Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Br:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][Br:22])=[CH:27][CH:28]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: BrCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(CCCBr)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 5-bromo-2-chlorobenzoic acid (2.31 g, 9.80 mmol) and oxalyl chloride (1.41 g, 11.11 mmol) in CH2Cl2 (30 mL) was added 0.05 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight and then the volatiles were removed under reduced pressure. The resulting crude 5-bromo-2-chlorobenzoyl chloride was dissolved in dichloromethane (30 mL), and the solution was cooled to 0˜5° C. Then AlCl3 (1.31 g, 9.8 mmol) was added in portions, the mixture was stirred for 30 min, and (3-bromopropyl)benzene (1.50 g, 6.53 mmol) in dichloromethane (4 mL) was added. The reaction solution was warmed to room temperature and stirred for 4 h. The reaction was quenched by pouring into ice water. The suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with water, 2× with 1M NaOH, and 2× with brine, and then dried over Na2SO4. After removal of the volatiles, the crude product was purified by column chromatography (eluent EA:PE=1:20) to obtain intermediate DD (2.4 g) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.68˜7.66 (d, 2H), 7.50˜7.47 (dd, 1H), 7.42 (d, 1H), 7.28˜7.19 (m, 3H), 3.33 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.17˜2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:10]([O:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1.[N:21]#[C:22][NH2:23].[Na].C1OCCOCCOCCOCCOCCOC1>CC(CC(=O)C)C>[C:22]([NH:23][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:10]([O:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1)#[N:21]
Reactant: COc1cc(-c2ccc(Br)nn2)ccc1OCC(C)C
Reactant: N#CN
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC(=O)CC(C)C
Product: COc1cc(-c2ccc(NC#N)nn2)ccc1OCC(C)C

Procedure:
3 g 3-bromo-6[4-(2-methylpropoxy)-3-methoxyphenyl]pyridazine, 1.3 g sodium cyanamide and 0.5 g 18-crown-6 are boiled under reflux in 30 ml 2-methyl-4-pentanone for 5 hours. The reaction solution is then evaporated in vacuo and the residue is boiled up briefly with 200 ml 2N sodium hydrogen sulphate solution, while stirring thoroughly, the reaction product precipitating as a fine crystalline precipitate. The precipitate is filtered off with suction and boiled up again with isopropanol, the mixture is cooled and the product is filtered off with suction and, after washing with isopropanol and petroleum spirit (b.p. 50°-70° C.), dried in vacuo. This gives 2.5 g (80.6%) of the title compound of m.p. 191° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[N:13]([CH2:2][C:3]3[CH:7]=[CH:6][O:5][N:4]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: ClCc1ccon1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1Cc1ccon1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A compound of 3-(chloromethyl)-isoxazole (1.2 g) was added dropwise at a temperature of 20° to 30° C. under stirring to a mixture of 7-fluoro-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.16 g), acetonitrile (50 ml) and potassium carbonate (1.5 g). The reaction mixture was heated under refluxing for 3 hours, cooled to room temperature, and filtered. The filtrate was concentrated under a reduced pressure to dryness. The resultant residue was mixed with toluene (150 ml) to form a suspension, which was then filtered to remove the undissolved materials therefrom. The filtrate was concentrated under a reduced pressure so as to obtain a viscous material, which was thereafter dissolved in a minimum amount of ethanol. The ethanol solution was cooled to precipitate a crystalline product. This product was separated by filtration and dried, so that the aimed compound, i.e. 7-fluoro-4-(isoxazol-3-ylmethyl)-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.3 g) was obtained. m.p. 206°-210° C.
Reaction SMILES: C([Li])(CC)C.CC12CO[C:10]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)([O:11]C1)[O:9]C2.C[O:28][B:29](OC)[O:30]C>C1COCC1>[B:29]([C:18]1[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:10]([OH:11])=[O:9])([OH:30])[OH:28]
Reactant: CC12COC(COc3ccc(C(F)(F)F)cc3)(OC1)OC2
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of sec-butyllithium (66 ml, 1.4M in cyclohexane) was added dropwise over 10 min to a stirred solution of the product from step (iii) (9.44 g) in THF (100 ml) at −78° C. After 3 h the mixture was warmed to −40° C. for 5 min, then cooled to −78° C. Trimethylborate (14.1 ml) was added, then after 10 min the reaction quenched with 2M hydrochloric acid. The mixture was warmed to RT and the organic phase separated. The aqueous layer was extracted with ethylacetate, the organics combined and evaporated under reduced pressure. The residue was dissolved in methanol (500 ml) then bondelut-NH2 resin(180 g) added and the mixture swirled for 0.5 h then filtered. The resin was washed with 10% acetic acid/methanol, the washings then evaporated under reduced pressure and dried under high vacuum. The residue was dissolved in methanol (50 ml), tetrahydrofuran (50 ml) and saturated aqueous sodium hydroxide solution (2 ml), left for 30 min then 2M hydrochloric acid (50 ml) added and the organics evaporated under reduced pressure. The residual aqueous layer was extracted with ethylacetate, the organics separated, dried and evaporated under reduced pressure, yield 5.05 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:30][N:29]([CH3:31])[C:27]([C:24]1[N:25]=[CH:26][C:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:22][CH:23]=1)=[O:28]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Yield: 93 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (CAS no. 915949-00-7) (446 mg, 2.4 mmol) and potassium carbonate (552 mg, 4 mmol) in acetonitrile (15 mL) was stirred at 120° C. for 2 hours. The mixture was evaporated and the residue dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with 50 to 100% ethyl acetate in isohexane to afford the product (772 mg, 93%). m/z 415 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)C(C)C)(C)C>CC(C)CC(=O)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:16]2[CH2:17][CH2:18][N:13]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15]2)=[N:3][N:4]=1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
1,4-dichlorophthalazine (741 mg, 3.72 mmol), 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (1.00 g, 4.09 mmol), N,N-diisopropylethylamine (0.972 mL), and 4-methyl-2-pentanone (6 mL) were heated at 120° for 16 hours. The solvent was removed and the residue purified by chromatography over silica using a gradient of hexanes/0-70% ethyl acetate. The compound was obtained as a white solid. MS (M+H)+=407.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[Cl:12][C:13]([Cl:17])=[C:14]([F:16])[F:15]>CC(C)=O.[OH-].[K+]>[Cl:12][CH:13]([Cl:17])[C:14]([F:16])([F:15])[O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: FC(F)=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(OC(F)(F)C(Cl)Cl)c1
Temperature: 0 °C
Yield: 27 %

Procedure:
In a 500 ml stirred reaction flask equipped with thermometer, air condenser, dropping funnel and ice water bath was placed 76.57 g (0.5 mol) of 5-methyl-2-nitrophenol in 150 ml of acetone and 5.5 g of powdered KOH (85 percent). The mixture was vigorously stirred at 10° C, whereupon 73 g of 2,2-dichloro-1,1-difluoroethene was gradually introduced. After stirring overnight, the reaction mixture was poured into ice water, and the lower organic layer separated by methylene chloride extraction. The extract was washed with diluted bicarbonate of soda solution, decolorized with charcoal, and dried over desiccant-grade magnesium sulfate. Evaporation of the solvent left an oily residue which was vacuum distilled at 5 mm to give 38.6 g of 2-(2,2-dichloro-1,1-difluoroethoxy)-4-methyl-1-nitrobenzene distilling at 156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=2[C:17](O)=[S:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=2[C:17]([NH:25][C:26]2[C:27]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[S:18])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Reactant: Cc1ccc(C(O)=S)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: Cc1ccc(C(=S)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 93 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-4-methylthiobenzoic acid and 3-amino-6-methyl-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (7.4 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH:16]([C:13]1[CH:14]=[CH:15][C:8]2[C:7](=[O:19])[C:6]3[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=3[CH2:11][O:10][C:9]=2[CH:12]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc2c(c1)OCc1ccc(Br)cc1C2=O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)OCc1ccc(C#N)cc1C2=O

Procedure:
Reflux a mixture of 8.39 gm. (0.0253 mole) of 9-bromo-6,11-dihydro-3-isopropyl-11-oxodibenz[b,e]oxepin, 4.83 gm. (0.0539 mole) of cuprous cyanide and 30 ml. of dimethylformamide for 8 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 36 ml. of chloroform, 25 ml. of saturated sodium cyanide solution and 25 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum. Purity the resulting oil (7.01 gm.) by column chromatography on silica gel with benzene as eluant to obtain the title product [yield 2.8 gm., m.p. 101°-108° C., showing a single spot, Rf =0.18 on thin layer chromatography or silica gel with benzene as the solvent system, pmr (CDCl3 1,23(6H, d, (CH3)2CH--), 2.95 (1H,m, (CH3)2CH--), 5.20 (2H,s, CH2O)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:29]O>>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH:20]([C:21]([O:23][CH3:29])=[O:22])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
Step-1: A mixture of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2 g, 6.42 mmol) and conc. sulfuric acid (0.45 mL) in methanol was refluxed overnight. The reaction mixture was concentrated, neutralized with aq. sodium bicarbonate and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-benzyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. MS (ES+): m/z 348.12 [M+Na]+
Reaction SMILES: [CH2:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N1CCC(NCC3C4C=CC=CC=4CCC4C=CC=CC3=4)CC1)=[N:8][C:9]=2[NH:13][CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].C(N)C=C.[Cl:44]C1N=C2C(N=CN2CC=C)=C(Cl)N=1>C(O)C>[Cl:44][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[CH:12][N:4]2[CH2:1][CH:2]=[CH2:3])=[C:9]([NH:13][CH2:14][CH:15]=[CH2:16])[N:8]=1
Reactant: C=CCNc1nc(N2CCC(NCC3c4ccccc4CCc4ccccc43)CC2)nc2c1ncn2CC=C
Reactant: C=CCn1cnc2c(Cl)nc(Cl)nc21
Solvent: CCO
Solvent: C=CCN
Product: C=CCNc1nc(Cl)nc2c1ncn2CC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yl)methylamino]piperidino}purine ##STR14## 0.75 ml of allylamine is added to a solution of 1.15 g of 2,6-dichloro-9-allylpurine in 15 ml of ethanol and the mixture is stirred for 1 hour at room temperature and then heated at 50° C. for 30 minutes. After evaporation of the solvent, the mixture is taken up in CH2Cl2 -H2O, decanted, and the solvent is evaporated. The residue is recrystallised from ethanol. 1 g of 2-chloro-6-allylamino-9-allylpurine, melting at 110°-112° C. is obtained. 0.85 g of that compound is dissolved in 20 ml to butanol, 1.04 g of 4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]-piperidine (oil), 0.5 g of K2CO3 and 0.1 g of potassium iodide are added to the solution obtained, and the mixture is heated at reflux for 10 hours. The reaction mixture is then concentrated and the residue is taken up in CH2Cl2 -H 2 O. The mixture is decanted, the organic phase is then evaporated, and the residue is chromatographed using ethyl acetate as eluant. 0.6 g of 9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methylamino]piperidino}-purine is isolated in the form of crystals melting (cap) at 142°-144° C. The 9-allyl-2,6-dichloropurine used as starting material was prepared by reacting allyl alcohol and 2,6-dichloropurine in tetrahydrofuran according to the Mitsunobu method. The amine used as starting material was prepared by debenzylation of the corresponding piperidine melting at 78°-81° C., which was itself prepared by reductive alkylation with NaBH3CN, in methanol, of a mixture of 1-benzylpiperidone and (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamine hydrochloride melting (cap) at 275°-280° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>C(=O)(O)[O-].[Na+].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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 40.4 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (90 mg, 0.19 mmol) in DMF (2.2 mL) zinc cyanide (45 mg, 0.38 mmol) was sparged with Ar for 15 min. To the solution was added Pd(PPh3)4 (22 mg, 0.019 mmol) and the vessel was sealed and heated to 130° C. microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated brine solution (30 mL) and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) followed by HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 15 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) and was washed with saturated sodium bicarbonate solution (3×30 mL) then freeze dried to provide 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (32 mg, 40%): mp 158-162° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.14 (dd, J=9.0, 0.9 Hz, 1H), 7.82 (dd, J=9.6, 1.5 Hz, 1H), 7.77-7.67 (m, 1H), 7.61-7.47 (m, 2H), 5.19-5.04 (m, 1H), 4.80-4.67 (m, 1H), 3.46-3.14 (m, 2H, overlaps with H2O), 3.12-2.94 (m, 1H), 2.02-1.70 (m, 4H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])=[O:4].[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][CH2:5][C:3](=[O:4])[NH:2][CH3:1])[C@@H:12]2[OH:13])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:36][CH:35]=1
Reactant: CNC(=O)CCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: CNC(=O)CCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
The compound (558 mg, 1.67 mmol) prepared in Example 6 was dissolved in dried pyridine (8 mL). To the solution was added 4,4′-dimethoxytrityl chloride (622 mg, 1.84 mmol), followed by stirring at room temperature. The reaction system was concentrated under reduced pressure, diluted with ethyl acetate, and then washed with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography eluting with chloroform:methanol (98:2, v/v) containing 0.5% triethylamine to give the title compound (749 mg, 70%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:5][CH2:4][NH:3]1.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([N:3]1[CH2:4][CH2:5][CH:6]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:7][CH:2]1[CH3:1])=[O:42]
Reactant: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in DMF (3 mL) were added 3-fluorobenzoic acid (12.51 mg, 0.0893 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (53.86 mg, 0.122 mmol) and triethylamine (0.0396 mL, 0.284 mmol). The mixture was stirred at room temperature overnight and purified by prep-LC-MS to give 20 mg of {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white powder. LC/MS found: 629.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[Br:19][C:20]1[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([NH:1][C@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(Br)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Yield: 55.8 %

Procedure:
(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg, 0.384 mmol) and 2-bromo-1,3-thiazole-4-carboxylic acid (96 mg, 0.460 mmol). The product was triturated using diethyl ether. Yield 55.8%. 1H-NMR (400 MHz; CDCl3): δ 1.12 (d, 3H), 4.27-4.52 (m, 3H), 6.97 (d, 1H), 7.85 (d, 1H), 8.00 (s, 2H), 8.07 (s, 1H), 8.23 (s, 1H), 8.64 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14]1[CH:19]=[C:18]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled with 3-butoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 263.