82%) was isolated by chromatography (5% MeOH-EtOAc ) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>COC(OC)C>[NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(Br)c(N)n1
Agent: COC(C)OC
Product: CC(=O)Nc1cnc(Br)c(N)n1

Procedure:
A mixture of 2,6-diamino-3-bromopyrazine (10.50 g, 0.056 mole) in dry 1,1-dimethoxyethane (168 ml) and acetic anhydride (7.91 ml, 8.56 g, 0.084 mole) was refluxed under nitrogen for 2.50 hrs. The cooled mixture was evaporated in vacuo. The residue was triturated with ether, filtered and dried in vacuo. Yield 10.31 g (80%), M.p. 218-221° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CC)C3)c2n1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
2-Butoxy-9-[(1-ethyl-3-piperidinyl)methyl]-8-methoxy-9H-purin-6-amine (99 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 5 hours the reaction mixture was stripped, quenched with water then saturated sodium hydrogen carbonate added, when a solid precipitated. This was filtered, washed with water and dried to yield 81 mg of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[N+](C1C([N+]([O-])=O)=C(O)C=CC=1)([O-])=O.[ClH:27].ClCl>O>[Cl:27][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: Cl
Agent: ClCl
Agent: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
160 parts of 2,4-dinitrophenol are suspended in 240 parts of water. Then 0.5 part of lignosulfonate (dispersant) is added to this suspension and the dinitrophenol is comminuted by ultrasonication. A reactor is charged with 210 parts of 14 % hydrochloric acid and the aqueous suspension of finely particulate 2,4-dinitrophenol and 60 parts of chlorine gas are added simultaneously at 0° C. The addition of the suspension of dinitrophenol is made over 120 minutes and the chlorine is simultaneously added over 130 minutes. When the addition of chlorine is complete, the product is isolated by filtration and washed with 250 parts of water, affording 162.4 parts of 2-chloro-4,6-dinitrophenol (corresponding to a yield of c. 83 %).
Reaction SMILES: [C:1]1([PH:7](=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:12]CN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]1([PH:7](=[O:8])[O:9][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=[PH](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CO[PH](=O)c1ccccc1
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of phenylphosphinic acid (5.00 g, 35.2 mmol), anhydrous methanol (7.0 mL, 170 mmol) and 4-dimethylaminopyridine (425 mg, 3.48 mmol) in 50 mL of THF (distilled from ketyl) was added EDAC (8.05 g, 42 mmol) at room temperature. The reaction was stirred for 24 hours then partitioned between HCl solution (75 mL of 1M aq) and ethyl acetate (75 mL). The organic layer was separated, washed with HCl solution (75 mL of 1M aq), sodium bicarbonate solution (75 mL of 5% aq) then dried (sodium sulfate) and concentrated in vacuo to afford the crude title compound as a colorless liquid (1.24 g, 7.95 mmol, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([CH2:47][CH2:48][OH:49])=[C:42]([CH3:50])[CH:41]=3)[C:21]([NH:23][C@@H:24]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:37][C:33]1[CH:32]=[C:31]([C@H:24]([NH:23][C:21](=[O:22])[CH:20]([NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])=[N:10][CH:11]=[CH:12]3)[C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([CH2:47][CH2:48][OH:49])=[C:42]([CH3:50])[CH:41]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C[C@@H](NC(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1)c1cc(C)c(CCO)c(C)c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@@H](NC(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1)c1cc(C)c(CCO)c(C)c1)c1cccc(N)c1
Yield: 71.5 %

Procedure:
A solution of 50D (580 mg, 0.74 mmol) in MeOH (30 mL) with Pd/C (35 mg) was stirred under H2 (50 psi) for 2 h. The reaction mixture was filtered and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to afford 50E (400 mg, 72%) as a yellow solid. MS (ESI) m/z 756.6 (M+H)+.
Reaction SMILES: NC(N)=[S:3].[C:5]([O:9][C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:13]1[CH2:15]O1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:13]1[CH2:15][S:3]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CO1)C(=O)OC(C)(C)C
Reactant: NC(N)=S
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CS1)C(=O)OC(C)(C)C
Yield: 83.6 %

Procedure:
Methanol (4 ml) and thiourea (83 mg, 1.096 mmol) were added to (S)-2-tert-butoxycarbonylamino-3-oxiranyl-propionic acid tert-butyl ester (Compound 30) (315 mg, 1.096 mmol), and the reaction solution was heated at reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-2-tert-butoxycarbonylamino-3-thiiranyl-propionic acid tert-butyl ester (Compound 31) (278 mg, 84%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13]C)=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[O:28][CH3:29]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[O:28][CH3:29])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(C(F)(F)F)ccc1Br
Product: COc1cc(C(F)(F)F)ccc1C(=O)c1cnc(SC)nc1N

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 1-bromo-2-methoxy-4-trifluoromethyl-benzene (prepared from 3-(trifluoromethyl)-anisole, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.F[C:18](F)(F)C(O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([CH3:18])[N:11]=1
Reactant: Nc1ccc(OCc2cnccn2)c(Cl)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cncc(COc2ccc(N)cc2Cl)n1

Procedure:
Compound 31A was prepared by a route analogous to that used for the preparation of Compound 16A. Analytical HPLC retention time=1.593 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=250+.
Reaction SMILES: C([O:5][C:6](=O)[CH:7]([CH:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(C)(C)C>C1COCC1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[CH2:16][CH2:17][CH3:18])[CH2:6][OH:5])=[CH:13][CH:12]=1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCCC(c1ccc(C(=O)OC)cc1)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-(4-chlorophenyl)-3-[4-(methoxycarbonyl)phenyl]hexanoic acid (prepared as described in PCT Patent Publication WO 2008/042223 A1 published on 10 Apr. 2008, 360 mg, 1.0 mmol) in anhydrous THF (10 mL) was cooled to 0° C., then borane dimethyl sulfide complex (0.3 mL, 3 mmol) was added slowly. The mixture was stirred at room temperature for five hours, then excess reagent was quenched with MeOH (2 mL). The mixture was concentrated, then the resulting residue was diluted with EtOAc (20 mL) and K2CO3 (aq). The organic layer was washed with water, dried over anhydrous Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound. MS (M±H)+ 347.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:6]1[CH3:21])[CH:2]([CH3:4])[CH3:3].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([CH3:21])=[C:7]2[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccncc2)c2cc(O)ccc2n1CC(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2CC(C)C

Procedure:
The above compound was prepared from 1-isobutyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:37][C:38]([CH3:42])([CH3:41])[C:39]=1[CH3:40])#[N:34].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([CH3:41])([CH3:42])[O:37][C:36](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.4 %

Procedure:
In 10 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 300 mg (0.67 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 147 mg (0.74 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 52 mg of ammonium acetate, and the mixture was stirred at room temperature for 18 hours and further stirred with heating at 50° C. for 7 hours. The solvent was evaporated off and the residue was washed with ethanol to give 246 mg of a dark brown crystal (yield: 58.4%; mp: 218-219° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Reaction time: 21 h
Yield: 74.4 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 ml, 2.40 mmol) in THF (2 ml) was added Et3 N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 74%) as a pale brown powder. 1H-NMR (CDCl3) δ 3.57 (s, 2H), 3.70 (s, 3H), 7.02–7.28 (m, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.48 (s, 1H), 8.00–8.11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (M++2), 401 (M++4).
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:2]1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>[Pd].C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:18][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:17][C:16]3=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cc2c(cc1C=Cc1ccccn1)OCO2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc3c(cc2CCc2ccccn2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) is hydrogenated on a Parr apparatus in 200 ml. of ehtanol with 2.0 g. of 10% palladium on carbon as catalyst. After the reduction is complete, the mixture is filtered and the solvent evaporated. The residue consisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine is immediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5 g., 0.044 mole) added. The solution is stirred for 30 min. A basic workup according to the procedure of Example 25 affords 10 g. of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide obtained analytically pure by crystallization from ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2Br)[NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:17]=[C:18]3[C:19]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(CN(N)c2ccc(OCc3ccccc3)cc2)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2nn(-c3ccc(OCc4ccccc4)cc3)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
A mixture of 1-[4-(benzyloxy)phenyl]-1-(2-bromo-5-methoxybenzyl)hydrazine (1.50 g), palladium(II) acetate (41 mg), 1,1′-bis(diphenylphosphino)ferrocene (151 mg), sodium tert-butoxide (436 mg) and toluene (18 mL) was stirred under an argon atmosphere at 90° C. overnight. The solvent was evaporated under reduced pressure, and the obtained mixture was diluted with ethyl acetate and water, and the organic layer was separated. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (163 mg).
Reaction SMILES: C(OC[O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)C.Cl>CO>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]=[CH:7][C:6]([OH:5])=[CH:11][N:10]=2)=[CH:17][CH:16]=1
Reactant: CCOCOc1cnc(-c2ccc(F)cc2)nc1
Agent: Cl
Solvent: CO
Product: Oc1cnc(-c2ccc(F)cc2)nc1
Temperature: 53 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Ether 109 (301 mg, 1.21 mmol) was treated with 1.25M HCl in MeOH (10 mL) and the mixture was stirred at 53° C. for 4 h. The resulting cooled solution was diluted with ice-water (100 mL) and extracted with CH2Cl2 (5×80 mL). The combined extracts were evaporated to dryness and the residue was triturated in pentane to give 2-(4-fluorophenyl)-5-pyrimidinol (111) (225 mg, 98%) as a white solid: mp (pentane) 200-202° C.; 1H NMR [(CD3)2SO] δ 10.55 (v br s, 1H), 8.42 (s, 2H), 8.29 (ddt, J=9.1, 5.7, 2.6 Hz, 2H), 7.28 (ft, J=9.0, 2.6 Hz, 2H); HRESIMS calcd for C10H8FN2O m/z [M+H]+ 191.0615. found 191.0616.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1CCO>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCC1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1=Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCC1
Reaction time: 20 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 7-(4-trifluoromethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (440 mg) in tetrahydrofuran-ethanol (10-10 ml) was added 1N sodium hydroxide (4.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7-(4-trifluoromethylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (392 mg) as colorless crystals.