Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (5.22 g, 20 mmol) in DMF (60 mL) were added K2CO3 (8.3 g, 60 mmol) and 1-fluoro-4-nitrobenzene (2.96 g, 21 mmol). After the resulting mixture was stirred at 100° C. for 24 hr under N2 atmosphere, the reaction mixture was cooled to RT before pouring into water (200 mL). The precipitate was collected, washed with water and dried to provide 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27) (6.8 g, 89%) as light yellow solid. LC-MS (ESI): m/z (M+1) 383.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17].[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][O:22][CH3:23])[C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: COCCl
Reactant: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCn1c(C(N)=O)c(OC(C)C)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
5-Methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide (106 mg, 0.43 mmol) in 4 mL of dimethylformamide is added to a suspension of sodium hydride (60% by weight) (30 mg, 0.75 mol) in 2 mL of dimethylformamide. After 1 hour chloromethyl methyl ether (60 μL, 0.79 mmol) is added, and the solution is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and subsequent chromatography eluting with 1:1 ethyl acetate:hexane gives 40 mg of 5-methoxy-1-methoxymethyl-3-(1-methylethoxy)-1H-indole-2-carboxamide. An analytical sample was obtained by recrystallization from ethyl acetate:hexane; mp 145°-147° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:38])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1C([O-])=O)=[O:29])=O)(C)(C)C.Cl.O1CCOCC1>>[C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)=[O:29])[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1-c1ccccc1NC(=O)[C@@H]1CCCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1-c1ccccc1NC(=O)[C@@H]1CCCN1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,2′S)-tert-butyl-2,2′-(biphenyl-2,2′-diylbis(azanediyl))bis(oxomethylene)dipyrrolidine-1-carboxylate d (0.140 g, 0.24 mmol) was suspended in a solution of 4M HCl/dioxane and stirred at room temperature for 4 h until LCMS indicated complete deprotection. The reaction mixture was concentrated to give (2S,2′S)—N,N′-(biphenyl-2,2′-diyl)dipyrrolidine-2-carboxamide e (0.09 g, 100%). LC/MS: mw 378.47; M+H+=379.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccncc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccncc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(4-pyridyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-aminomethylpyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[NH:23][N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](=O)([O-])[O-].[K+].[K+].IC>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:44])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)-amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1,4-dihydrotetrazol-5-one (25 mg in 1.5 mL dry N,N-dimethylformamide) at 0° C. was added 13 mg potassium carbonate followed by 0.033 mL of a 10% solution of iodomethane in methylene cloride, and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The organic portion was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (20 mg).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:15])[C:5]([CH3:13])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(Cc1ccccc1)C(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(Cc1ccccc1)C(O)/C=C/I
Temperature: 0 °C

Procedure:
An ice-cold solution of 7.5 g. of 1-iodo-4,4-dimethyl-5-phenyl-trans-1-penten-3-one in 150 ml. of methanol was treated with 0.89 g. of sodium borohydride and stirred at 0° for 11/2 hours. The solvent was evaporated and the residue was dissolved in water and then extracted with ether. The ether was dried and evaporated to afford 7.5 g. of the title product as an oil, λmaxEtOH 3.0, 3.45, 6.23, 6.70, 6.82, 6.90, 7.23, 7.34, 7.87, 8.55, 9.28, 9.71, 10.0, 10.56, 13.04, 13.6 and 14.2μ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCOCC1>[C:16]1([C:14](=[O:15])[CH:13]=[CH:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([O:1][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 90 °C
Yield: 16.5 %

Procedure:
A solution containing 2.0 g of the product obtained in Example 8 and 10.0 g of stearoyl chloride in 10 ml of dioxane was stirred and heated for 18 h at 90° C. After cooling petroleum ether was added and the product was filtered. Recrystallization from dichloromethane-petroleum ether yielded 0.64 g (17%) of the desired product desired, m.p. 112°-118° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[CH:36][C:37]2[O:41][CH:40]=[CH:39][C:38]=2[CH:42]=1)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:32]3[N:31]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:33]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1ccc2occc2c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4occc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (147.7 mg, 0.72 mmol), HOBt (143 mg, 0.94 mmol) and EDC (180 mg, 0.94 mmol) in DMF (2.0 mL) was stirred for 0.5 h at room temperature under an atmosphere of N2. A solution of N-hydroxybenzofuran-5-carboximidamide INT-68 (218 mg, 0.79 mmol) in DMF (2.0 mL) was added to the mixture. After 1 h at room temperature, the mixture was stirred at 85° C. overnight. The reaction mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried over Na2SO4, and concentrated. The resulting crude material was chromatographed (EA/hexanes) to provide 110 mg (44%) of 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 69 as a white solid. LCMS-ESI (m/z) calculated for C20H15N3O3: 345.4; found 346.1 [M+H]+, tR=2.77 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=4.5, 1.9 Hz, 2H), 8.35 (dd, J=8.9, 2.2 Hz, 1H), 8.12 (dd, J=8.6, 1.7 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.80 (s, 1H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.O.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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
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+]
Solvent: CC#N
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(CO)c2)n1
Reaction time: 0.42 h
Yield: 54.4 %

Procedure:
In a hard walled glass tube, a solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (250 mg, 0.75 mmol), 3-(hydroxymethyl)phenylboronic acid (137 mg, 0.9 mmol) and Na2CO3 (79.7 mg, 0.75 mmol) in acetonitrile/water (6 mL, 2:1) is degassed over nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (43.5 mg, 0.04 mmol) is added and the tube is sealed and set in a microwave for 25 minutes at 130° C. The reaction is dilute with 25 mL of water and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate, filtered and concentrate in reduced pressure. The residue is purified by chromatography (SiO2 packed column), eluted with EtOAc/DCM to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol [165 mg, Example 78 (a)]. LCMS: RT=2.24 minutes, MS: 405 (M+H); 1H NMR (300 MHz, CDCl3): □8.05 (1H, s), 7.95 (1H, b)), 7.48 (3H, b), 7.42 (1H, s), 7.2 (1H, s), 6.45 (1H, s), 4.95 (1H, b), 4.78 (2H, b), 4.05 (3H, s), 3.72 (2H, b), 3.1 (2H, t, J=3.5 Hz); and to afford (3′-chloro-4′-{2-[6-(3-hydroxymethyl-phenyl)-2-methoxy-pyrimidin-4-ylamino]-ethyl}-biphenyl-3-yl)-methanol [110 mg, Example 78(b)]. LCMS: RT=2.12 minutes, MS: 477 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:36])[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=4)[CH2:20]3)[N:13]=[N:14][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:38][OH:39]>>[C:16]([C:15]1[N:14]=[N:13][C:12]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:36])[C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=3)[CH2:20]2)=[N:11][C:10]=1[NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[O:39][CH3:38])=[CH:8][CH:7]=1)(=[O:17])[NH2:18]
Reactant: CO
Reactant: CCOc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C#N)cc4)n3)C2)cc1
Agent: Cl
Product: CCOc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C(=N)OC)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-5-(4-Cyanophenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (194) (90 mg, 0.18 mmol) was dissolved in 25 mL dry MeOH. It was chilled in an ice bath, and was then charged with HCl gas from a lecture bottle using a long needle to bubble the gas into the bottom of the solution until saturation reached. The resulting mixture was stirred at RT for overnight, and was placed back to the ice bath for repeated HCl gas charging till saturation. The resulting mixture was stirred for another overnight, and concentrated in vacuo to dryness to afford crude (R)-methyl 4-(6-carbamoyl-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)benzimidate (501). It was dissolved in 15 mL dry MeOH. To it was added dimethylamine (2M in THF, 1.0 mL). The mixture was sent to 60° C. bath and stirred for 1 hour. It was cooled to RT, concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and next MeCN as mobile phases to isolate the title compound, (R)-5-(4-(N,N-dimethylcarbamimidoyl)phenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (502), as HCl salt (59 mg). LC-MS (ESI): m/z (M+1) 532.2. UV: λ=267 nm.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=O)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[O:19].C(N(CC)CC)C>CO>[CH:1]([C:4]1[C:12](/[CH:13]=[N:16]/[NH:17][C:18]([NH2:20])=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: NNC(N)=O
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)c1nn2ccccc2c1/C=N/NC(N)=O
Yield: 70.6 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g, 1 equivalent), semicarbazide hydrochloride (0.35 g, 1.2 equivalents), and triethylamine (0.4 mL, 1.1 equivalent) in 5 mL of methanol was reflux for 30 minutes. The solution was concentrated and the crude solids produced were extracted with THF, and the mixture was filtered through a 1 inch thick layer of sodium sulfate on top of a thin pad of silica gel to remove the ammonium salt. The filtrate was concentrated and the solid deposited was recrystallized from THF and hexanes to give (E)-2-((2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methylene)hydrazinecarboxamide (0.46 g, 70% yield) as a yellow solid. Compound 1074.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([CH2:26][CH3:27])[N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:9]=12)=[O:4].[CH3:28][NH:29][C:30]([C@@H:32](OS(C1C=CC(C)=CC=1)(=O)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([CH2:26][CH3:27])[N:8]2[CH2:13][CH2:12][N:11]([CH:32]([C:30](=[O:31])[NH:29][CH3:28])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:9]=12)=[O:4]
Reactant: CNC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Reactant: CCc1nc(C(=O)NC)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1
Product: CCc1nc(C(=O)NC)c2n1CCN(C(C(=O)NC)c1ccccc1)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
Prepared by reaction of 3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methylamide (22 mg; 0.057 mmol) with toluene-4-sulfonic acid (S)-methylcarbamoyl-phenyl-methyl ester. Purification by preparative HPLC afforded the mixture of 2 diastereoisomers. LC-MS: tR=0.86 min., [M+H]+=528.45 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21][N:42]=[N+:43]=[N-:44])[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26]
Reactant: CCCc1nc2c(C)cc(CO)cc2n1Cc1ccc(C(=O)OC)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2c(C)cc(CN=[N+]=[N-])cc2n1Cc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
Intermediate (8a) (2.4 g, 6.5 mmol) was added to 125 mL of DCM followed by DIPEA (4.6 mL, 26.1 mmol) and 4-dimethylaminopyridine (80 mg, 653 μmol). Methanesulfonyl chloride (1.0 mL, 13.1 mmol) was then added at 0° C. and the mixture was warmed to room temperature. After 3 hours, the mixture was concentrated and the material redissolved in 40 mL DMF. Sodium azide (467 mg, 7.2 mmol) was added and the mixture was heated at 80° C. for 1 hour. The mixture was then cooled to room temperature. The solution was partitioned between EtOAc (100 mL) and 50 mL 10% LiCl (aqueous). The organic layer was concentrated and flash chromatographed 20-70% EtOAc:hexanes to yield Intermediate (8b) as a yellow oil (2.1 g). MS m/z: [M+H+] calcd for C21H22FN5O2, 396.2. found 396.0.
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.2 ml) was added to a solution of the product of Step 2 (0.91 g, 3.31 mmol), 1H-inden-2(3H)-one (0.41 g, 3.31 mmol) and NaBH(OAc)3 (1.05 g, 4.9 mmol) in anhydrous 1,2-dichloroethane (12.5 ml). The resulting mixture was stirred overnight at room temperature under N2 than quenched by addition of 1N NaOH aq (1 ml). This was diluted to 60 ml with Et2O and washed with N2. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a yellow solid (0.98 g, 72%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=9.0 Hz, 1H), 7.34-7.49(m, 5H), 7.15-7.18(m, 4H), 7.07(dd, J=1.7, 9.0 Hz, 1H), 6.49(d, J=1.7 Hz, 1H), 4.11-4.18(m, 2H), 3.55(s, 3H), 3.2(dd, J=6.2, 16 Hz, 2H), 2.8(dd, J=6.2, 16 Hz, 2H), 2.68(s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.[CH:17]([O:20]C)(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:13][C:7]1[C:6]2[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3][C:2]([CH3:16])([CH3:1])[C:11]=2[CH:10]=[C:9]([CH3:12])[C:8]=1[CH:17]=[O:20]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C=O)C(C)(C)CCC2(C)C
Yield: 71.9 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,1,4,4,5,7-hexamethylnaphthalene (5.0 g) of TiCl4 (7.32 g) in methylene chloride (40 ml) was treated with Cl2CHOCH3 (2.66 g) in methylene chloride (5 ml), at 0° and over 20 min. The temperature of the reaction mixture was allowed to reach 20° (20 min) and said mixture was then poured on ice water and extracted with ether. The organic phase was successively washed with a 10% aqueous solution of NaOH, water and an aqueous solution saturated with NaCl, then dried over Na2SO4, evaporated and recrystallized from methanol. 4.06 g (yield 72%) of 5,6,7,8-tetrahydro -1,3,5,5,8,8-hexamethyl-2-naphthalenecarbaldehyde were obtained, the product being identical in data to that described in b).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 3-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E10 (113 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.0 (1H, s), 8.70 (1H, d), 8.50 (1H, d), 8.17 (2H, m), 7.50 (1H, m), 7.17 (1H, d), 6.62 (1H, d), 4.70 (2H, dt), 4.17 (1H, m), 3.22 (2H, dt), 1.95 (2H, m), 1.55 (2H, m), MS(ES+) 323 [M+H]+.