Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:36])[CH3:35])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000056 mol) and potassium carbonate (0.016 g, 0.00012 mol) in anhydrous N,N,-dimethylformamide (1 mL) was added acetic anhydride (0.009 g, 0.000084 mol) at room temperature. The reaction mixture was stirred for 1hours. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 5 μm, 100×20 mm; 20%-85% over 7.5 min with 0.05 M ammonium acetate, 251 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetany}-1-ethanone (0.014 g, 0.000035 mol).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C=O)C>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[S:22][CH:21]=[N:20][C:19]=2[CH3:18])[CH2:25][CH2:26]1)=[O:6]
Reactant: Cc1ncsc1N1CCNCC1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncsc1N1CCN(C(=O)/C=C/C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (33 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-methyl-5-piperazin-1-yl-thiazole dihydrochloride (38 mg, 0.15 mmol) and N-ethyl-N,N-diisopropylamine (0.7 mmol, 120 μl) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 32 mg of a solid (0.09 mmol, 70%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:10]([F:24])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:26]([C:29]1([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[CH2:31][CH2:30]1)[CH:27]=O>C(O)(C)C>[F:24][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:1]=3)[CH:4]=2)[CH:23]=[CH:22][C:11]=1[O:12][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(Oc1ccc(-c2cnc(N)nc2)cc1F)C(=O)OC(C)(C)C
Solvent: CC(C)O
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A mixture of tert-butyl 2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenoxy]propanoate (0.33 g, 1.0 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.24 g, 1.0 mmol) in isopropanol was heated at 100° C. overnight. After cooling to RT, the mixture was purified by RP-HPLC (pH 2.0) to afford the desired product (0.22 g, 42%). LCMS: (M+H)=525.2.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21](=[O:28])[NH:20][N:19]=2)[CH:12]=1)=[O:9])[CH3:6])C.[OH-].[Na+]>CC(N(C)C)=O>[CH3:6][CH:5]1[NH:7][C:8](=[O:9])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[C:27]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=4[C:21](=[O:28])[NH:20][N:19]=3)[CH:12]=2)[C:4]1=[O:3]
Reactant: CCOC(=O)C(C)NC(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC1NC(=O)N(c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)C1=O

Procedure:
To a solution of 2-{3-[3-(4-oxo-3,4,5,6,7,8-hexahydro-phthalazin-1-ylmethyl)-phenyl]-ureido}-propionic acid ethyl ester (5) (0.715 g, 1.80 mmol) in dry DMA (2 ml) was added finely powdered sodium hydroxide (71 mg, 1.80 mmol). The reaction mixture was then immersed in a preheated oil bath at 50° C. and heated for 10 minutes before being quenched by addition of HCl (1N, 0.5 ml). The reaction mixture was then concentrated to dryness in vacuo. The crude oil was subjected to flash chromatography eluent 4:1, hexane:ethyl acetate (Rf=0.18, neat ethyl acetate). Main peak in LC-MS, (0.25 g, 95% purity); 1H NMR (300 MHz, D6 DMSδ ppm 12.61 (s, 1H), 8.41 (s, 1H), 7.40 (dd, J=11.46, 4.58 Hz, 1H), 7.29-7.12 (m, 2H), 4.32-4.15 (m, 1H), 3.94 (s, 2H), 2.46 (m, 4H), 1.61 (s, 4H), 1.34 (d, J=6.94 Hz, 3H). M/z (LC-MS, ESP), RT=3.04 mins (M+H 353.2).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[C:25]1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[CH3:25][NH2+:14][CH3:8]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Product: C[NH2+]C
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (2.0 g) is dissolved in toluene and an excess of anhydrous dimethylamine is bubbled into the reaction mixture, the solvent removed in vacuo and the residue triturated with cold diethyl ether to give 1.1 g of product.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.ClCCl.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCOC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCCOC2CC2)cc1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a mixture of 500 mg of 3-(cyclopropyloxy)propan-1-ol and 5 mL of dichloromethane were added 1.2 mL of triethylamine and 1.3 g of p-toluenesulfonic acid chloride under ice-cooling, followed by stirring for 4 hours. The reaction mixture was diluted with chloroform, washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 522 mg of 3-(cyclopropyloxy)propyl p-toluenesulfonate.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:11][CH:12]=1)#[CH:5]
Reactant: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 2.27 g (0.0068 mole) of 1-(trimethylsilylethynyl)-4-(3,5-dimethoxyphenylethynyl)benzene, 1.88 g (0.0136 mole) potassium carbonate, 30 ml of methanol and 30 ml of methylene chloride. The mixture was stirred at room temperature overnight under nitrogen. The dark brown suspension was filtered through an alumina bed to remove some color, and the still dark color filtrate was washed twice with water (30 ml each). The aqueous layers were combined and extracted twice with methylene chloride (20 ml each). The methylene chloride layers were combined and dried over anhydrous MgSO4, filtered and concentrated. 1.13 g of brown oil was obtained. The crude oil was purified by Preparative LC using 1:10 EtOAc:hexane as eluting solvent. 240 mg (13.5% yield) of yellow solid was obtained. 1HNMR 3.20 ppm (s, 1H); 3.83 ppm (s, 6H); 6.50 ppm (t, 1H); 6.71 ppm (d, 2H); 7.50 ppm (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:25]3[C:16](=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=3)(O)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.Cl.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:25]3[C:16](=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:27]3[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)c2ccccc2C(O)(c2ccc(Br)cc2)c2cc3ccccc3cc21
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2c3ccccc3c(-c3ccc(Br)cc3)c3cc4ccccc4cc23)cc1
Yield: 81.9 %

Procedure:
Into a 300-cm3 eggplant-shaped flask filled with air, 3.0 g (5.22×10−3 mol) of 5,12-bis(4-bromophenyl)-5,12-dihydroxytetracene synthesized as described above was weighed. Into the eggplant-shaped flask, 150 cm3 of acetic acid, which was used as a solvent, was poured, whereby an acetic acid solution was prepared. Stannous chloride and a 35% of aqueous solution of hydrochloric acid were mixed at a weight ratio of 1:1, whereby a hydrochloric acid solution of stannous chloride was prepared. To the acetic acid solution, 20 cm3 of the hydrochloric acid solution was added. The solution mixture was subjected to reaction for three hours at room temperature. The reaction mixture was transferred to a separatory funnel. Toluene was added to the reaction mixture. This mixture was sufficiently washed with distilled water. The organic layer in the separatory funnel was dried with 5 g of magnesium sulfate. The solvents were removed from the organic layer in an evaporator, whereby a white solid was obtained. The white solid was purified by silica gel chromatography using a mixture containing toluene and hexane at a ratio of 1:2 and reprecipitation using dichloromethane and hexane, whereby 2.3 g of 5,12-bis(4-bromophenyl)-tetracene was obtained as shown in FIG. 6. The yield of 5,12-bis(4-bromophenyl)-tetracene was 82%.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[N:10][C:11]=1[Cl:12].[OH-].[Na+]>O1CCOCC1.O>[Cl:5][C:6]1[CH:7]=[C:8]([O:13][CH:2]([F:4])[F:3])[CH:9]=[N:10][C:11]=1[Cl:12]
Reactant: FC(F)Cl
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cnc(Cl)c(Cl)c1

Procedure:
Chlorodifluoromethane was passed at 50° C. into a mixture of 32.8 g (0.2 mol) of 5,6-dichloro-3-pyridinol in 200 ml of 1,4-dioxane and 40 g (1 mol) of sodium hydroxide in 100 ml of water until starting material was no longer present. The further procedure was then carried out as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH3:14][N:15]1CCCC1=O.O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:11]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CN1CCCC1=O
Reactant: CCCOCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOCCc1ccc(C#N)cc1
Temperature: 125 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
1-Bromo-4-(2-propoxy-ethyl)-benzene described in Preparation Example 195 (790 mg, 3.2 mmol), zinc cyanide (380 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) were added to N-methylpyrrolidinone (10 mL), and this mixture was stirred at 125° C. for 4 hours. This reaction mixture was allowed to cool, and water (50 mL) and ethyl acetate (50 mL) were added thereto. This mixture solution was filtered through Celite pad. The organic layer was separated, then, washed with water (3 times) and brine, and then, concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1), and the title compound (120 mg, 0.62 mmol, 19%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([N:16]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][CH2:26]2)[CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+]>C(O)C>[C:1]([NH:11][C@H:12]([C:14]([N:16]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][CH2:26]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl N-carbobenzoxy-L-alanyl-N-(5-indanyl)-glycinate (14.0 g, 33.0 mmol) in 150 ml ethanol was added sodium hydroxide (25 ml of a 2N aqueous solution, 49.5 mmol) and mixture stirred at room temperature for 20 h. The volatiles were removed under reduced pressure and the residue dissolved in ether and saturated sodium bicarbonate. The organic layer was separated and extracted with saturated sodium bicarbonate. The combined basic extracts were cooled in an ice bath and acidified with concentrated HCl. The aqueous solution was extracted thoroughly with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28].N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccccc1C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccccc1C(F)(F)F
Temperature: 65 °C

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-trifluoromethylphenyl)pyrazole (0.114 g) in tetrahydrofuran (2.5 ml) was added t-butyl nitrite (87 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated. The residue was taken up in t-butanol and freeze dried to give the title compound as a pale brown solid, m.p. 142-3° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][C:22](=[O:29])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)c2ccccc2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
To N-[3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl]-benzamide (0.084 g, 0.21 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, N-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzamide as a white solid (0.015 g, 25%). M.p.>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.31 (s, 1H), 8.49 (d, J=7.2 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.92 (s, 1H), 7.86 (m, 2H), 7.48 (m, 3H), 4.28 (m, 1H), 3.22-2.91 (m, 4H), 2.13 (m, 1H), 1.96 (m, 1H); LCMS [M+H]: 293.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[N:3]=[C:2]1[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].Br[CH:24]([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:24]([N:8]1[CH2:7][CH2:6][C:5]2[N:1]=[C:2]([C:11]3[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])[NH:3][C:4]=2[CH2:10][CH2:9]1)([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCN(C(C)C)CC3)c(C)cc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4, 347 mg, 0.84 mmol), 2-bromopropane (790 μL, 8.40 mmol), N,N-diisopropylethylamine (1.46 mL, 8.4 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 4 h at 80° C., then cooled to room temperature. The resulting solution was diluted with ethyl acetate (50 mL) and washed with brine (4×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.22 g (crude) of the title compound as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[C:14]([CH3:15])=[N:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:16].[H][H]>CCO.[Pd]>[ClH:16].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[C:14]([CH3:15])=[N:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ncnn1-c1cc(F)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ncnn1-c1cc(F)ccc1CN
Yield: 91 %

Procedure:
A solution of 4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (2.9 g, 14 mmol) in EtOH (100 mL) was mixed with 1N—HCl (15 mL) and 10% Pd—C (0.7 g, Aldrich). This mixture was hydrogenated in a Parr shaker at 45-55 psi of hydrogen for 20 h. The catalyst was filtered over Celite®, and washed with EtOH. The filtrate was concentrated, and the residue triturated with EtOH-Et2O to obtain 3.17 g (13 mmol, 91% yield) of the title compound as an off-white powder: HPLC 0.47 min (AP 100% at 254 nm); LC/MS m/z 207 (M+H); 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.40 (3H, s, CH3), 3.77 (2H, d, J=5.5 Hz, NCH2), 7.52-7.62 (1H, m), 7.66 (1H, dd, J=9.2, 2.6 Hz), 7.87 (1H, t, J=7 Hz), 8.14 (1H, s), 8.47 (3H, brs, NH3+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][CH:28]([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([CH:28]([F:36])[F:27])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(difluoromethyl)aniline (Intermediate-29, 0.058 g, 0.40 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 3.95 (s, 3H), 7.04 (m, 1H), 7.35 (d, 1H), 7.41 (m, 1H), 7.50 (m, 3H), 7.69 (d, J=8.7 Hz, 1H), 7.77-7.82 (m, 3H), 8.07 (s, 1H), 10.25 (s, 1H), 12.52 (br s, 1H); MS (m/z): 485.06 (M+H+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[OH:20][C:19]1[C:18]2[O:17][N:16]=[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:13]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(OC)cc2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2c(-c3ccc(OC)cc3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 41.8 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-methoxyphenyl)isoxazole-5-carboxylate (13.7 g, 26.7 mmol) was dissolved in 230 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (53.5 mL, 53.5 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 50 mL of 1M HCl and 300 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 11.4 g of crude oil. The crude intermediate was dissolved in 150 mL of CH2Cl2. Thionyl chloride (2.7 mL, 36.7 mmol) was added and the reaction mixture was stirred for 16 h. The mixture was filtered through a medium porosity funnel. The solid was rinsed twice with cold CH2Cl2 and dried under vacuum to give 3.51 g of the title compound. MS: (+) m/z 315.40 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: OCc1ccco1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound.