Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:13]([NH:15][C@H:16]([C:21]([NH:34][C@@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]([OH:41])[C:37]([O:39][CH3:40])=[O:38])=[O:23])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(=O)O
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of 83 mg of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucine and 40 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 3 ml of N,N-dimethylformamide were added 0.049 ml of diphenylphosphoryl azide and 0.058 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol = 10/1 by volume: Rf = 0.43) to obtain 43 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-leucyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[C:38]([C:54]([F:57])([F:56])[F:55])[CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C38H50F3NO5=657.80. found: [M+H]+=658.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[CH:29][CH:28]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyrimidine (example E.63) (0.15 g, 0.43 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.11 g, 63%). MS (ISP) 408.4 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C@@H:3]([CH3:9])[C@H:4]([NH:5][C:11]([O:13][CH3:14])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mmol) in saturated sodium bicarbonate solution (47.6 mL) was treated dropwise with methyl chloroformate (453 μL, 553 mg, 5.85 mmol) followed by stirring at RT for 18 h. The mixture was extracted with ether and the aqueous phase was cooled to 0° C. and acidified to pH 2-3 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×). The combined organic layers were extracted with saturated sodium chloride solution and dried (Na2SO4). Concentration in vacuo afforded the title compound (640 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.48 (d, J=7.8 Hz, 1 H), 4.52 (d, J=4.7 Hz, 1 H), 3.71 (s, 3 H), 3.39 (s, 3 H), 1.25 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Thus 1 part of triphenylcarbinol is reacted with 2 parts of malonic acid at 170° for 3 hours to provide 3,3,3-triphenylpropionic acid and this acid is converted into the acid chloride by reaction with thionyl chloride. Reacting the acid chloride with 2 parts of 2-azabicyclo[2.2.2]octane provides the amide, 2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane and reduction of this amide with 1 part of LiAlH4 in tetrahydrofuran provides 2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]octane. The addition of concentrated hydrochloric acid to an ethereal solution of above amine provides 2-(3,3,3-triphenyl propyl)-2-azabicyclo[2.2.2]octane hydrochloride, melting at 221°-223° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][S:32][CH:33]([C:37](O)=[O:38])[C:34](O)=[O:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[OH:38][C:37]1[CH:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=2)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:3][C:34](=[O:35])[C:33]=1[S:32][CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)COc1cccc(C(C)=O)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using ethyl (3-acetylphenoxy)acetate (2.00 g, 9.00 mmol), trimethyl silyltriflate (4.18 mL, 21.62 mmol), triethylamine (5.01 mL, 36.00 mmol), methylene chloride (23 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 116°-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, 3H), 2.77 (t, 2H), 3.05 (t, 2H), 4.89 (d, 2H), 6.80 (s, 1H), 7.20 (m, 7H), 7.44 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1[C:26](=[O:27])[CH2:25][CH2:24]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:24][CH2:25][CH2:26][O:27][C:13]=23)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(NCCN1CCCCC1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCN1CCCCC1)c1c2n(c3ccccc13)CCCO2
Yield: 29 %

Procedure:
N-[2-(1-Piperidyl)ethyl] 1H-indole-3-carboxamide (D2) was treated initially with N-chlorosuccinimide then with 3-bromo-1-propanol, then with potassium carbonate in acetone following the method described in Example 3. The crude product was chromatographed on silica gel eluting with chloroform/methanol (19:1) to give a pale yellow oil, which crystallised from ether to afford the title compound (E5) as a white solid (29%) mp 124-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (105 mg, 0.32 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (83 mg, 0.64 mmol) followed by benzoyl chloride (49 mg, 0.35 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 130 mg (94%) as a pale yellow solid. MS (ESI+APCI) M+1=433.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=O.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:20][N:19]=1
Reactant: Cc1ccsc1C(=O)c1ccccc1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccsc1-c1n[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-methylthiophene-2-carbonyl)benzoic acid (0.446 g, 1.81 mmol) and hydrazine hydrate (0.41 mL, 7.3 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.23 (m, 1H), 8.01-7.80 (m, 2H), 7.68 (d, J=5.1, 1H), 7.62-7.42 (m, 1H), 7.10 (d, J=5.1, 1H), 2.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]#[N:20])[CH2:14]2)=[CH:9][CH:8]=1.Cl.[NH2:25][OH:26].C(N(CC)C(C)C)(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:25][OH:26])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#C[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carbonitrile (0.211 g, 0.001 mol) and hydroxylamine hydrochloride (0.047 g, 0.001 mol) were dissolved in ethanol (4 ml) and N,N-diisopropylethylamine (0.120 ml, 0.001 mol) was added. The reaction mixture was stirred under reflux for three hours. The reaction was cooled to room temperature, the solvent was evaporated and the residue extracted with dichloromethane and purified by column chromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to yield (0.220 g, 94% of theory) of a yellow oil. MS (m/e)=344.3(M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1)[CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2]
Reactant: CCOC(=O)CCc1c(O)c2ccccc2oc1=O
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester in THF at −78° C. was added LDA (1.5M, 3.05 mL) dropwise. A yellow precipitate was formed during the addition. The reaction was stirred at −78° C. for 15 min and allowed to warmed to 0° C. and stirred for 30 min, after which BnBr (0.24 mL in THF) was added dropwise. The reaction was warmed to room temperature, stirred for 12 hours, cooled to 0° C. and quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to a crude colorless oil, which was purified by column chromatography to provide 2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester as a colorless oil (250 mg). MS: 351[M−H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 18 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 mg, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1729 found 261.1727.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Sc1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 0.96 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.0 mmol of benzenethiol, and 1.0 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid (m.p. 78°-80° C.). 1H NMR (DMSO-d6) δ3.37 (bs, 2H), 6.35 (m, 2H), 6.93 (m, 3H), 7.29-7.49 (m, 10H).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>C(O)CO.[S]>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([OH:1])=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [S]
Solvent: O
Solvent: OCCO
Product: Oc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A solution of 4.76 g (85.3 mmol) of potassium hydroxide in 20 ml of ethylene glycol is added dropwise over the course of 2 hours at 180° C. to 7.26 g (21.3 mmol) of 2-(3-benzyloxyphenyl)-5-bromopyrimidine and 0.035 g (1.08 mmol) of sulfur in 60 ml of ethylene glycol. The mixture is kept at 180° C. for a further 3 hours, poured into water and acidified by means of 37% strength hydrochloric acid, and the solid which precipitates is isolated by filtration. Purification by chromatography (silica gel/hexane: ethyl acetate=32) gives 4.77 g of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine. ##STR28##
Reaction SMILES: [C:1]([CH:8]([O:23][NH2:24])[CH:9]([F:22])[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[CH3:27]I>C(O)C>[C:1]([CH:8]([O:23][NH2:24])[CH:9]([F:22])[CH2:10][N:11]([CH3:27])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)NCC(F)C(ON)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)CC(F)C(ON)C(=O)OC(C)(C)C)cc1

Procedure:
0.54 g (1.5 mmol) of N-(3-BOC-aminoxy-2-fluoropropyl)-4-toluenesulfonamide are dissolved in 10 ml of ethanol and 1.5 ml of 1N sodium hydroxide solution and, after the addition of 0.21 g (1.5 mmol) of methyl iodide, maintained at 70° for 10 hours in a bomb tube. After cooling, the reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate. The resulting solution is washed with water and dried over magnesium sulfate, yielding, after evaporation of the solvent, starting compound c.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.NC1C=C(O)C(C)=CC=1>CO>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)=[CH:35][CH:36]=1)#[N:39]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C#N)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 4-aminobenzonitrile according to the procedure from Example 137C substituting 4-aminobenzyonitrile for 5-amino-o-cresol to provide the title compound as an off white solid after trituration of the reaction product from methanol (20 mg, 23%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.63 (s, 1 H), 8.92 (s, 1 H), 8.69 (s, 1 H), 7.96 (d, J=8.82 Hz, 2 H), 7.66-7.90 (m, 4 H), 7.35-7.46 (m, 3 H), 6.95-7.11 (m, 3 H), 6.55-6.64 (m, 1 H), 3.77 (s, 3 H), 3.18-3.30 (m, 1 H), 1.35 (d, J=6.99 Hz, 6 H); MS (ESI+) m/z 547.3 (M+H)+, (ESI−) m/z 545.3 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=4[CH:10]=[CH:9][CH:8]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(C4CCCCC4)cc3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(Cc2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cc2ccccc2)c2ccccc2c1=O

Procedure:
The product of Example 139A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66-11.72 (bs, 1H), 8.32 (dd, J=7.8, 1.5 Hz, 1H), 7.97-8.00 (m, 1H), 7.92 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.86 (ddd, J=7.8, 7.1, 1.3 Hz, 1H), 7.24-7.37 (m, 4H), 7.11-7.23 (m, 4H), 4.32-4.32 (bs, 2H), 3.77 (s, 2H); LC/MS (APCI) M/Z 406 (M+H)+.
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]([NH:34][NH2:35])=O)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:35][N:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (500 mg) was added acetic acid (3 ml), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]3[O:31][CH2:30][CH2:29][O:28][C:25]=3[CH:26]=2)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:18]2[C:27]3[C:22](=[CH:23][C:24]4[O:31][CH2:30][CH2:29][O:28][C:25]=4[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N(c1ncnc3cc4c(cc13)OCCO4)CC2
Yield: 87 %

Procedure:
To 6-chloroindoline (52 mg, 0.339 mmol) and pyridine (23.3 mg, 0.294 mmol) in i-PrOH (3 mL) was added 4-chloro-6,7-(ethylenedioxy)quinazoline (65 mg, 0.284 mmol). The mixture was heated to reflux under dry N2(g) for 16 hours and then concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3, and the organic phase was washed with brine, dried over Na2SO4(s), and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone/hexanes to afford 84 mg of 4-(6-chloro-2,3-dihydro-indol-1-yl)-7,8-dihydro-[1,4]dioxino [2,3-g]quinazoline as its free-base (M.P. 209°-211° C.; GC/MS: 339 (M+); anal. RP18-HPLC RT: 5.02 min).