Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:35]>O1CCOCC1>[ClH:35].[CH3:12][CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 64 h
Yield: 76 %

Procedure:
A mixture of 1,1-dimethylethyl 5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 4; 53.7 mg, 0.117 mmol) and 4M HCl in dioxane (2 ml) was stirred at room temperature for 64 h. The mixture was concentrated in vacuo, the residue triturated with Et2O and dried in vacuo to leave a light brown solid (35.1 mg, 76%). 1H NMR (400 MHz, d6-DMSO) δ 9.52 (2H, br. s), 8.52 (1H, d), 8.40 (1H, dd), 8.02 (1H, dd), 7.57, (1H, d), 7.51-7.48 (2H, m), 4.99 (1H, sept.), 4.38 (2H, s), 3.39-3.34 (4H, m), 1.39 (6H, d); m/z (ES) 361 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:16]([CH2:18][C:19]([O:21]C)=[O:20])[CH:17]=2)=[O:11])=[C:8]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>CO.O>[CH2:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=2)=[O:11])=[C:8]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)CCOc1cc(OCC(C)C)ccc1C(=O)c1ccc(OCC(C)C)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
In 2 ml of methanol is dissolved 0.13 g of methyl 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]acetate, to which is added 0.2 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour and then at 50-60° C. for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 0.07 g of 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]acetic acid as a white-colored solid product.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C:13]3=[O:21])[CH2:9][CH2:10][C@@H:2]12.Cl[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.Cl>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@H:8]([CH2:11][N:12]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[O:14][C:13]4=[O:21])[CH2:9][CH2:10][C@H:2]3[CH2:1]2)=[N:24][CH:25]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1

Procedure:
The title compound was synthesized according to Preparation 11 from 3-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzoxazol-2-one (Preparation 12) and 2,5-dichloropyridine. mp (—HCl) 247-248° C. HRMS calcd for C21H23ClN4O2: 398.1510, found: 398.1484.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=1.C(O)(=O)C>C(O)C>[CH:15]1([C@@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: CC(C)(CO)n1cc(N)cn1
Reactant: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@](C#N)(C4CC4)C3=O)n2)cn1
Yield: 37.9 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 105, 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol (120 mg) obtained in Step H of Example 103 and acetic acid (48 μL) in ethanol (20 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The obtained 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), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (110 mg).
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:29])[CH3:28])(C(C)(C)C)(C)C.CO.Cl.O>O1CCCC1>[OH:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of 4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (391.7 mg) in tetrahydrofuran (12 mL)-methanol (12 mL) was added 6 mol/L hydrochloric acid (12 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless oil (yield: 203.6 mg, 71%).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][NH:6][C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)c[nH]c1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g), phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium (0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 1 hr. 8 mol/L aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 90° C. for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1), and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield 815 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.NC1C=CC=CC=1.[C:22](#[N:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CCCCC.C(OCC)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:22](=[NH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1N
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
2,6-dimethylaniline (6.15 mL, 50.0 mmol) was added to 100 mL of diethylether and cooled to 0° C. Butyllithium (26.0 mL of 2.0 M solution in diethylether, 52.0 mmol) was added dropwise to the cooled aniline solution, affording an off-white solid after complete addition. The slurry was warmed to room temperature and stirred for 2 hours. Benzonitrile (5.2 mL, 51.0 mmol) was added slowly resulting in the formation of a suspended yellow-orange solid after complete addition. Stirring was continued for 1 hour and the solvent was removed in vacuo. Tetrahydrofuran (150 mL) was added and the mixture was refluxed overnight under argon, yielding a dark orange-red solution. Distilled water (2.0 mL, 112 mmol) was added and the mixture became a milky yellow solution after stirring for 30 minutes at room temperature. Solid, presumably lithium hydroxide, was removed via aerobic filtration and the remaining solvent was removed in vacuo, to produce a light yellow solid. The solid was slurried in 80 mL of pentane and stirred for 2 hours. Filtration of the slurry yielded 10.28 g (92%) of white solid. 1H NMR (400 MHz, CDCl3): 7.93 (d, 2H), 7.48 (m, 3H), 7.06 (d, 2H), 6.90 (t, 1 H), 4.58 (s, 2H), 2.17 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[C:8]([N+:16]([O-])=O)[C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].Cl>C(O)(=O)C.[Pd]>[NH2:16][C:8]1[C:7]2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:1][CH3:2])[C:12]=2[CH:11]=[C:10]2[O:13][CH2:14][O:15][C:9]=12
Reactant: CCn1cc(C(=O)O)c(=O)c2c([N+](=O)[O-])c3c(cc21)OCO3
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(N)c3c(cc21)OCO3
Yield: 87.2 %

Procedure:
A suspension of 5-Ethyl-9-nitro-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (6 g, 19.59 mmol) and Pd/C (1 g, 0.940 mmol) in a mixture of acetic acid (150 mL) and con. HCl (50 mL) was hydrogenated on a Parr apparatus at 50 psi of H2 for 1 h at r.t. LCMS indicated completion of the reaction. The catalyst was filtered off. The filtrate was added dropwise into water (675 mL). The light yellow precipitates were collected by filtration, washed with water and dried in vacuo to afford 9-amino-5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (4.72 g, 17.09 mmol, 87% yield). LCMS: (M+H)+: 277.2.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[Cl:35])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)ccc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.27 mmol) was added to a stirred solution of {6-chloro-4-[4-(2,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.037 g, 0.06 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] through the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 86%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (br. s, 1 H) 8.33 (s, 1 H) 8.16 (d, J=7.82 Hz, 2 H) 7.99 (s, 1 H) 7.85-7.93 (m, 2 H) 7.77 (d, J=8.80 Hz, 1 H) 7.55 (d, J=8.80 Hz, 2 H) 7.49 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.86 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C25H16Cl3O4S [(M−H)−] 517, obsd. 517.3.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8](OC)[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][C:5]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:4]1)[CH3:2].C(#N)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([N:3]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][C:5]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C(OC)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCn1nc(NCc2ccc(F)cc2)cc1Cc1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 1-ethyl-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1H-pyrazol-3-yl-(4-fluoro-benzyl)-amine (531, 0.12 g, 0.32 mmol) in acetonitrile (10.0 mL, 0.191 mol) were added triethylsilane (0.60 mL, 0.0038 mol) and trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at 80° C. for 2 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give crude compound. 1H NMR indicated that the reaction was incomplete. The crude compound was dissolved in dichloromethane (15.0 mL), trifluoroacetic acid (0.30 mL) and triethylsilane (0.60 mL). The reaction was stirred at 43° C. for 72 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-0165, 18.7 mg, 17%). MS (ESI) [M+H+]+=350.3.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:31]([F:33])[F:32])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])=[C:8]2[O:30][CH:31]([F:33])[F:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(OC(F)F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-4-difluoromethoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.034 g), methanol (8.0 mL), tetrahydrofuran (8.0 mL), water (5.0 mL) and lithium hydroxide (0.027 μg) was stirred at room temperature for 1 hour. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient of acetonitrile in water gave title compound as a yellow solid, 0.09 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc([N+](=O)[O-])c2)c(Br)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 4-(3-amino-5-bromo-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (5 g), 3-nitrobenzyl bromide (2.72 g), potassium carbonate (3.65 g) and potassium iodide (400 mg) in DMF (100 ml) was stirred for 65 h at room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(O)cc1)NCCc1cccc(OCc2ccccc2)c1
Yield: 56.2 %

Procedure:
A solution of 2-[3-(phenylmethoxy)phenyl]ethylamine (2.80 g, 12.3 mmol), 4-hydroxyphenylacetic acid (2.25 g, 14.8 mmol), N, N-diisopropylethylamine (2.79 mL, 16 mmol), and EDCI (3.07 g, 16 mmol) in 20 mL of DMF was stirred at room temperature for 10 h. The reaction mixture was poured into 100 mL of water and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (SiO2, hexanes/ethyl acetate, 1:1) to provide the title compound (2.50 g, 56% yield): ES-MS, (m/z) 362 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][O:19][C:20](/[N:22]=[N:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])=[N:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: C1COCCO1
Product: CCOC(=O)N=NC(=O)OCC
Reaction time: 2 h

Procedure:
Combine 3,5-di-t-butyl-4-hydroxythiophenol (751mg), diethylazodicarboxylate (496μL, 3.15mmol) and p-dioxane (5mL). Place under an argon atmosphere and stir for 2 hours to give a complex of 3,5-di-t-butyl-4-hydroxythiophenol and diethyl azodicarboxylate.
Reaction SMILES: [CH:1]1([N:7]([CH3:39])[C:8](=[O:38])[CH2:9][CH2:10][CH:11]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:12]([C:30]#[N:31])=[CH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:15]=2[N+:27]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>CO.[Zn]>[NH2:31][C:30]1[C:12]([CH:11]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:10][CH2:9][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:39])=[O:38])=[CH:13][C:14]2[C:15](=[CH:16][CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=2)[N:27]=1
Reactant: CN(C(=O)CCC(C(C#N)=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCOCC1)C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN(C(=O)CCC(c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCOCC1)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A solution of 5-cyano-6-(2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid cyclohexyl-methyl-amide (0.37 g, 0.697 mmol) in methanol was divided evenly into two microwave tubes containing Zn (0.9 g, 13.8 mmol) and NH4Cl (0.1 g, 1.87 mmol). The reaction mixture was subjected to μW at 95° C. for 900 sec. The reaction mixture was filtered through Celite®, and the filtrate was evaporated in vacuo to yield a crude product which was purified on a silica gel column (10% MeOH/dichloromethane) to yield the title compound as a residue.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH2:24])[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:24][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[N:7]=1
Reactant: NCC1CCCO1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCC2CCCO2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 34.8 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), tetrahydrofurfuryl amine (Aldrich Chemical Company) (0.212 mL, 2.05 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to obtain crude pink solids. Recrystallization from EtOH/MeOH gave 0.044 g (35%) of the title compound as an off-white solid. Mp: 280° C. 1H NMR (CDCl3; 500 MHz): δ 1.59 (m, 1), 1.87 (m, 2), 2.00 (m, 1), 2.39 (s, 3), 3.48 (m, 1), 3.71 (m, 2), 3.86 (t, 1, J=7.3), 4.06 (m, 1), 6.74 (s, 1), 6.95 (s, 1), 7.38 (t, 1, J=7.1), 7.51 (t, 2, J=7.6), 7.80 (d, 2, J=8.0), 11.41 (s, 1). MS m/z: 309 (M+1). Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 69.88; H, 6.51; N, 18.03.
Reaction SMILES: [CH2:1](N)[CH:2]([CH3:4])[CH3:3].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:7]>C(O)C>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH:27][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:30]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CN
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCC(C)C)cc21
Reaction time: 16 h

Procedure:
Isobutylamine (2.50 cc) is added to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.86 g) in absolute ethanol (25 cc). The mixture is brought to 150° C. for 16 hours and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue obtained is purified by chromatography on a column (height: 16.5 cm; diameter: 2.8 cm) silica gel (0.04-0.06 mm) with a slight excess presof sure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (1.5 liters) and 50:50 (1 liter), collecting 50-cc fractions. Fractions 4 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarbothioamide (1.3 g).