Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][N:10]=[C:9]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:8]=1.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12]([C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][N:10]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3ccccn3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]piperidine-1-carboxylate 39 g (111 mM) in methanol 50 is added 100 ml solution of HCl in dioxane and stirred at room temperature for 3 hrs. Solid precipitated is then filtered and washed with cold acetonitrile to obtained 2-[3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl]pyridine dihydrochloride as white solid.
Reaction SMILES: C([O:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH:12]=[CH:13]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[OH:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]4C=C[C@H](C4)[C@@]3(COCc3ccccc3)S2(=O)=O)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(N2C[C@H]3[C@H]4CC[C@H](C4)[C@@]3(CO)S2(=O)=O)cc1C(F)(F)F
Yield: 82.3 %

Procedure:
A solution-suspension of Example 30 (50 mg, 0.11 mmol) and Degussa-type Pd/C (10 mg; 20 wt %) in 4 mL EtOAc/MeOH (2:1) was stirred under 1 atmosphere of hydrogen at ambient temp for 5 hrs. The reaction vessel was then purged with N2 to give a black suspension that was then filtered. The resulting colorless filtrate was concentrated in vacuo to give 35 mg of a mixture of starting material and product in a 2:1 ratio. The mixture was dissolved in CH2Cl2, loaded onto a preparative TLC plate, and eluted with 30% acetone/heptane to afford 15 mg Example 32 (36% yield) as a colorless film. HPLC: 98% at 3.015 min (retention time) (YMC ODS-A column 4.6×50 mm eluting with 10-90% aqueous MeOH over 4 min containing 0.1% H3PO4, 4 mL/min, monitoring at 220 nm); and MS (ES): m/z 445.11 [M−H+ OAc]−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14])([O-])=O.O.O.[Sn](Cl)[Cl:22].Cl>C(O)C>[ClH:22].[CH:15]1[C:12]2[C:13]([NH2:14])=[N:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:10][C:11]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccccc2Nc2ccccc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Combine 2-(2-Nitro-phenylamino)-benzonitrile (6.14 g, 25.66 mmol), tin(II) chloride dihydrate (17.37 g, 76.99 mmol), 5N HCl (105 ml), and ethanol (65.0 ml). Stir the mixture at reflux for 24 hours then cool it to ambient temperature and chill it in the refrigerator for 2 hours. Remove the ethanol under vacuum and chill in the refrigerator again. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 6.31 g (100%) of a yellow solid: mass spectrum (ion spray): m/z=210.0 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=2[N:13]=[C:12]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:21][C:15]1[C:14]2[N:13]=[C:12]([CH2:22][O:23][CH2:24][CH3:25])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]=2[C:18]([CH3:20])=[CH:17][N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (4 eq) was added dropwise to a mixture of 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine (2.25 g, 8.11 mmol), triethylamine (10.2 mL, 73.0 mmol) and chloroform (225 mL). The solvent was removed under reduced pressure to provide an oil. The oil was dissolved in 10% sodium hydroxide (200 mL) then extracted with chloroform (3×300 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure to provide a clear oil. The oil was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide a white solid. This material was dried overnight under vacuum at 80° C. to provide 0.71 g of N-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide as a white solid, m.p. 173-175° C. Analysis: Calculated for C15H25N5O3S: % C, 50.69; % H, 7.09; % N, 19.70; Found: % C, 50.51; % H, 6.91; % N, 19.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperazine-1-carboxylate (0.0860 g, 0.212 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0282 g, 0.193 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperazine-1-carboxylate (0.0945 g, 91%).
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc(-c2cnn[nH]2)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc(-c2cccc(Br)c2)n1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Methyl iodide (323 μl, 5.2 mmol) was added to a stirred mixture of 5-(3-bromophenyl)-1H-[1,2,3]triazole (776 mg, 3.46 mmol) and potassium carbonate (1.19 g, 8.6 mmol) in DMF (20 ml) at room temperature under nitrogen. The reaction mixture was stirred overnight and then concentrated under reduced pressure. Water (50 ml) was added and then the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were concentrated under reduced pressure while dry loading onto silica gel. The residue was purified by column chromatography (silica gel, 50% Et2O/isohexane) to yield first 4-(3-bromophenyl)-2-methyl-2H-[1,2,3]triazole (344 mg, 42%), the solvent polarity was increased to 80% Et2O/isohexanes to yield 5-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (15 mg, 2%), and then the solvent polarity was increased to 100% Et2O to yield 4-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (147 mg, 18%).
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](C(=O)C(C)(C)C)[N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:1]2[CH2:6][CH2:5]3)=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3NC4)ccc21
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1

Procedure:
Reaction of Intermediate 14 with 4-chlorobenzaldehyde affords the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].Br[CH2:17][CH2:18][Cl:19].[Cl-].[NH4+]>O1CCCC1>[Cl:19][CH2:18][CH2:17][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)C
Reactant: ClCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 22.2 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 93.6 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was stirred for 30 minutes. The reaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyrate was added dropwise. The mixture was then further stirred for 45 minutes, after which a solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and, then, at room temperature for 2 hours. After an excess amount of an aqueous solution of ammonium chloride was added, the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. Finally, the residue was distilled under reduced pressure to provide 24.7 g of the title compound as colorless oil. b.p. 54°-56° C./0.25 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]=3[N:14]([CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: CC(C)Br
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno-[2,3-b]pyridine-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) are added K2CO3 (1.76 g) and 2-bromopropane (1.19 mL). The reaction is heated to 90° C. and stirred for 18 h. The reaction mixture is concentrated in vacuo. The resulting residue is partitioned between H2O (100 mL) and CH2Cl2 (200 mL). The aqueous layer is extracted with CH2Cl2 (3×150 mL). The combined organic layers are dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow solid is purified via column chromatography (CH2Cl2, CH2Cl2:CH3OH; 99:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yellow solid. This material is recrystallized from ethanol then methanol to yield 0.808 g (39%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31].O>C1C=CC=CC=1>[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][NH:22][CH:21]([C:30]([O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])=[O:31])[CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: C=CCC1(C2=CC(C(=O)OCC(Cl)(Cl)Cl)NCC2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (3.3 g, 10.0 mmol) in 50 mL of benzene, and added 2,2,2-trichloroethylchloroformate (3.0 mL, 4.6 g, 21.8 mmol). Refluxed for 20 hours under a nitrogen atmosphere. Cooled to room temperature, and added water. Extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 3.7 g (75% yield) of 2,2,2-trichloroethyl 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1,2,5,6-tetrahydro-pyridinecarboxylate as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][C:31]=1[CH:42]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:42][C:31]3[CH:32]=[C:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:34]=[CH:35][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccccc2)ccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(-c2ccccc2)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-fluoro-biphenyl-3-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 563.0.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:10]2[C:11](=[O:12])[N:6]([C@@H:4]3[CH2:5][C@H:2]([O:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3]3)[C:7]3[N:8]([N:31]=[CH:32][N:33]=3)[C:9]=2[CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)#[N:27]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h
Yield: 57 %

Procedure:
To a mixture of 4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), rhodium(I) acetate (0.003 g) and toluene (20 mL) was added dropwise ethyl diazoacetate (0.66 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 57%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3CC[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O.[C:17](O)(=O)[CH3:18]>CO.[Pd]>[CH:12]12[CH2:11][CH2:10][CH:9]([CH2:8][NH:7][CH2:6]1)[C:18]1[C:13]2=[CH:14][C:4]([NH2:1])=[CH:5][CH:17]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCC2CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CCC2CNC1
Reaction time: 3 h
Yield: 89 %

Procedure:
4-Nitro-1-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (250 mg, 1.15 mmol) was placed in methanol (10 mL) and acetic acid (0.2 mL). 10% Palladium on carbon (6.8 mg) was then added. The reaction was hydrogenated at 50 psi for 3 hours. The mixture was then filtered through celite and concentrated under reduced pressure. The residue was taken up in toluene (20 mL) and concentrated under reduced pressure to obtain 10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine as a light brown oil (193 mg, 89%). LCMS (m/e) 189 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.89 (d, 1H, J=7.8 Hz), 6.53 (dd, 1H, J=2.4 and 7.8 Hz), 6.48 (d, 1H, J=2.3 Hz), 3.20-2.80 (m, 8H), 2.02 (d, 2H, J=8.7 Hz), 1.82 (d, 2H, J=10.7 Hz).
Reaction SMILES: CN(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])=[CH2:7].[F:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:16][CH2:17][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:8])=[CH2:7])=[CH:10][CH:11]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: FCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1ccc(OCCF)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To 30 ml of dimethylformamide were added 7.0 g of 4-isopropenylphenol, 6.1 g of 1-fluoro-2-chloroethane and 8.7 g of potassium carbonate. With stirring, they were reacted at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, and poured into water. The mixture was then extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 9.0 g of crude 4-(2-fluoroethoxy)isopropenylbenzene.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:24]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(C=C2SC(N3CCN(S(C)(=O)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 52 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (50 mg, 92 μmol) (from Example 23) chloroform (5 mL), methyl sulfonyl chloride (3 equiv, 32 μL) and TEA (3 equiv, 40 μL). The reaction was stirred at 60° C. under N2. The reaction solution was diluted with DCM (70 mL), washed with aq NH4Cl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 90:10) to provide the title compound as a white solid (30 mg, 52%). 1H NMR (DMSO-d6) δ 7.99 (2H, s), 7.94 (1H, s), 7.62 (1H, s), 7.18 (1H, s), 7.13 (1H, dd, J1=2.0 Hz, J2=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 5.37 (2H, s), 4.06 (2H, m), 3.88 (3H, s), 3.74 (2H, m), 3.31-3.36 (4H, m), 2.85 (3H, s); MS (ESI) 624 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N:13]1([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-4-fluoronitrobenzene (3.3 g, 19.9 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (3.5 mL, 20 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:16]#[N:17])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(C#N)c1

Procedure:
The title compound, MS: m/e=319.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-cyano-benzene boronic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.06 g, 5.53 mmol), 3,5-Dibromo-1-methyl-1H-pyridin-2-one (1.23 g, 4.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400 mg, 0.691 mmol), and cesium carbonate (4.50 g, 13.8 mmol) was added 45 mL 1,4-dioxane and tris(dibenzylidineacetone)dipalladium(0) (422 mg, 0.461 mmol). This was heated in a a 120° C. oil bath for 6 hours under argon. This ws partitioned between ethylacetate and dilute aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 2 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one (484 mg, 1.28 mmol). MS (ESI) 380.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:21]([OH:26])[OH:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Yield: 55.6 %

Procedure:
Prepared according to the method described in Example 51b) from 3-(benzyloxy)bromobenzene (2.16 g, Example 93a), n-butyllithium (2.5 M in hexanes, 3.6 ml) and triisopropyl borate (3.4 g), in tetrahydrofuran (2×10 ml). After work up the residue was purified by column chromatography over silica eluting with ethyl acetate:hexane:acetic acid (20:79.5:0.5) then methanol to give the sub-title compound as a white solid (1.04 g). This was used without analysis.