Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].Cl.Cl.[CH3:30][N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([NH2:37])[CH2:32]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:37][CH:33]4[CH2:34][CH2:35][CH2:36][N:31]([CH3:30])[CH2:32]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: CN1CCCC(N)C1
Agent: Cl
Product: CN1CCCC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)C1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.06 g) was reacted with 1-methylpiperidin-3-amine dihydrochloride similar to as described in Example 2 to afford 22.3 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methyl-3-piperidyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 11.28 (d, J=7.4 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.08-4.88 (m, 2H), 4.63-4.46 (m, 2H), 3.99-3.83 (m, 1H), 2.74-2.64 (m, 1H), 2.48-2.42 (m, 1H), 2.06 (t, J=8.0 Hz, 1H), 1.97 (t, J=10.6 Hz, 1H), 1.75 (m, J=13.8 Hz, 2H), 1.59-1.51 (m, 1H), 1.49 (s, 6H), 1.36-1.19 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH2:19][CH2:18]1
Reactant: OC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
N-(3-bromopropyl)phthalimide (26.8 g), 4-hydroxypiperidine (15.0 g) and potassium carbonate (27.6 g) were added to N,N-dimethylformamide; and the reaction mixture was stirred at room temperature overnight. After the addition of water, extraction was performed with ethyl acetate; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the title compound (13.9 g).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[N-:13]=[N+:14]=[N-:15].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCOCC1.O.O1CCOCC1>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([N:13]=[N+:14]=[N-:15])=[O:10])=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C=CC(=O)Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Temperature: 7.5 °C
Reaction time: 1.5 h

Procedure:
3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane (50 mL) is slowly added to an ice cooled solution of sodium azide (16 g, 246.6 mmol) in water/dioxane (50 mL, 1/1, v/v) so as to maintain the temperature between 5-10° C. The mixture is stirred for 1.5 hours then poured over 300 g of ice. The resulting white solid is filtered and washed with additional water. The solid (20.72 g, 110.7 mmol) was dried over P2O5 under vacuum overnight and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:24])([CH3:23])[C:19](=[O:22])[NH:20][N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)(=O)=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:24])([CH3:23])[C:19](=[O:22])[N:20]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NNC(=O)C2(C)C)cc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C4) and tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B4*HCl)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH:7]([CH3:13])[CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:13][CH:7]1[CH2:6][C:5]2[N:4]=[CH:3][C:2]([O:1][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:11][C:10]=2[C:9](=[O:12])[CH2:8]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC1CC(=O)c2cc(O)cnc2C1
Product: CC1CC(=O)c2cc(OCc3ccc4ccccc4n3)cnc2C1
Yield: 67 %

Procedure:
By the method of Example 1, 7,8-dihydro-3-hydroxy-7-methyl-5 (6H)-quinolone and 2-chloromethylquinoline were converted to present title product in 67% yield, m.p. 141-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.F[C:26]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=[CH:28][N:27]=1.O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:26]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:29]=[CH:28][N:27]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1c(C(F)(F)F)ccnc1F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C(F)(F)F)ccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A mixture of 4-(benzyloxy)aniline (1010 mg), DIEA (1.771 mL) and methyl 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylate (1130 mg) in NMP (10 mL) was stirred at 150° C. for 2 h and at 200° C. for 1 h under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (225 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7]=12.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(C2CCCCC2)c2c(Cl)nncc12
Product: Cc1c(C)n(C2CCCCC2)c2c(OCc3ccccc3)nncc12
Yield: 92.8 %

Procedure:
The title compound was prepared as a white powder in 92.8% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclohexyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=[CH:4][CH:3]=1>CC1C=CC=CC=1C>[CH3:12][CH:11]1[C:6]2[C:7](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: C=CCCCc1ccccc1C
Solvent: Cc1ccccc1C
Product: Cc1cccc2c1CCCC2C
Temperature: 120 °C
Reaction time: 28 h

Procedure:
Three hundred milliliters of a solution obtained by mixing o-xylene as a diluent and 5-OTP as a reactant in a weight ratio of 9:1 was introduced into a liquid-phase batch reactor. Then, the mixture was heated to 120° C. at normal pressure by using a mantle. Thereafter, 9 g of the dealuminated zeolite beta catalyst prepared in the above 1 was added to the reaction solution and the resulting mixture was allowed to react under stirring at 200 rpm for 28 hours while maintaining the reaction temperature at 120° C.±1° C. The concentration of the product over the reaction time was analyzed by gas chromatography (Model No.: 6890N, manufactured by Agilent Technologies). The analyzed results for the product were shown in Table 1.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH2:45][C@H:46]1[CH2:50][CH2:49][CH2:48][O:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH2:45][C@H:46]2[CH2:50][CH2:49][CH2:48][O:47]2)=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 20.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N—[(R)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.6 mg) was obtained.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[S-:25][C:26]#[N:27].[K+].P(OP(OP(OP(O)(O)=O)(O)=O)(O)=O)(O)(O)=O.Cl(O)(=O)(=O)=O>O1CCCC1.O>[OH:1][C@@H:3]1[C@@H:2]([S:25][C:26]#[N:27])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: N#C[S-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](SC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg.) and potassium thiocyanate (2 g.) in dry tetrahydrofuran (40 ml.) were treated with tetraphosphoric acid (about 2 ml.), and the reaction was stirred at room temperature for 2 hours. Perchloric acid (60%, 0.1 ml.) was added, and after a further 30 minutes the solution was diluted with water and extracted with ether. The extract was washed with water, dried over sodium sulphate and evaporated to give a colourless oil which was purified by preparative tlc and recrystallisation from acetone/petrol to give the title compound, as white prisms m.p. 165°-170° [α]D + 78°.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(Br)sc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ncsc1-c1ccccc1
Yield: 12.8 %

Procedure:
A solution of 4-acetamido-2-bromo-5-phenylthiazole (US Pat. No. 3,244,723) (5.5 g) and sodium acetate (1.55 g) in methanol (110 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the filtrate was evaporated to dryness. The residue was recrystallised three times from benzene-petroleum ether (b.p. 60°-80° C.) to give 4-acetamido-5-phenylthiazole (1.5 g) m.p. 105°-7° C. (Found: C, 60.3; H, 4.65; N, 12.7. C11H10N2OS requires: C, 60.5; H, 4.6; N, 12.8%).
Reaction SMILES: [Na].C(O)C=C.[C:6]([S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])(=O)[CH3:7].C([O:22][CH:23]1[NH:26]C(=O)C1)(=O)C>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][CH2:10][S:9][CH:6]1[NH:26][C:23](=[O:22])[CH2:7]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)CCCSC(C)=O
Reactant: CC(=O)OC1CC(=O)N1
Agent: [Na]
Solvent: C=CCO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CCCSC1CC(=O)N1
Reaction time: 1 h
Yield: 48 %

Procedure:
Sodium (1.15 g) was added to allyl alcohol (50 ml) and this solution treated with allyl 4-(acetylthio)butanoate (10.Og) at room temperature for 20 mins. 4-Acetoxyazetidinone (6.5 g) was added and stirring continued at 20° C. for 1 h The resulting mixture was poured into excess ethyl acetate and the layers separated. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (diethyl ether) to give the title compound as a yellow oil, 5.5 g. 48% yield
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br.C([O-])(O)=O.[Na+]>CCOCC.[Cl-].[Al+3].[Cl-].[Cl-]>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 4-acetylbenzoate (5.12 g, 26.6 mmol) in ether (50 ml) containing aluminium chloride (0.025 g, 0.19 mmol) is added bromine (1.31 ml, 26.6 mmol) and the reaction mixture is stirred for 2 h. The reaction mixture is poured into saturated NaHCO3 solution and stirred for 30 min. and the layers are separated. The organic layer is washed with NaHCO3, H2O, dried over MgSO4, concentrated to half of its volume and refrigerated overnight. The resulting solid is filtered to yield ethyl 4-(2′-bromoacetyl)benzoate (5.89 g, 81.6%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nsc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3snc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the crude {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (method 31) in pyridine (10 mL) at r.t., a solution of the p-toluoyl chloride (0.616 g, 4 mmol) in DCM (10 mL) was added dropwise and the resulting solution was stirred at r.t. for 2 days. The reaction mixture was diluted with DCM (100 mL) washed with water (2×100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 20-30% EtOAc in hexanes as eluent. Product isolated was 0.276 g. m/z 604 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[Cl:12][C:13]1[C:14]([C:19](O)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:11])[F:10])[N:3]=2)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: O=C(O)c1ncccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)n1)c1ncccc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of 0.81 g of 2-amino-6-trifluoromethylpyridine, 0.78 g of 3-chloropicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 70° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.33 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[CH3:18][C:19]([CH3:35])([CH3:34])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28](O)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1>>[CH3:18][C:19]([CH3:34])([CH3:35])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][C:4]3[O:5][C:6]4[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=4[CH:8]=3)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([CH2:18][CH3:19])[CH:5]=1.O1CCOCC1.[OH-].[Na+].Cl>CO>[CH2:18]([N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:8][C:9](=[O:10])[C:4]([C:3]([OH:20])=[O:2])=[CH:5]1)[CH3:19]
Reactant: CCN1C=C(C(=O)OC)C(=O)CC1c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)cc1-c1ccc(Cl)cc1

Procedure:
The starting material was obtained by dissolving 1.85 g. of 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methyl ester (prepared as described in Example 1) in 10 ml. of dioxane and 10 ml. of methanol and heating the solution under reflux for 3 hours in the presence of 20 ml. of 1-N sodium hydroxide. The mixture was cooled down, acidified with 0.5-N hydrochloric acid, the separated crystals were filtered off under suction and recrystallized from methanol/ether. Yield 1.3 g.; melting point 142°-144° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C1(C2CCNCC2)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Agent: Fc1ccc(C2CCNCC2)cc1
Agent: c1ccc(C2CCNCC2)cc1
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccccc4)CC3c3ccsc3)CC2)cc1

Procedure:
The title compound was prepared from 1-benzyl-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine and 4-(4-fluorophenyl)piperidine according to procedures described in Example 1. 4-(4-fluorophenyl)piperidine was prepared according to procedures used to prepare 4-phenylpiperidine in Example 1. Mass Spectrum (CI) m/e 435 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](O)[CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:16]([O:18][C:21]1[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](C)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
From 3.6 g of MA-Ala-Val-Ala-OH (0.012 mol), 1.5 g (0.012 mol) of p-nitrophenol, and 2.5 g (0.0125 mol) of dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran was prepared 2.0 g (40% yield) of MA-Ala-Val-Ala ONp; m.p. 174°-6° C. Recrystalized from ethylacetate/hexane. Molar extinction coefficient, ε274 nm =9300 (DMSO).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]2[CH3:31])=[CH:12][CH:11]=1>C(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:19][C:18]([C:1](=[O:3])[CH3:2])=[C:17]2[CH3:31])=[CH:14][CH:15]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Acetyl chloride (120 41, 1.67 mmol) was slowly added to a stirred slurry of aluminum chloride (223 mg, 1.67 mmol) in methylene chloride (15 ml) at -5° C. After 30 minutes, a solution 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl)-1H-pyrrole (Example 1) (500 mg, 1.52 mmol) in methylene chloride (20 ml) was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was poured over ice-water and extracted with methylene chloride. The organic fraction was washed with brine, dried (MgSO4), filtered and concentrated. The crude yellowish solid (570 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]ethanone (170 mg, 30%) as a white solid: mp (DSC) 211° C. Anal Calc'd. for C20H18NSFO3 ·0.25 H2O: C, 63.90; H, 4.96; N, 3.75. Found: C, 63.96; H, 5.04; N, 3.65.
Reaction SMILES: [Na].Br[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.N1C=CC=CC=1.[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27]>>[CH3:14][O:13][C:12]1[C:3]([O:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[C:4]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: OCC(F)(F)F
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1Br
Agent: [Na]
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2ncccc2c1OCC(F)(F)F

Procedure:
To a solution of 0.5 g (0.02 g atom) of sodium in 30 ml of 2,2,2-trifluoroethanol were added 5.6 g (0.02 mole) of 5-bromo-6-methoxy-8-nitroquinoline and 7 ml of pyridine. The mixture was heated under reflux for 158 hr and filtered to remove 1.3 g of starting material. The filtrate was concentrated to 50 ml, diluted with diethyl ether, washed with water and dried (potassium carbonate). Solvent removal left a tan crystalline powder, mp 109°-115° which was extracted with benzene. (A trace of insoluble red crystals was discarded.) The benzene solution was concentrated and the resulting residue was crystallized from diethyl ether-petroleum ether (20°-40°) (5:1) to give 0.4 g of pale tan crystals of 6-methoxy-8-nitro-5-(2,2,2-trifluoroethoxy)quinoline, mp 117°-119°. Concentration of the mother liquor provided an additional 2 g of product, mp 100°-111°. Crystallization of the first fraction from diethyl ether and vacuum drying, overnight, at 60°, gave the analytical sample, mp 120°-121°.