Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.O>CC(O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1

Procedure:
According to Scheme 16, a solution of 3,5-dinitroaniline (1.83 g, 10 mmol) and 2,5-dimethoxytetrahydrofuran in 20 mL of HOAc was refluxed overnight. The reaction mixture was poured into water and extracted with EtOAc. The ethyl acetate layer was washed with water followed by aq NaHCO3 and brine. After drying, the solvent was removed to provide 1.52 g of 1-(3,5-dinitrophenyl)pyrrole.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO>C(Cl)Cl>[CH:5]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:23](=[O:28])[C:24]([F:25])([F:26])[F:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2C1CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1C1CCCCC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.77 ml, 0.77 mmol) was added slowly to a solution of 1-(1-cyclohexyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (0.176 g, 0.52 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 21 hr. MeOH (10 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a orange oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.193 g (100% yield) of white solid.
Reaction SMILES: [S:1]1[C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([O-:11])=[O:10].[Na+].[Na+].C(=O)=O.[H][H].[S]>O.[N+]([O-])([O-])=O.[Ag+].[Ag]>[S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10]
Reactant: O=C([O-])c1ccc(C(=O)[O-])s1
Reactant: [H][H]
Agent: [Ag+]
Agent: [Ag]
Agent: O=C=O
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)s1
Temperature: 350 °C

Procedure:
The di-silver of thiophene-2.5-dicarboxylic acid was prepared in 96 mole % yield by reacting 34.4 grams, 0.2 moles, of disodium thiophene-2,5-dicarboxylate in 500 milliliters of water with 0.4 moles of silver nitrate in 500 milliliters of water, collecting the precipitated silver salt on a filter, followed by washing and drying of the salt. The di-silver salt, 7.75 grams, and 0.02 moles, which decomposes at 315° C, was placed as a thin layer of powdered silver salt along the length of a Vycor reactor tube and heated in a furnace under nitrogen at 350° C for two minutes. Carbon dioxide (CO2) evolved with a sudden puffing up. Combustion of the silver salt subsided with the formation of the polymer and with cessation of evolution of CO2. Heating was stopped and the nitrogen purge was maintained while the tube and contents cooled to room temperature. The calculated loss of CO2 for 0.04 moles CO2 was 1.76 grams. Actual weight loss was 1.95 grams. The resulting carbon-like polymer containing silver analyzed: carbon 15.4%, hydrogen 0.6%, sulfur 4.4%, and silver 79.7%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)=[O:14]>CCCCCC.C1COCC1>[OH:14][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Nc1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
Butyllithium, 1.6M in hexane (146 ml) was added dropwise at −78° C. under N2 flow to a solution of 2-bromopyridine (0.1348 mol) in THF (300 ml). The mixture was stirred at −78° C. for 20 minutes. A solution of N-(4-formylphenyl)acetamide (0.1226 mol) in THF (300 ml) was added at −60° C./−70° C. The mixture was stirred at −60° C./−70° C. for 1 hour, then poured out into ice water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether and 2-propanone. The precipitate was filtered off and dried, yielding 5.09 g (17%) (±)—N-[4-[hydroxy(2-pyridinyl)methyl]phenyl]acetamide (compound 688).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:18].O>C(Cl)(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][Br:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc(C#Cc2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: BrCc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
The resulting acetylene compound (116 mg) was dissolved in 1 ml of chloroform, and 0.1 ml of phosphorus tribromide was added. The mixture was stirred at room temperature for 1 hour. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give 150 mg (yield 99%) of the captioned compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CC([O-])(C)C.[K+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.O>O1CCCC1.CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[N:14]=[C:15]([CH3:20])[CH:16]=[C:17]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)[N:18]=1
Reactant: OC1COC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC2COC2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A solution of oxetan-3-ol (173 mg, 2.34 mmol) in 5 mL of tetrahydrofurane was treated with potassium tert-butylate (288 mg, 2.57 mmol) and stirred for 10 minutes at 20° C. 2,4-Dichloro-6-methylpyrimidine (381 mg, 2.34 mmol) was added and the resulting mixture stirred for 2 hours at 20° C. Addition of water and extraction with ethyl acetate, followed by chromatography on silica gel using heptane/ethyl acetate 7:3 v/v as a solvent gave the title compound as a yellowish foam (206 mg, 44%). MS ISP (m/e): 201.2 (33) [(M+H)+].
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>C(#N)CC.ClCCl>[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:21]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: COC(=O)CC(=O)CCl
Solvent: CCC#N
Solvent: ClCCl
Product: COC(=O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Yield: 48.3 %

Procedure:
Methyl 4-chloro-3-oxobutanoate (4.32 ml, 37.44 mmol, 2 eq) is added to a solution of 4-(3-chloropropoxy)benzamide (4 g, 18.72 mmol, 1 eq) in propionitrile (50 ml). The mixture is heated at reflux for 48 h. The mixture is then diluted with dichloromethane and filtered. The solvent is removed under vacuum and the residue is purified on silica gel (eluent: ethyl acetate) to give 2.8 g methyl {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetate ax62 as a brown oil.
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3CCCC[O:23]3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37])[CH2:3][CH:4]([CH3:6])[CH3:5]>C(O)=O.[Zn]>[CH:22]([O:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH:36]([CH3:38])[CH3:37])[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28])=[O:23]
Reactant: CC(C)CC(O)c1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)CCc1c(-c2ccccc2C(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 58.3 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.057 mmol) in HCOOH (2 mL) was added Zn dust (18.7 mg, 0.285 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(5-isopentyl-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (15 mg, 57.9% yield) as a solid. LCMS: MH+ 452 and TR=2.286 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[Cl:37][C:38]1[CH:39]=[C:40]([OH:47])[CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]([O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:38]([Cl:37])[CH:39]=1)=[O:9]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Cl)c(Cl)c4)cc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Oc4ccc(C(=O)Oc5ccc([N+](=O)[O-])c(Cl)c5)c(Cl)c4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-(chlorocarbonyl)phenyl ester obtained was dissolved in 150 ml of benzene and then added dropwise to a solution of 1.2 g of 3-chloro-4-nitrophenol in 110 ml of dry pyridine. The mixture was stirred at 65° C. overnight, then poured into a mixture of 500 ml of ice-water and 100 ml of concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed three times with 100 ml of 3N hydrochloric acid each time and three times with 200 ml of water each time, then dried and evaporated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid 3-chloro-4-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester obtained was chromatographed on silica gel with toluene/acetone (volume ratio 19:1). The fractions which were almost pure according to thin-layer chromatography (2.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 132° C., cl.p. >250° C. (decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]O)([OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][O:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1C1(O)CCCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC3(CC2)OCc2ccccc23)cc1
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of (RS)-1-benzyl-4-(2-hydroxymethyl-phenyl)-azepan-4-ol (7.0 g, 22 mmol) and triethylamine (3.1 ml, 22 mmol) in tetrahydrofuran (80 ml) was added a solution of methanesulfonyl chloride (1.7 ml, 22 mmol) in tetrahydrofuran (20 ml) at 0° C. After completed addition the temperature was allowed to rise to room temperature. Stirring for 2 h was followed by addition of another portion of triethylamine (3.1 ml, 22 mmol). Stirring was continued over night. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the organic layer was concentrated in vacuo. Flash column chromatography using heptane/ethyl acetate as eluent gave the title compound as a light yellow oil (4.0 g, 61%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7].[H][H]>C(O)C.[C].[Pd]>[CH2:17]([CH:5]1[CH2:4][CH2:3][CH2:2][N:8]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(=Cc1ccccc1)CCCCl
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NN1CCCC(Cc2ccccc2)C1=O

Procedure:
10% palladium-carbon powder (50.36% aqueous, 1.92 g) was added to a solution of the (E)/(Z) mixture of tert-butyl N′-[5-chloro-2-(1-phenylmethylidene)pentanoyl]hydrazinecarboxylate obtained in the process of Example 12 in ethanol (20 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 10 days. Thereafter, the reaction solution was filtered through celite and the solvent was evaporated under reduced pressure. DBU (0.598 mL) was added to a solution of the resulting residue in THF (50 mL) and the mixture was heated under reflux for 44 hours. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 727 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)[CH:5]=[C:4]([CH3:33])[N:3]=1.[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:14]([CH2:13][C:12]1[CH:30]=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=2)[CH:9]=[CH:10][C:11]=1[O:31][CH3:32])[CH:15]1[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 92 (100 mg, 0.22 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (61 mg, 0.26 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24].[I-].C[NH+]1C=CN(C)C1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC.O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([C:23](=[O:24])[C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([S:19][CH3:18])[CH:21]=1)=[N:3][CH:4]=[C:5]2[C:16]#[N:17]
Reactant: CSc1cccc(C=O)c1
Reactant: COc1cc2c(C#N)cnc(Br)c2cc1OC
Agent: CN1C=C[NH+](C)C1
Agent: [H-]
Agent: [I-]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(C#N)cnc(C(=O)c3cccc(SC)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a stirred solution of 1-bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (100 mg, 0.34 mmol), 3-methylsulfanyl-benzaldehyde (104 g, 0.68 mmol) and 1,3-dimethyl-1H-imidazolium iodide (153 mg, 0.68 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (27.3 mg, 0.68 mmol). The mixture turned black instantly. The reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6,7-dimethoxy-1-(3-methylsulfanyl-benzoyl)-isoquinoline-4-carbonitrile (70 mg, 57% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:13][C:12]=2[CH3:26])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:12]([CH3:26])=[CH:13][C:14]([NH2:18])=[CH:15][C:16]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2c(C)cc(N)cc2C)cc1Cc1ccc(F)cc1
Yield: 61.2 %

Procedure:
460 mg (1.02 mmol) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methokybenzyl]-3,5-dimethylphenylcarbarnate (Example IX) are stirred in 10 ml of trifluoroacetic acid/dichloromethane (10% strength solution) at room temperature overnight. After neutralization with NaHCO3 solution, the organic phase is separated, dried over sodium sulphate and concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 218 mg (55%) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:11]([N:8]1[CH2:7][CH2:6][C:5]([CH2:4][CH2:3][OH:2])([OH:18])[CH2:10][CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of compound 24 (1.70 g, 6.07 mmol) in anhydrous THF (40 mL) at 0° C. was slowly added a solution of lithium aluminium hydride (1.0M in THF) (12.1 mL, 12.1 mmol). The solution was then stirred at 0° C. for 1 hr and allowed to return to room temperature to be stirred for an additional 2 hrs. The resulting solution was poured in a cold 10% solution of sodium sulphate (300 mL), extracted with diethyl ether (3×75 mL), washed with brine and finally dried over magnesium sulphate to give the crude compound 25 (1.32 g, 87%) which was used as such in the next step. 1H NMR (400 MHz, MeOD) δ: 1.65 (m, 4H), 1.72 (t, 2H, J=7.06 Hz), 2.45 (m, 2H), 2.62 (m, 2H), 3.56 (s, 2H), 3.76 (t, 2H, J=7.06 Hz), 7.31 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[C@H:16]3[O:17]C(C)(C)[O:19][CH2:20][C@H:15]3[O:14][C@@H:13]2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[C@@H:16]([OH:17])[C@@H:15]([CH2:20][OH:19])[O:14][C@@H:13]2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1OS(=O)(=O)c1ccc(C)cc1
Solvent: CC(=O)O
Solvent: O
Product: CO[C@H]1O[C@H](CO)[C@H](O)[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
Compound 35.4 (32.18 g, 89.9 mmol) was dissolved in 400 mL of a 3:1 mixture of acetic acid and water. The mixture was heated to 50° C. for 2 h and the solvent was removed under reduced pressure. The residue was subjected to a column chromatography eluting with EtOAc to give compound 35.5.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:27]=[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:10]([CH3:16])[C:11]([C:13]([NH2:15])=[O:14])=[CH:12][N:7]2[N:6]=1)(=[O:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>C1COCC1>[CH3:30][N:31]([CH3:33])/[CH:32]=[N:15]/[C:13]([C:11]1[C:10]([CH3:16])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:8]2[N:7]([N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:27]=2)[CH:12]=1)=[O:14]
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(N)=O)cn2n1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)/N=C/N(C)C)cn2n1
Temperature: 100 °C

Procedure:
To a solution of 2-acetylamino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid amide (Int. 22, 100 mg, 0.27 mmol) in THF (2 mL) was added N,N-dimethylformamide dimethyl acetal, (53 μL, 0.40 mmol) and the reaction mixture was heated at 100° C. for 10 mins using microwave irradiation. The solvent was removed in vacuo to afford crude 2-acetylamino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide intermediate. To a solution of the material thus obtained in acetic acid (2 mL) was added 4-hydrazino-benzonitrile hydrochloride (43 mg, 0.25 mmol). The mixture was heated at 90° C. for 15 minutes using microwave irradiation. The solvent was removed in vacuo and the residue azeotroped with toluene (2×5 mL). The resultant residue was purified by flash chromatography eluting with a gradient of 0-100% cyclohexane in EtOAc and then with 10% MeOH in EtOAc followed by preparative C18 HPLC, eluting with a gradient of 10-90% MeCN in water (+0.1% formic acid) to afford the title compound as a white solid (15 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:31][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 90 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and tetrahydro-2H-pyran-4-amine to yield the title compound as a white solid (34 mg, 90% yield). MS (apci) m/z=411.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2].Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:45])[CH:41]=2)[N:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:34][C:35]1[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:45])[CH:41]=3)[N:36]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Br)cc1
Reactant: Fc1ccc2nc(CBr)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To 3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (C-3; 2.0 g, 3.9 mmol) in MeCN (25 mL) was added 2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol), and Cs2CO3 (2.5 g, 7.7 mmol). The reaction was stirred at room temperature overnight, after which LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was recrystallized in EtOAc:hexane to give the desired product (F-1, 1.9 g). The filtrate was concentrated and purified on silica gel (0 to 15% EtOAc in hexanes) to give an additional 1 g of F-1.