Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>C(O)(=O)C>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A reaction mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 2.43 g of 3-dimethylamino-1-[3-(trifluoromethyl)phenyl]-2-propen-1-one in 25 ml of glacial acetic acid was refluxed for 6 hours and then the solvent was removed in vacuo giving a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried with anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected as crystals, mp 148°-150° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitropyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-nitro(2-pyridyl))amino]ethyl}amine (73174).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1C)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][N:22]=2)[C:18]#[N:19])[CH2:10][CH2:9]1)[CH3:2].Cl.Cl.N1CCC(NC2C=C(C=CN=2)C#N)CC1.[Cl:44]C1C=CC(C=O)=CC=1OCC>>[Cl:44][C:25]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][N:22]=3)[C:18]#[N:19])[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: Cl
Agent: N#Cc1ccnc(NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1Cl

Procedure:
The title compound was prepared in analogy to the synthesis of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile (example 189) from 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (intermediate B15) and 4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 3.8 mg (6%). MS (ISP): 371.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH:11]#[C:12][CH2:13][CH3:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:11]=[C:12]([CH2:13][CH3:14])[O:10][C:3]=2[CH:4]=1
Reactant: C#CCC
Reactant: COc1ccc(I)c(O)c1
Product: CCc1cc2ccc(OC)cc2o1
Yield: 81 %

Procedure:
This material was prepared from 2-iodo-5-methoxyphenol (1 g, 4 mmole) and 1-butyne in a manner as previously described for example 12a to give 570 mg (81%) of a brown oil. 1H NMR (CDCl3) δ7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.04 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H][H]>[Pd].CO.O>[C:1]1([CH3:29])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=3[CH:12]=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)OCc4ccccc4)cccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)O)cccc32)cc1
Yield: 77.1 %

Procedure:
The mixture of benzyl 1-(4-toluenesulfonyl)indole-4-carboxylate (550 mg) and 10% palladium on charcoal (200 mg) in methanol (20 ml) and water (2 ml) was hydrogenated at ambient temperature (an initial hydrogen pressure was set to 3.5 atm.). The theoretical amount of hydrogen was absorbed in 6 hours. The resulting mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was diluted with chloroform and the solution was dried over magnesium sulfate. Filtering and removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-n-hexane (1:3) to give 1-(4-toluenesulfonyl)indole-4-carboxylic acid (330 mg) as a brown powder.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[S:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:48]([CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:42]=2[CH:41]=1)C1C=CC=CC=1.C(S)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C@@H:10]1([C:40]2[S:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:48]([CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:42]=3[CH:41]=2)[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: c1ccc(CCc2cccc3sc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCS
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2cc3c(CCc4ccccc4)cccc3s2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 30.8 %

Procedure:
To a solution of 2-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-(2-phenylethyl)benzo[b]thiophene (0.58 g) and ethanethiol (1.13 mL) in dichloromethane (10 mL) was added boron trifluoride diethyl ether complex (1.43 mL) at room temperature, and the mixture was stirred for 3 hours. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (94 mg).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)([CH3:17])[CH3:16])=[CH:14][C:9]=2[O:8][CH2:7]1>C1C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:17])[CH3:16])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Reactant: O=C(O)CS
Solvent: c1ccccc1
Product: CC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 45.8 %

Procedure:
600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amount of D-100camphorsulfonic acid were added to 97 g of 2-(1,3-benzodioxol-5-yl)-2-propanol. The obtained mixture was heated under reflux for 4 hours and distilled to remove the solvent. The pH of the residue was adjusted to 10 with a 1N aqueous solution of sodium hydroxide. The resulting mixture was washed with ethyl acetate. 4N hydrochloric acid was added to the mixture under cooling with ice to acidify the aqueous layer. The resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 62.70 g of the title compound as a colorless crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O.[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
The first step was to protect 6-aminocaproic acid using benzyl chloroformate to give N-benzyloxycarbonyl-6-aminocaproic acid. This first step was carried out as follows. A solution of 6-aminocaproic acid (32.8 g, 0.25M) in 75 mL of H2O and 42 mL of 6N NaOH was cooled in a salt-ice bath to below 10° C. With stirring, benzyl chloroformate, 46.9 g, 0.275M) and 2N NaOH (138 mL) were alternatively added in small portions over 90 min. After the addition was complete, the solution was brought to room temperature, and stirring was continued for an additional 1 hr. The product was precipitated by lowering the pH to 2 with concentrated HCL, and H2O was added as required to keep the suspension stirring. The white precipitate was filtered, then resuspended and triturated with 1 liter of water. The solid was filtered, washed with water, compressed and then washed with hexane. The solid was then thoroughly dried in a vacuum desiccator to yield 55 grams (83% yield) of N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:10](=[O:13])[CH2:11][CH2:12][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:28])=[N:7][CH:8]=1
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (55.4 mg) in ethanol (1 mL) were added pyridine-2-carbaldehyde (21.7 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (5.6 mg) and triethylamine (11.4 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (27.7 mg, yield 37%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:12]2.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.O>[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][N:16]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:15][CH2:14]1)[CH2:12]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (100 mg, 0.24 mmol) in DCM (3 mL) were added triethylamine (0.1 mL, 0.72 mmol) and pivaloyl chloride (40 mg, 0.32 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 60% ethyl acetate/hexane as an eluent to get the desired compound as a creamy white solid (50 mg, 55%); 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 3.79-3.74 (m, 2H), 3.44 (t, J=10.1 Hz, 2H), 2.99 (s, 2H), 1.75-1.68 (m, 2H), 1.35-1.29 (m, 2H), 1.18 (s, 9H); ES-MS: 380.2 (M+1)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH:20](O)[C:19]3[CH:23]=[C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:26][C:18]=3[O:17]2)[CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH:11]1[CH2:16][CH2:15][C:14]2([CH:21]=[CH:20][C:19]3[CH:23]=[C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=[CH:26][C:18]=3[O:17]2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)C=CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Temperature: 25 °C

Procedure:
To a stirred suspension of the alcohol from example 2 above (310 mg, 0.7 mmol) in toluene (8 ml )was added p-toluene sulfonic acid (200 mg). This was boiled without a condenser until the reaction mixture was a gum. It was then cooled to r.t., sat. NaHCO3 (1 00 ml ) and EtOAc (1 00 ml ) were added. The biphasic mixture was stirred at r.t until all of the gummy solid dissolved. The layers were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 166 mg of a pale yellow oil, 55.8%.1H NMR (CDCl3)δ7.28-6.79 (m, 7H), 6.30 (d, J=1OHz, 1H), 5.55 (d, J=10 Hz, 1H), 3.83 (s, 2H), 2.91 (s, 7H), 2.62-2.48 (m, 1H), 2.20 (d, J=12 Hz, 2H), 2.00-1.82 (m, 4H), 1.45 (dt, J=13 Hz, J=4 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH2:25]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:28]#[CH:29])[CH3:26].C(N(CC)CC)C>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:26]#[C:25][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[N:21][CH:20]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC[Si](C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an argon flushed pressure vial (15 mL) was added copper (I)iodide (0.0070 g, 0.037 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.012 g, 0.015 mmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol). The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM:MeOH:NH4OH)) to yield the product as a light yellow solid. MS m/z=446.1 [M+1]+. Calc'd for C23H27N7OSi: 445.2.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.N([O-])=O.[Na+].N.[ClH:15]>O>[Br:8][C:7]1[C:2]([Cl:15])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: Cl
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 1.5 h

Procedure:
The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10° C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5° C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20° C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C:12]2=[N:11][N:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C:12]3=[N:11][N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-n2cccn2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of pyrazole (33.7 mg, 0.495 mmol) and sodium hydride (19.79 mg, 0.495 mmol) in N,N-dimethylformamide (DMF) (1 ml) was cooled to 0° C. and 1,1-dimethylethyl 3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (50 mg, 0.165 mmol, commercially available from e.g. Allichem, Ark Pharm or Bepharm) was added. After completion of the addition, the mixture was stirred at room temp for 30 mins and then at 110° C. After 3 h, the DMF was evaporated and a few drops of NH4Cl solution were added followed by ethyl acetate (50 ml). The solution was dried (Na2SO4), filtered and concentrated. The product was purified by MDAP to give desired product in 24.1 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[C:4]([F:12])[C:3]=1[F:13].CCN(C(C)C)C(C)C.[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=2)[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH:31][C:5]3[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[C:3]([F:13])[C:4]=3[F:12])[CH:27]=2)[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To 1,2,3,4-tetrafluoro-5-nitrobenzene (3.0 g, 15.4 mmol) and DIEA (3.7 ml, 21.0 mmol) in dry THF (20 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (1.7 g, 14.0 mmol) in THF (5 ml) drop wise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 16 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=4:1). This was recrystallized from Et2O (20 ml) and hexanes (˜150 ml) to give the title compound as red crystals (0.650 g, 16%). 1H NMR (400 MHz) 11.84 (s, 1H), 8.67 (s, 1H), 8.06 (m, 1H), 5.57 (s, 1H), 1.82 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 298; Found: [M+H]+ 299.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:15][CH:16]=4)[CH:11](O)[C:10]=3[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>[Pd].O>[N:1]1([CH2:7][C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([CH2:21][N:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1c2cc(CN3CCCCC3)ccc2-c2ccc(CN3CCCCC3)cc21
Agent: [Pd]
Agent: Cl
Solvent: O
Product: c1cc2c(cc1CN1CCCCC1)Cc1cc(CN3CCCCC3)ccc1-2
Reaction time: 0.75 h

Procedure:
A mixture of 6.15 g (0.016 mole) of 2,7--bis(piperidinomethyl)fluorene-9-ol, 12.1 ml of 10% hydrochloric acid, sufficient deionized water to bring the total volume to 150 ml, and 3.0 g of 10% palladium on charcoal catalyst is placed in a Paar hydrogenation apparatus and hydrogenated at room temperature for a period of 2 hours and 45 minutes. The resulting mixture is filtered and sufficient 20% sodium hydroxide solution is added to render the mixture basic to phenolphthalein indicator. The reaction mixture is extracted four times with chloroform, the extracts combined, washed twice with deionized water, treated with charcoal, filtered, and the major portion of the solvent removed at atmospheric pressure. The residue is recrystallized twice from methanol and once again from acetone yielding 2,7-bis(piperidinomethyl)fluorene having a m.p. 135°-6°C, λmax0.1N HCl 270, and E1cm1% 807.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[S:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)NC1CCCCC1SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1CCCCC1SCc1ccccc1
Yield: 93.3 %

Procedure:
2-Acetamido-1-benzylthio-cyclohexane (74 mg) prepared as above was added to 1 molar aqueous sodium hydroxide solution (30 ml) and refluxed for 19 hours. The reaction mixture was cooled, diluted to 100 ml with water and extracted with diethyl ether (3×50 ml). The ethereal layer was washed with water (25 ml), dried and evaporated to give 2-amino-1-benzylthio-cyclohexane (58 mg). Mass spec. m/e 221 (parent ion), IR 3300 (broad), 1600 and 1500 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[CH:22]=[C:21]([N:23]([CH:31]2[CH2:33][CH2:32]2)C(=O)OC(C)(C)C)[N:20]2[N:34]=[CH:35][C:36]([CH:37]=[O:38])=[C:19]2[N:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:31]1([NH:23][C:21]2[N:20]3[N:34]=[CH:35][C:36]([CH:37]=[O:38])=[C:19]3[N:18]=[C:17]([NH:5][C:4]3[CH:3]=[C:2]([F:1])[CH:8]=[C:7]([F:9])[CH:6]=3)[CH:22]=2)[CH2:32][CH2:33]1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3cc(F)cc(F)c3)nc12
Reaction time: 1 h
Yield: 79 %

Procedure:
3,5-Difluoroaniline (29 mg, 0.22 mmol), Cs2CO3 (67 mg, 0.21 mmol) were added to Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (50 mg, 0.15 mmol) dissolved in 1,4-dioxane (1 mL). Racemic BINAP (6 mg, 0.06 mmol) and palladium(II) acetate (4 mg, 0.04 mmol) were then added. The mixture was sealed and irradiated at 110° C. for 20 min in the microwave. Et2O (3 mL) was added and the solution was filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with 20% 2-propanol/hexanes. The product was filtered to yield 7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 80%). LCMS (M+1=330)