Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:12](=O)([O-])[O-].BrC[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20].[K]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:9]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[C:8]([CH3:12])[C:6]=2[CH:7]=1
Reactant: CC(C)C(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
1-[5-Bromo-2-hydroxyphenyl]ethanone (8.4 g) was dissolved in N,N-dimethylformamide (50 mL). To the reaction mixture were added carbonate (16.2 g) and 1-bromo-3-methylbutan-2-one (8.4 g) synthesized in Example A75(1) at room temperature potassium, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtered through celite, water (100 mL) was added, and the mixture was extracted with diethyl ether (50 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title object compound (10.2 g, 77%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:4]1[CH:3]=[C:2](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[C:6]([Cl:8])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (100 mg, 0.27 mmol) and ethyl acrylate (3.06 mL, 30.58 mmol) in dimethylformamide (3 mL) was stirred at room temperature. Triethylamine (0.15 mL, 1.08 mmol) was added followed by triphenylphosphine (42.6 mg, 0.16 mmol) and palladium acetate (18.16 mg, 0.008 mmol). The reaction mixture was purged with argon and heated under reflux for about 20 hours. The reaction mixture was cooled to room temperature and the residue was poured into water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. Ethyl(2E)-3-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]prop-2-enoate (64.8 mg, 61.59%) was isolated by silica gel column chromatography using ethyl acetate in hexane (15-17%) as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C>[CH:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:19])[CH3:18]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(C=O)c1
Temperature: 50 °C

Procedure:
50 g of 3-hydroxybenzaldehyde are dissolved, under nitrogen, in 250 ml of DMF. 60 g of K2CO3 and then 60 ml of 2-iodopropane are added and the reaction mixture is heated for 18 hours at 50° C. and poured into 2.5 liters of water. Extraction is carried out with ethyl ether and the ether phase is washed with a dilute solution of NaOH, dried over MgSO4 and concentrated under vacuum to give 53.5 g of an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.[CH3:24][CH2:25][N:26](C(C)C)C(C)C.BrCC#N>>[C:25]([CH2:24][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH:4]=1)#[N:26]
Reactant: CN(C)C(=O)CN(Cc1cc(CN)ccn1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Product: CN(C)C(=O)CN(Cc1cc(CNCC#N)ccn1)C(=O)OC(C)(C)C

Procedure:
General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-[(dimethylcarbamoyl)methyl]carbamate (1.0 equiv.), DIPEA (2.0 equiv.) and bromoacetonitrile (1.1 equiv.). Purification by preparative TLC (10% MeOH and 1% NH4OH in DCM) gave the title product as light yellow oil. 1H NMR (300 MHz, methanol-d4): δ ppm 8.42 (d, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 4.58 (m, 2H), 4.19 (m, 2H), 3.93 (s, 2H), 3.65 (s, 2H), 2.98 (m, 6H), 1.42 (m, 9H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][NH2:21].Cl>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N:20]1[CH:5]=[CH:4][CH:3]=[N:21]1
Reactant: NNc1cc(F)ccc1F
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Product: Fc1ccc(F)c(-n2cccn2)c1
Yield: 97.6 %

Procedure:
Add 1,1,3,3-tetramethoxypropane (8.2 g, 50 mmol) to a mixture of 2,5-difluorophenylhydrazine (9.022 g, 62.6 mmol) and hydrochloric acid (5M, 5 mL, 25 mmol) in ethanol (50 mL) and heat and stir under reflux under nitrogen for 17 hr. Cool the mixture, evaporate the ethanol in vacuo, suspend the residue in DCM (80 mL), filter the DCM solution and pass through an SCX-2 column. Collect the eluent and pass through a second SCX2 column and evaporate the eluent to give 1-(2,5-difluoro-phenyl)-1H-pyrazol as a liquid (8.79 g, 97%). MS (m/z): 181 (M+1).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3](OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)(=[O:5])=[O:4].[Br:28][C:29]1[C:38]([OH:39])=[C:37]([CH3:40])[CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([C:41]([F:44])([F:43])[F:42])=[N:34]2>>[F:1][C:2]([F:27])([F:26])[S:3]([O:39][C:38]1[C:29]([Br:28])=[C:30]2[C:35](=[CH:36][C:37]=1[CH3:40])[N:34]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:32]=[CH:31]2)(=[O:5])=[O:4]
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1O
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Product: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 7C was prepared following the procedure used to prepare compound 1F of Example 1 except that 5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-ol (7B) was used instead of compound 1E. LCMS-ESI+ (m/z): 437.8, 439.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>Cl.CCCCO>[CH:17]1([NH:22][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NC3CCCC3)ncn2)cc1
Temperature: 200 °C
Yield: 83 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 26 mg of cyclopentylamine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-Cyclopentyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:4])[CH3:3].[H][H]>CN(C)C=O.[Pd]>[CH3:4][C:2]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
6-Nitrobenzothiazol-2-yl tert-butyl carbamate (4.68 g, 15.8 mmol) was dissolved in dimethylformamide (120 mL) and palladium on charcoal (841 mg, 10% Pd, 0.79 mmol Pd) was added. The air was replaced with hydrogen (1 bar) and the mixture was vigorously stirred at 60° C. until completion of the reaction (2 h). The palladium was removed by filtration through a pad of celite and the solution was concentrated to 20 mL. Water (200 mL) was added. After stirring for 1 h, the precipitated 6-aminobenzothiazol-2-yl tert-butyl carbamate was filtered off and washed with water. Additional product was obtained by repeated filtration of the mother liquor. A total of 3.24 g (12.2 mmol, 77%) of a grey solid was obtained. LC/ESI-MS: m/z=266 [M+H]+; m/z=264 [M−H]−; Rt=2.54 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].Cl.[NH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[C:22]([F:31])[CH:21]=1)[CH3:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([NH:17][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:19])=[CH:21][C:22]=1[F:31])([CH3:29])[CH3:30])#[N:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C(C)(C)C#N)c(F)c1

Procedure:
The amide is synthesized according to modified example 1 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (781 mg, 3.68 mmol) prepared according to scheme 2, 2-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (1.07 mg, 4.41 mmol) prepared according to scheme 7, Et3N (1.23 mL, 8.82 mmol) and HATU (1.68 g, 4.41 mmol) in DMF (15.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5u) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA), (565 mg as TFA salt, 1.10 mmol, 30%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=6.84 Hz, 3H), 1.71 (s, 6H), 4.87-5.00 (m, J=7.23, 7.23 Hz, 1H), 5.09 (s, 2H), 7.16-7.29 (m, 3H), 7.36-7.51 (m, 2H), 8.19 (s, 1H), 8.86 (d, J=7.62 Hz, 1H). MS [M+H], calcd: 401.4. found: 401.3.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1ccccc1C(F)(F)F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 31 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 5 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 17.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[O:11][CH3:12])=[O:5])C.CO[CH:21](OC)[CH2:22][C:23]#[N:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([C:9]1[C:10]([O:11][CH3:12])=[C:6]2[C:4]([OH:5])=[C:22]([C:23]#[N:24])[CH:21]=[N:18][N:7]2[CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cn(N)c(C(=O)OCC)c1OC
Reactant: COC(CC#N)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn2ncc(C#N)c(O)c2c1OC
Temperature: 80 °C
Yield: 10 %

Procedure:
To a mixture of amine 393E (0.34 g, 1.33 mmol) in toluene (2.6 ml) was added 3,3-dimethoxy-propionitrile (0.4 ml, 2.66 mmol) and TsOH.H2O (50 mg, 0.266 mmol), the mixture was heated at 80° C. for 4 h, then DBU (0.404 mg, 2.66 mmol) was added, and heated for another 0.5 h. The residue was purified by silica gel flash column chromatography to give 0.46 g of crude 393F (10% MeOH—CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:27]([CH3:26])[CH2:28][CH2:29][CH3:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CCCNC
Product: CCCN(C)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and N-Methylpropylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-propyl-amine, MS: 373 (MH+, 1Cl).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 35.6 %

Procedure:
The title compound (47 mg) was prepared according to Example 193 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 218 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C16H18N4, 266.15; found, m/z 267.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93-7.91 (m, 2H), 7.58-7.56 (m, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.43-3.40 (m, 2H), 3.18-3.16 (m, 2H), 2.82-2.80 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC.CCOCC>[OH:18][CH:17]([C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1)[C:8]#[C:7][C:6]([O:10][CH3:11])=[O:9]
Reactant: C#CC(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 1.5 h

Procedure:
71.6 ml of n-butyllithium solution (1.6M in hexane) were added to a solution of 9.6 ml (0.115 mol) of methyl propiolate in 195 ml of tetrahydrofuran/ether/hexane (4:2:1) at -110° . The mixture was stirred at -110° for 20 minutes, whereupon 15.0 g (76.4 mmol) of 3,4,5 -trimethoxybenzaldehyde in 15 ml of ether were added within 20 minutes. The reaction mixture was stirred at -78° for a further 90 minutes, then brought slowly to room temperature and thereupon treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. Chromatography on silica gel with ethyl acetate/hexane (1:2) yielded methyl 4-hydroxy-4-(3,4,5 -trimethoxyphenyl)-2-butynoate.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of (5R)-5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.22 g, INTERMEDIATE 9) and triphenylphosphine (3.44 g) was heated to 65° C. for 6 h in 444 ml of tetrahydrofuran and 56 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (1.74 g, 87%). Mass spectrum (ESI) 228.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[O:4][C:5]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][C:7]=1[OH:8].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]2[N:22]=[C:23]([SH:25])[N:24]=[C:17]2[N:16]=1>>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]2[N:22]=[C:23]([S:25][C:2]3[C:3](=[O:13])[O:4][C:5]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][C:7]=3[OH:8])[N:24]=[C:17]2[N:16]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: CCC1(CC)CC(O)=C(Cl)C(=O)O1
Product: CCC1(CC)CC(O)=C(Sc2nc3nc(C)cc(C)n3n2)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one (from Step 1) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4). 1H NMR (CDCl3): δ 0.97 (t, 6H, J=7.5 Hz), 1.85 (m, 2H), 1.94 (m, 2H), 2.63 (s, 3H), 2.71 (s, 3H), 2.78 (s, 2H), 6.78 (s, 1H). Anal. Calcd. For C16H20N4O3S.0.5H2O: C, 53.76; H, 5.92; N, 15.68. Found: C, 53.96; H, 5.84; N, 15.37.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][CH2:9][C:8]2([CH3:12])[CH:3]1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.[C:15](O)(=O)C.[CH:19]([NH2:21])=[NH:20]>C(O)CCC>[CH3:1][C:2]1([CH3:14])[CH:3]2[CH2:4][C:5]3[CH:15]=[N:20][CH:19]=[N:21][C:6]=3[CH2:7][C:8]2([CH3:12])[CH2:9][CH2:10][CH2:11]1
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CC1(C)CCCC2(C)CC(=O)CCC12
Solvent: CCCCO
Product: CC1(C)CCCC2(C)Cc3ncncc3CC12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 5,5,8a-trimethyl-octahydro-naphthalen-2-one (prepared as described by Strike in Journal of the American Chemical Society, 1964, 86(10), pages: 2044-2050) (10 g, 0.05 mol), formamidine acetate (27 g, 0.26 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. A mixture of products 5,7,7,8,10,10-hexamethyl-5,6,7,8,9,10-hexahydro-benzo[h]quinazoline and 6,6,9a-Trimethyl-5,5a,6,7,8,9,9a,10-octahydro-benzo[g]quinazoline (˜5 g) is obtained, which may be separated using techniques known to those having skill in the art. Suitable techniques include chromatography such as high performance liquid chromatography, referred to as HPLC, and particularly silica gel chromatography and gas chromatography trapping known as GC trapping.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9](OC)=[C:8]([C:20]#[N:21])[C:7]2=[O:22])[CH3:5])[CH2:3][CH2:2]1.O.[NH2:24][NH2:25]>C(O)C>[NH2:21][C:20]1[C:8]2[C:7](=[O:22])[N:6]([CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)[C:9]=2[NH:25][N:24]=1
Reactant: NN
Reactant: COc1c(-c2ccn(C)n2)cn(C(C)C2CC2)c(=O)c1C#N
Solvent: CCO
Solvent: O
Product: CC(C1CC1)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of 1-(1-cyclopropylethyl)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step C of Example 163 (22 mg), hydrazine monohydrate (18 mg) and ethanol (2 mL) was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate). The residue was crystallized from ethyl acetate/hexane to give the title compound (13 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:11][CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide (17.3 gm; 102 mmol), and potassium carbonate (16.90 gm; 122 mmol) in 2-butanone (100 mL) and reflux. After 17 h, allow the mixture to cool to room temperature, decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine organic layers and wash with water, 1 N NaOH, and then water, dry over MgSO4, and concentrate to give a residue. Distill the residue to give the title compound: bp: 122-125° C. (15 mm); TLC (10% Et2O/hexanes; Rf 0.35).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[O:29][CH3:30])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2c(OC)cccc2OC)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2c(OC)cccc2OC)sc2ncccc12
Yield: 88 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(α-hydroxy-2,6-dimethoxybenzyl)thieno[2,3-b]pyridine-3-sulfonamide (0.13 g, 0.22 mmoles), CH2Cl2 (5 ml), triethylsilane (0.35 ml, 2.2 mmoles) and boron trifluoride etherate (0.16 ml, 1.3 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.11 g (85%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16](=O)[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1coc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccc(F)cc1)C2
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.12 g) and aminoguanidine hydrochloride (59 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.046 ml), and the mixture was stirred at 90° C. for 1 hour and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol and isopropylether, and dried to give (E)-6-(4-fluorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 34) (0.12 g).