Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3](=[O:6])[CH2:4][CH3:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.Cl>C(OCC)C>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[O:6][C:3]([CH2:4][CH3:5])=[C:2]([CH3:1])[N+:7]=2[O-:8])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCC(=O)C(C)=NO
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C

Procedure:
1.00 g (8.69 mmol) of 2,3-pentanedione 2-oxime and 1.34 g (9.55 mmol) of 4-chlorobenzaldehyde are initially charged in 2 ml (34.94 mmol) of glacial acetic acid. With ice-cooling of the reaction mixture, hydrogen chloride gas is then introduced for 30 min. 10 ml of diethyl ether are then added to the reaction mixture. A precipitate is formed, which is filtered off with suction and washed twice with in each case 2 ml of diethyl ether. The precipitate is resuspended in about 5 ml of water, and the suspension is made basic using ammonia. The suspension is then extracted four times with in each case 10 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.CCN(C(C)C)C(C)C.[Br:29][CH2:30][C:31](Cl)=[O:32].O>C(Cl)Cl>[Br:29][CH2:30][C:31]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][C@H:4]1[CH2:3][OH:2])=[O:32]
Reactant: O=C(Cl)CBr
Reactant: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C(=O)CBr)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate hydrochloride (0.83 g, 2.9 mmol) was dissolved in methylene chloride (10 mL) together with DIPEA (1.5 mL, 8.6 mmol). Bromoacetyl chloride (0.48 g, 3.0 mmol) was added at 0° C. by means of drops. The mixture was stirred at RT for 1 h and then water (10 mL) was added. The phases were separated by means of a phase separator column. The organic solution was collected and the solvent was removed by evaporation. There was obtained 1.1 g (100%) of benzyl (3S)-4-(bromoacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate as a brown oil. LCMS: m/z 370 (M−1)−.
Reaction SMILES: [C:1]([C:4]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([C:4]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)nc1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)c(C(C)=O)n1
Reaction time: 1.5 h

Procedure:
Ethyl 2-acetyl-6-methoxynicotinate (0.92 g, 4.13 mmol) in 20 ml of methanol is stirred with lithium hydroxide monohydrate (0.18 g, 4.20 mmol) in 3 ml of water. After 1.5 hours, the water and methanol are removed by rotoevaporation The residue is dissolved in chloroform and 3N hydrochloric acid. The aqueous phase is extracted with chloroform and the combined organic extracts are washed with brine and dried and the solvent is removed to give 2-acetyl-6-methoxynicotinic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[CH2:11]([O:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:27])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[CH3:12]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCCl)OC1=O
Product: CCOC(=O)c1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 4-(1-piperazinyl)benzoic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].N1C=CC=CC=1.[SH2:15]>C(N(CC)CC)C>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]([NH2:7])=[S:15]
Reactant: CN(C)CCCC#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(C)CCCC(N)=S
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A reaction mixture was prepared containing 95.2 g. of 4-dimethylaminobutyronitrile, 134.3 g. of pyridine, 257.6 g. of triethylamine and 113 g. of H2S. The reaction mixture was placed in an autoclave and the autoclave shaken for about 16 hours at 55° C. The reaction mixture was then removed from the autoclave and the volatile constituents removed by evaporation in vacuo. The resulting residue comprising 4-dimethylaminothiobutyramide formed in the above reaction was digested with about 1.5 l. of boiling ethyl acetate. The mixture thus produced was filtered through cellulose (hyflo supercel). The filtrate was concentrated until crystals appeared. The crystals were separated by filtration and the separated crystals washed with ethyl acetate. Sixty grams of 4-dimethylaminothiobutyramide melting at about 77° C. were obtained.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([CH2:38][OH:39])[NH:5][C:6](=[O:37])[C@H:7]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:8][C:9](=[O:26])[C@H:10]([CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)[NH:11][C:12](=[O:19])[C@@H:13]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1.[OH-].[Na+].Cl>CO>[NH:14]1[C:15](=[O:18])[CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:40])=[O:2])[CH2:38][OH:39])=[O:37])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:26])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:19]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine methyl ester (VI) (0.553 g) in absolute methanol (50 ml) containing sodium hydroxide (40 mg) is stirred at room temperature for 2 hours. The reaction mixture is then neutralized to pH 7.5 with dilute hydrochloric acid and evaporated to dryness. The solid residue is triturated thoroughly in absolute methanol and filtered. The filtrate is evaporated to the tetrapeptide VII.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](Cl)[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.C(O)(=[O:28])C>>[Br:1][CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:28])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3
Reactant: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: CC(=O)O
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Temperature: 130 °C
Yield: 93 %

Procedure:
A suspension of 1-bromomethyl-4-chloro-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxaline (91.0 g, 208 mmol) in glacial acetic acid (750 ml) was heated at 130° C. for 2.5 h. The solvent was removed under reduced pressure and the residue was stirred with ice-cooled water to give 81.2 g (93%) of the title compound. M.p. 247°-248° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20](O)[CH:21]([F:27])[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(OCC)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:21]([F:27])[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: OC(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(c1ccccc1)C(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Reaction time: 2 h

Procedure:
With efficient stirring, a solution of 25 ml of benzoyl chloride in 250 ml of diethyl ether is added dropwise at 0°-5° C. to a mixture of 250 ml of 2n NaOH solution and 27.6 g of 1-(2,4-dichlorophenyl)-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanol (prepared in accordance with Example P1a). The reaction mixture is stirred for another 2 hours at 0°-5° C. and then further without cooling until it has reached room temperature. The separated ethereal phase is washed with four 50 ml portions of 0.2n NaOH solution and then with water until neutral, dried over sodium sulfate, filtered and concentrated by evaporation, affording as crude product 40 g of an oil which is purified by flash distillation at 0.07 mbar and 180° C. Recrystallisation from diisopropyl ether affords approx. 26 g of the product which melts at 104°-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17]3[C:7]([CH2:8][C@@H:9]4[C@@H:14]([C:15]=3[CH:16]=1)[CH2:13][C@H:12]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:11][N:10]4[CH3:26])=[CH:6][NH:5]2.[C:27](O)(=O)C.CSC.B>C(O)=O>[CH2:21]([N:20]([CH2:23][CH3:24])[C:19]([NH:18][C@H:12]1[CH2:13][C@H:14]2[C@@H:9]([CH2:8][C:7]3[C:17]4[C:4](=[CH:3][C:2]([NH:1][CH3:27])=[CH:16][C:15]2=4)[NH:5][CH:6]=3)[N:10]([CH3:26])[CH2:11]1)=[O:25])[CH3:22]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(N)cc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CC(=O)O
Agent: B
Solvent: CSC
Solvent: O=CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(NC)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
At -20° C., 355 mg of 3-(13-amino-6-methyl-8α-ergolinyl)-1,1-diethylurea is reacted to the N-formyl compound with the mixed anhydride of acetic acid and formic acid and the N-formyl compound is reduced with borane-dimethyl sulfide (S. Krishnamurty, Tetrahedron Letters 1982: 3315). After chromatography, 260 mg of 1,1-diethyl-3-(6-methyl-13-methylamino-8α-ergolinyl)urea is obtained.
Reaction SMILES: C[Li].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.Cl[Si](C)(C)[CH3:17].Cl>O1CCCC1>[OH:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](=[O:11])[CH3:17])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)COc1ccc(O)cc1
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(O)cc1
Temperature: 22 °C
Reaction time: 40 h

Procedure:
Methyllithium (140 ml of 1.5 molar lithium bromide complex in diethyl ether) was added to a stirred solution of 4-hydroxyphenoxyacetic acid (7.6 g) in anhydrous tetrahydrofuran (500 ml) at 0°-10° C. under argon. The reaction mixture was stirred for 40 hours at 22° C., cooled in an ice-bath and chlorotrimethylsilane (39 ml) was added over 15 minutes. The temperature was allowed to rise to 22° C. and the reaction mixture was poured into 1N hydrochloric acid (360 ml) and stirred for 30 minutes. The product was extracted into ethyl acetate (4×200 ml) and the combined extracts washed with aqueous sodium bicarbonate (2×300 ml), brine (100 ml), dried and the solvent removed under reduced pressure. The crude ketone was purified by chromatography using 31/2% tetrahydrofuran in dichloromethane as eluent. The appropriate fractions were combined and evaporated to yield 1-(4-hydroxyphenoxy)propan-2-one (2.0 g) as a white solid, m.p. 110°-112° C. (from ethyl acetate); microanalysis: found C, 65.5; H, 6.1%; required for C9H10O3 : C, 65.1; H, 6.0%. (A similar procedure for the preparation of methyl ketones is described by G. M. Rubottom and Chong-Wan Kim, J.O.C. 1983, 48, 1550-1552).
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[H][H]>CO.[Pd]>[N:1]1([C:7]2[C:12]3[CH2:13][CH2:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2c(c(N3CCNCC3)n1)CCO2
Yield: 38.6 %

Procedure:
A mixture of commercially available 4-(piperazin-1-yl)-furo[3,2-c]pyridine [CAS-No. 81078-84-4] (1 g, 4.92 mmol), Pd/C 5% (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9 ml) was stirred in a hydrogen atmosphere at room temperature for 48 h. After removal of the catalyst by filtration the mixture was evaporated, the residue was dissolved in dichloromethane/MeOH/NH4OH 80:10:1, washed with 2N sodium carbonate solution, dried (MgSO4) and evaporated. The crude material (0.68 g) was purified by chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield 4-(piperazin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine as a white solid (0.39 g, 39%), MS (ISP) m/z=206.2 [(M+H)+], mp 89.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:43]1[C:47](=[O:48])[C:46]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]2[C:44]1=[O:53].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:53]=[C:44]1[C:45]2[C:46](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](=[O:48])[N:43]1[O:22][CH2:21][CH2:20][CH2:19][O:18][C:16]1[CH:17]=[C:2]([Cl:1])[CH:3]=[C:4]([CH:15]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(OCc1ccccc1)c1cc(Cl)cc(OCCCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A solution of alcohol 26 (5.96 g, 18.6 mmol), triphenylphosphine (5.40 g, 20.5 mmol), and N-hydroxyphthalirnide (2.10 g, 20.5 mmol) in tetrahydrofuran (186 mL) was cooled to 0° C. and reacted slowly with diethyl azodicarboxylate (3.50 mL, 22.3 mmol). After warming to ambient temperature and stirring 16 hrs, the reaction was concentrated in vacuo and purified by chromatography on silica gel (10% ethyl acetate in hexanes) giving product 27 (5.18 g, 60%). 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, 2H, J=5.6 Hz, 3.1 Hz), 7.75 (dd, 2H, J=5.6 Hz, 3.1 Hz), 7.63 (t, 1H, J=1.5 Hz), 7.51 (dd, 1H, J=2.4 Hz, 1.4 Hz), 7.40 (m, 5H), 7.12 (t, 1H, J=2.3 Hz), 5.35 (s, 2H), 4.41 (t, 2H, J=6.1 Hz), 4.28 (t, 2H, J=6.1 Hz), 2.25 (pentet, 2H, J=6.1 Hz).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:39][C:40]1[CH:41]=[CH:42][C:43](F)=[N:44][CH:45]=1>CN(C)C=O.O>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[N:44][CH:45]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cn3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 77.5 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (400 mg, 1.00 mmol) in dimethylformamide (5 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.5 mL, 1.50 mmol). After 1 hour 5-bromo-2-fluoropyridine (350 mg, 2.00 mmol) was added and stirring was maintained at 80° C. for 16 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by column chromatography to afford 6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (430 mg, 0.775 mmol, 77.5% yield) as a yellow solid. LCMS (m/z, ES+)=559 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:16][CH2:17][CH2:18][NH:19][CH2:20][C@H:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:22][CH:23]=[CH2:24])=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(C(C)C)CC)(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(#N)C.C(OCC)(=O)C>[Cl:32][C:27]1[CH:26]=[C:25]([C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][N:19]2[C:13](=[O:15])[C:5]3[C:6]4[C:11]([CH:12]=[C:3]([C:1]#[N:2])[C:4]=3[S:16][CH2:17][CH2:18]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: C=CC[C@H](CNCCSc1c(C#N)cc2ccccc2c1C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a solution of 3-cyano-2-[(2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoic acid (Intermediate 6, 135 mg, 0.28 mmol) in dry acetonitrile (6 mL) under nitrogen at 0° C. was added diisopropylethyl amine (146 μL, 0.84 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl, 86 mg, 0.34 mmol). Stirring was continued for 45 min as the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 0.5 N HCl and brine, dried (Na2SO4), and evaporated to a residue which was chromatographed on silica gel in 25-40% EtOAc/Hexanes to give 85 mg of partially purified material. A portion (50 mg) of this material was chromatographed on silica gel in 20% EtOAc/Hexanes to give 35 mg of the title compound.
Reaction SMILES: COC1C=CC(C2C(C)(C)CC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1(CCOC2C=C[C:57]([CH2:58][NH:59][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH2:69]3)=CC=2)CCCCCC1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][N:59]([CH2:58][CH3:57])[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[C:77]([CH3:79])([CH3:78])[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:80][CH3:81])[CH:74]=4)[CH2:69]3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (522 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (521 mg). This compound (519 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (365 mg).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24](O)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(Cl)c(Cl)c2)nn2cccnc12

Procedure:
The product from Example 105B and 2-(3,4-dichlorophenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.87 (d, J=5.9 Hz, 1H), 8.49 (dd, J=4.0, 1.8 Hz, 1H), 7.59-7.62 (m, 2H), 7.32-7.36 (m, 1H), 7.01 (dd, J=7.0, 4.0 Hz, 1H), 3.67-3.70 (bs, 2H), 1.39 (s, 9H); MS (ESI) m/z 377, 379 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].OS(O)(=O)=O.[OH2:14].[CH3:15]O>>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:15][OH:14])[CH:4]=1)#[N:2]
Reactant: O
Reactant: CO
Reactant: N#Cc1ccncc1
Agent: O=S(=O)(O)O
Product: N#Cc1ccnc(CO)c1
Yield: 39.5 %

Procedure:
A solution of 4-cyanopyridine (5.20 g, 50.0 mmol) in 90 ml of methanol is treated with a mixture of H2SO4 (6.42 g, 65.5 mmol, 1.31 equiv.) and water (45 ml) at once followed by the addition of (NH4)2S2O8 (22.8 g, 100 mmol, 2.0 equiv.). The contents were heated to reflux at which point vigorous refluxing ensued for several minutes. After refluxing for 24 h, the reaction mixture is partially concentrated to remove most of the methanol, treated with ice-water mixture and basified with ammonium hydroxide (20 ml, 29% aq). The residue is extracted four times with chloroform, the combined extracts are dried with anhyrous Na2SO4 and concentrated at reduced pressure. Chromatography is accomplished using 300 g of silica gel packed and eluted with acetone-methylene chloride (1:6) to provide 2.65 g (39.5%) of 4-Cyano-2-hydroxymethylpyridine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc([N+](=O)[O-])cc3nc21
Yield: 82 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid (3.4 g, 12.32 mmol) and POCl3 (20 ml) is refluxed for 8 hours. The reaction mixture is poured into ice waterl, neutralized with concentrated NH4OH, and the resulting solid is collected by filtration,washed with water and dried to afford 2.8 g (82%) of 1-ethyl-4-chloro-7-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][NH:19][CH:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[CH3:21])[CH:5]=1)([O-:3])=[O:2].[CH2:28](I)[CH3:29].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[CH:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCI
Reactant: COc1nc2cc([N+](=O)[O-])cc(CNC(C)P(=O)(OC)OC)c2nc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)C(C)P(=O)(OC)OC

Procedure:
300 mg (0.75 mmol) of dimethyl N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-aminoethylphosphonate, 0.482 ml (8 eq.) of ethyl iodide and 1.4 ml (11 eq.) of diisopropylethylamine are stirred at 700 for 24 hours in 10 ml of acetonitrile. The reaction mixture is evaporated and the residue is stirred in diethyl ether. The solid is filtered off, washed with diethyl ether and the filtrate is evaporated. The title compound is obtained as a brownish oil.
Reaction SMILES: [CH3:1][CH:2]1C(=O)C2C=CSC=2CC1.[O:12]1[C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[C:15]=2[CH:14]=[CH:13]1.C(I)C>>[CH2:1]([CH:19]1[C:20](=[O:21])[C:15]2[CH:14]=[CH:13][O:12][C:16]=2[CH2:17][CH2:18]1)[CH3:2]
Reactant: CC1CCc2sccc2C1=O
Reactant: O=C1CCCc2occc21
Solvent: CCI
Product: CCC1CCc2occc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6,7-dihydro-1-benzofuran-4(5H)-one and ethyl iodide and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.00, 1.54, 1.95, 2.29, 2.91, 6.67, 7.3; MS (EI) m/z (rel. intensity) 164 (M+, 36), 164 (36), 136 (90), 135 (24), 108 (76), 88 (13), 86 (69), 84 (99), 80 (58), 52 (21), 51 (57). HRMS (FAB) calcd for C10H12O2+H 165.0916, found 165.0919. Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 72.81; H, 7.60.