Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[C:18]([N:28]=[N+]=[N-])[C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])[CH3:3].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:28][C:18]1[C:19](=[O:27])[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:17]=1[CH2:16][CH2:15][C@@H:14]1[C@@H:24]2[CH2:25][CH2:26][C@@:9]2([CH3:10])[C@H:11]1[CH2:12][CH2:13][C@@H:8]2[C:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 55 %

Procedure:
To a stirred solution of N-(1,1-dimethylethyl)-4-azido-3-oxoandrost-4-ene-17β-carboxamide (1.3 g, 3.15 mmole) in tetrahydrofuran (20mL)-water (7 mL) was added triphenylphosphine (1.41 g, 5.38 mmole). The reaction was heated at reflux temperature for 16 hours. Most of the tetrahydrofuran was removed under vacuum. Dichloromethane was added to the mixture and the organic solution was placed atop a column of silica gel and flash chromatographed (hexane-30% ethyl acetate). The fractions containing the product were combined and concentrated to a white solid which was crystallized from diethyl ether to give the 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.67 g, 54.9%). IR 3476, 3442, 3382, 1672, 1659, 1620(m), 1580(m) cm-1 ; MS (CI) m/z 387 (100%, M+ +1); (EI) m/z 386 (10%, M+), 343 (100%); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 --Me), 1.16 (s, C19 --Me), 1.34 (s, tBu-Me's), 3.49 (2H, br s, NH2), 5.08 (1H, s, NHCO); 13C NMR (CDCl3) δ 132.97, 138.39, 171.69, 194.22. This compound has the following structure: ##STR5##
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:29][O:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1>C(O)C>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][CH2:19][CH2:18][N:17]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:4])[C:14]=2[N:15]=[C:16]1[CH2:29][O:30][NH2:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 114.1 %

Procedure:
Hydrazine hydrate (8 mL of 55%) was added to a suspension of tert-butyl (3-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propyl)carbamate (4.25 g, 8.23 mmol) in ethanol (70 mL). The reaction became homogeneous after about 2 minutes. A precipitate started forming after about 1 hour. After stirring at ambient temperature for a total of 2 hours the reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was azeotroped twice with toluene to provide 3.63 g of tert-butyl[3-(4-amino-2-aminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH:31](O)[CH3:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH:31]([C:23]1[S:22][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=1)[CH3:32])=[O:9])([CH3:6])[CH3:5]
Reactant: CC(O)c1nc2ccccc2s1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)c1nc2ccccc2s1
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a solution of 108 mg 2-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 72 mg 1-benzothiazol-2-yl-ethanol and 372 mg diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine in 2.5 mL dry THF a solution of 322 mg bis(1H,1H,2H,2H-perfluorooctyl)azodicarboxylate in 2.5 mL dry THF was added slowly at 0° C. After 16 h at room temperature and under argon atmosphere 372 mg diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine and 322 mg bis(1H,1H,2H,2H-perfluorooctyl)azo-dicarboxylate were added. After additional 24 h the solvent was evaporated, the residue taken up in 5 mL methanol and purified using a FluoroFlash-SPE cartridge with methanol/water 80/20. After removal of methanol the remaining phase was extracted with ethyl acetate twice. The combined organic fractions were washed with 2 M sodium hydroxide and water, dried over magnesium sulphate, filtrated and condensed to yield 137 mg 2-{[1-(1-benzothiazol-2-yl-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].NC(C1C=CC=C(OC)C=1)[C:19](O)=[O:20]>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:20][CH3:19])[CH:2]=1)[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COc1cccc(C(N)C(=O)O)c1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C(=O)O)c1cccc(OC)c1

Procedure:
Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-(3-methoxy-phenyl)-acetic acid. LCMS-ESI+: calc'd for C11H13NO5: 239.08 (M+); Found: 239.94 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.51 g, 3 mmol), 4,4-difluoropiperidine hydrochloride (0.71 g, 4.5 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 6 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc: cyclohexane, gradient 0:100 to 75:25) to give 3-(4,4-Difluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.69 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 3.94 (dd, J=8.7, 7.1 Hz, 2 H); 3.78 (dd, J=8.7, 5.3 Hz, 2 H); 3.17-3.10 (m, 1 H); 2.45-2.41 (m, 4 H); 2.10-1.94 (m, 4 H); 1.43 (s, 9 H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]([O:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([I:30])[CH:27]=2)[NH:22]1)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][CH:21]1[N:22]2[C:23]3[C:24]([C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)=[CH:25][C:26]([I:30])=[CH:27][C:28]=3[CH2:29]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCC1Cc2cc(I)ccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)CC2COC(C)=O
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of diethyl ethoxymethylenemalonate (2.73 mL) and (5-iodo-2,3-dihydro-1H-indol-2-yl)methyl acetate (Preparation 8, 3.90 g) is heated to 120° C. under a stream of nitrogen. After starting material is consumed, the mixture is cooled and diluted with EtOAc. The crude product is chromatographed eluting with 20, 40, and 60% EtOAc in heptane (500 mL each) to give 5.28 g (88%) of the corresponding enamine as a brown oil. A portion of this material (4.61 g) is dissolved in Eaton's Reagent (10 mL) and heated to 80° C. for 1 h. Upon cooling, the crude mixture is poured into a cold beaker and a 50% NaOH solution is slowly added until pH=7. The cloudy solution is then poured into CH2Cl2. The organic layer is separated and washed with brine, dried (Na2SO4), filtered, and concentrated to give a brown solid. The crude product is chromatographed eluting with 0-4% methanol in CH2Cl2 to give 880 mg (21%) of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 442 (M+H)+, 464 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CN=C1.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirring solution of 4-bromo-2,6-dimethylphenol (6 g, 29.85 mmol) in CH2Cl2 (80 mL) at 0° C. was added imidazole (4.1 g, 59.70 mmol) and triisopropylsilyl chloride (7.1 mL, 32.84 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel; eluting with ethyl acetate-hexanes (1:9) to afford (4-bromo-2,6-dimethylphenoxy)triisopropylsilane as a colorless oil (1.6 g, 15%): 1H NMR (300 MHz, DMSO-d6): δ 7.19 (s, 2 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.70.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:23][CH2:24][CH2:25][C:26]#[N:27]>O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:23][CH2:24][CH2:25][C:26]#[N:27]
Reactant: CN(C)c1cccc(O)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 3-dimethylaminophenol (5 g), potassium carbonate (10.05 g) and dimethylformamide (85 ml) was stirred at room temperature for 5 hours. 4-Bromobutyronitrile (7.3 ml) was added and the suspension stirred for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to yield 4-(3-dimethylaminophenoxy)butyronitrile.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:18][CH2:17][C:8]2[N:9]=[C:10]([N:12]=CN(C)C)[S:11][C:7]=2[C:6]1=O)C.[N+]([O-])(O)=O.[C:24]1([NH:30][C:31]([NH2:33])=[NH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[C:24]1([NH:30][C:31]2[N:33]=[CH:4][C:5]3[CH2:18][CH2:17][C:8]4[N:9]=[C:10]([NH2:12])[S:11][C:7]=4[C:6]=3[N:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C=Nc1nc2c(s1)C(=O)C(=CN(C)C)CC2
Reactant: N=C(N)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Nc1nc2c(s1)-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 100 °C
Yield: 7.5 %

Procedure:
A mixture of N′-(6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-N,N-dimethyl-formamidine (200 mg, 0.72 mmol), N-phenyl-guanidine nitrate (142 mg, 0.72 mmol), NaOH (57 mg, 1.44 mmol) and 2-methoxyethanol (4 mL) was heated under microwave irradiation (300 W, 100° C.) for 30 min. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) afforded the title product as a dark yellow solid (16 mg, 8%): mp 240° C. (dec). 1H-NMR (DMSO-d6): δ 9.42 (s, 1H, NH), 8.23 (s, 1H, Py-H), 7.77 (d, 2H, J 7.7, Ph-H), 7.26 (t, 2H, J 7.7, Ph-H), 6.91 (t, 1H, J 7.2, Ph-H), 2.93 (s, 4H, CH2—CH2). MS (ESI+): m/z 296.07 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](=O)[NH:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCC2CN(Cc3ccccc3)CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCNCC3C2)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
To a solution of the lactam from Example 22C (0.46 g) in THF (5 mL) was added 1M LiAlH4 (4.0 mL). The mixture was heated at 50° C. for 2 h, cooled to 15° C., and quenched by cautious addition of water (0.15 mL), followed by 15% NaOH (0.15 mL), then water (0.456 mL). The mixture was stirred for 5 minutes and filtered and washed with THF (3×5 mL). The filtrate was concentrated in vacuo to afford 442 mg of the title compound as a clear oil (quantitative yield). MS (Cl) m/z 217 (M+H)+; 1H NMR: δ 1.8-1.5 (m, 3H), 2.33-2.10 (m, 2H), 2.8-2.4 (m, 8H), 3.75 (s, 2H), 7.25 ppm (m, 5H).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[C:20]([NH:19][CH2:18][CH2:17][C:14]1[C:13]2[CH:23]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11][C:12]=2[O:16][CH:15]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)NCCc1coc2ccc(C=O)cc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at ambient temperature to a solution of 6.88 mmol of the product obtained in Step D in 30 ml of acetone. The solution is stirred for 2 hours at ambient temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica gel to yield the title product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10](=[O:20])[C:11]([CH3:19])=[CH:12]C2C=CC=CC=2)[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1>CCCCCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]2[C:8]=1[CH:19]=[C:11]([CH3:12])[C:10](=[O:20])[NH:9]2
Reactant: COc1ccc(C)c(NC(=O)C(C)=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Temperature: 125 °C
Yield: 85.2 %

Procedure:
N-(5-Methoxy-2-methylphenyl)α-methylcinnamamide (21.3 g, 75.8 mmol) and aluminum chloride (50.4 g, 378 mmol) were combined with chlorobenzene (158 ml), and heated in a bath at 125° C. for 45 minutes while stirring. After cooling, the mixture was poured into ice-water, to which hexane was added. Precipitated crystals were collected by filtration, and dissolved in chloroform-methanol (4:1). After drying and condensing, the resultant residue was washed with chloroform to obtain 12.22 g of the title compound as pale brown crystals (85.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[CH3:17].O.O.[Sn](Cl)Cl>C(O)C>[NH2:14][C:4]1[C:3]([CH3:17])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1N
Temperature: 25 °C

Procedure:
A suspension of 7-chloro-1,4-dihydro-6-methyl-5-nitroquinoxaline-2,3-dione (0.050 g, 0.20 mmol) and tin (II) chloride dihydrate (0.133 g, 0.60 mmol) in ethanol (1.0 mL) was refluxed for 6 h. The suspension was then cooled to room temperature and the solid was collected by vacuum filtration, washed with ethanol (1 mL), and dried further under vacuum to obtain 0.036 g (82%) pure (HPLC) title compound as an off-white solid; mp-darkens at 323° C.; 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 5.47 (s, 2H), 6.46 (s, 1H), 11.15 (s, 1H), 11.72 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(F)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16]>>[NH2:20][C:18]1[N:17]=[C:15]([NH2:16])[C:12]2[CH2:13][CH:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][C:11]=2[N:19]=1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: N#CNC(=N)N
Product: Nc1nc(N)c2c(n1)CCC(Cc1ccccc1)C2

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfudc acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[N:38][CH:39]=1)(=[O:33])=[O:32]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:36]2[CH:37]=[N:38][CH:39]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:35]=2)[CH:3]=[CH:4][C:5]=1[F:29])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Product: CS(=O)(=O)c1cncc(-c2ccc(F)c(C3(c4ccnc(C(F)(F)F)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Example 1 in 58% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (64.8 mg, 0.14 mmol) and 5-(methylsulfonyl)pyridin-3-ylboronic acid (30.6 mg, 0.15 mmol).
Reaction SMILES: [C:1]([CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1)#[N:2].Cl[C:30]([O:32][CH3:33])=[O:31]>CC#N>[C:1]([C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][N:5]([C:30]([O:32][CH3:33])=[O:31])[CH2:4]1)#[N:2]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CN(Cc3ccccc3)CC2C#N)cc1OC1CCCC1
Solvent: CC#N
Product: COC(=O)N1C[C@@H](C#N)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a solution of 3-cyano-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(phenylmethyl)pyrrolidine (300 mg, 0.79 mmol) in 2 mL of CH3CN in a thick-walled glass sealable tube was added methyl chloroformate (300 mg, 3.19 mmol). The tube was sealed and the resulting solution was heated to 80° C. for 12 hr. After cooling to room temperature, the solution was concentrated. Silica gel chromatography of the residue (2:1, hexanes:ethyl acetate) provided trans-3-cyano-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(methoxycarbonyl)pyrrolidine as a white solid (233 mg, 85%), m.p. 101°-104° C. Anal. Calcd for C19H24N2O4 : C, 66.26; H, 7.02; N, 8.13. Found: C, 66.14; H, 7.06; N, 8.10.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:14]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: Clc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Yield: 94 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (9.0 g., 0.046 mole), the product of Example 1, was stirred with triethyl orthoformate (90 ml.) at 100° C. for one hour. The mixture was cooled to room temperature and the solid precipitate was collected by filtration and washed with cyclohexane and dried to afford 8.8 g. (94% yield) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 287°-290° C. (decomp.). Mass spectrum: m/e, 204 (P).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:18]4[CH:23]([CH3:25])[CH3:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36]I.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:36])[CH2:19][C@H:18]4[CH:23]([CH3:24])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (71.4 mg, 0.145 mmol) in THF (0.483 mL) at 0° C. was added methyl iodide (31.1 μl, 0.498 mmol) followed by sodium hydride (7.65 mg, 0.319 mmol). The mixture was stirred for 3 hours at room temperature, quenched with ice, and diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C28H36ClN6O [M+H]+ 507. found 507.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[C:6]2=[N:7][C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[N:10]=[CH:9]1
Reactant: O=C1CCCCC1n1cnc2ccc(O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2ncn(C3CCCCC3O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
2-(5-Hydroxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclohexanone (0.200 g, 0.865 mmol) was taken up in ethanol (4 mL) and sodium borohydride (9.8 mg, 0.26 mmol) added. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.135 g). LCMS m/z=234.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.60 (m, 4H), 1.75-1.95 (m, 2H), 2.00-2.15 (m, 2H), 4.00-4.10 (m, 1H), 4.38 (q, J=8.1 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 9.52 (s, 1H).