Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=C[CH:23]=2)C([O-])=O)=[O:13])=[CH:8][C:7]=1[CH3:26])([CH3:5])[CH3:4].[CH3:27]I.[C:29]([O:32][CH2:33]C)(=[O:31])[CH3:30]>CN(C=O)C>[CH:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][C:12]([N:14]([C:15]2[CH:23]=[C:30]([CH:21]=[CH:17][CH:16]=2)[C:29]([O:32][CH3:33])=[O:31])[CH3:27])=[O:13])=[CH:8][C:7]=1[CH3:26])([CH3:4])[CH3:5]
Reactant: CCOC(C)=O
Reactant: CI
Reactant: Cc1cc(OCC(=O)Nc2cccc(C(=O)[O-])c2)ccc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(N(C)C(=O)COc2ccc(C(C)C)c(C)c2)c1
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (0.16 g, 55% w/w) was washed free of mineral oil and taken up in DMF (5 mL). The solution was cooled in an ice bath while a solution of 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate (0.80 g, 2.34 mmol) in DMF (10 mL) was added. The mixture was allowed to stir for 1 h, then was treated with methyl iodide (0.60 g), and the resulting mixture stirred overnight. It was diluted with ethyl acetate (50 mL), and this was washed with three 50 mL portions of water and then brine. The aqueous phases were back-extracted in sequence with ethyl acetate, and the organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was separated by column chromatography to afford the product, methyl 3-[N-[2-(4-isopropyl-3-methylphenoxy)-acetyl]-N-methylamino]-benzoate, as a pale yellow oil (0.68 g, 1.91 mmol, 82%). 1H NMR (CDCl3, 300 MHz): δ 8.03 (1H, d, J=7.6 Hz), 7.90 (1H, t, J=2.1 Hz), 7.51 (1H, t, J=7.9 Hz), 7.44 (1H, dd, J=8.0, 1.7 Hz), 7.06 (1H, dd, J=9.1, 5.3 Hz), 6.59–6.52 (1H, m), 4.38 (2H, s), 3.93 (3H, s), 3.32 (3H, s), 3.02 (1H, m, J=7.0 Hz), 2.25 (3H, s), 1.15 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 357 (22), 356 (100).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].[CH2:37]([N:39]([CH2:42][CH3:43])[CH2:40]C)[CH3:38].ClC(OC(C)=C)=[O:46].N1CCCC1>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:40]([N:39]3[CH2:42][CH2:43][CH2:38][CH2:37]3)=[O:46])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: C=C(C)OC(=O)Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.204 mmol) in tetrahydrofuran (1 mL) was treated with triethylamine (0.8 mmol) and isopropenyl chloroformate (0.3 mmol). The reaction was stirred for 3 h then pyrolidine (2 mmol) was added and the reaction heated at 50° C. for 18 h. The reaction was concentrated in vacuo and redissolved in methylene chloride (20 mL) and washed with water (2×10 mL). The methylene chloride was evaporated to give the crude produce which was purified using a Gilson reverse phase HPLC to provide the title product (37%). ESMS [M+H]+: 576.2
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: COc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[CH3:39]I>CN(C=O)C>[CH3:39][N:32]([C:29]1[CH:28]=[CH:27][C:26]([N:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[CH:9][C:4]2=[O:3])=[CH:31][CH:30]=1)[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CI
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(NC(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N(C)C(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a stirring suspension of sodium hydride (9.1 mg, 0.23 mmol), N-(4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)phenyl)pivalamide (15 mg, 0.030 mmol) in DMF (2 mL) was added Methyl iodide (10 μL, 0.16 mmol). The reaction was stirred at room temperature for 1.5 h. The reaction was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 10 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 2 H), 7.39-7.48 (m, 2 H), 7.32-7.39 (m, 2 H), 7.26 (d, J=2.01 Hz, 1H), 5.98-6.09 (m, 2 H), 4.55-4.64 (m, 1 H), 4.16-4.28 (m, 2 H), 3.59-3.71 (m, 2H), 3.27 (s, 3 H), 2.43 (t, J=7.40 Hz, 2 H), 1.98-2.22 (m, 2 H), 1.74-1.98 (m, 2 H), 1.53-1.66 (m, 2 H), 1.12 (s, 9 H), 0.96 (t, J=7.28 Hz, 3 H). MS (ESI) 504 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].C1CCN2C(=NCCC2)CC1.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([CH3:41])[O:30][C@@H:28]([OH:29])[C@@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:29][C@@H:28]1[O:30][C@@H:31]([CH3:41])[C@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47]
Reactant: CC(=O)CCC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](C)O[C@H]1O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)CCC(=O)O[C@H]1[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Trichloroacetonitrile (1.3 mL, 13 mmol) and DBU (51 μL, 0.3 mmol) were added to a solution of the residue 211 (1.0 g, 2.3 mmol) in anhydrous DCM (6 mL) at 0° C. After 2 h, the mixture was concentrated. The residue was eluted from a column of silica gel with 3:1 cyclohexane-EtOAc and 0.2% Et3N to give 212 as a white foam (1.0 g, 95%); 1H NMR: δ 8.67 (s, 1H, NH), 7.40-7.30 (m, 10H, Ph), 6.19 (d, 1H, J1,2=1.9 Hz, H-1), 5.48 (dd, 1H, J1,2=2.0, J2,3=3.3 Hz, H-2), 4.95 (d, 1H, CH2Ph), 4.73 (d, 1H, CH2Ph), 4.66 (d, 1H, CH2Ph), 4.58 (d, 1H, CH2Ph), 4.51 (d, 1H, CH2Ph), 4.00 (dd, 1H, J3,4=9.5 Hz, H-3), 3.95 (dq, 1H, J4,5=9.6, J5,6=6.3 Hz, H-5), 3.52 (pt, 1H, H-4), 2.80 (m, 4H, Lev), 2.20 (s, 3H, Ac), 1.36 (d, 3H, H-6). Anal. Calcd for C27H30Cl3NO7.0.5H2O: C, 54.42; H, 5.24; N, 2.35. Found: C, 54.06; H, 5.06; 2.05.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:40](=[O:41])[C:39]6[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=6[F:47])[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine (80 mg, 0.17 mmol) in THF (3 mL) was added TEA (25 μL, 0.25 mmol) and 2,6-difluorobenzoyl chloride (22 μL, 0.18 mmol). The reaction was stirred at rt for 2 h, and the reaction was diluted with 30 mL DCM and adsorbed onto silica. The crude product was purified by flash chromatography and reversed-phase HPLC to generate, after lyophilization, the title compound as a TFA salt (38 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.84 (s, 1H), 9.59 (s, 1H), 8.88 (d, J=6.7 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.58-7.62 (m, 1H), 7.41-7.52 (m, 4H), 7.24 (t, J=8.0 Hz, 2H), 7.13-7.16 (m, 2H), 6.61 (d, J=5.3 Hz, 1H), 4.04-4.12 (m, 1H), 3.22-3.28 (m, 2H), 3.06-3.12 (m, 2H), 2.82 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([OH:18])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[OH:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)c2ccccc2)c(O)cc1Br
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cc2ccccc2)c(O)cc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
To a solution of (4-bromo-2-hydroxy-5-methoxyphenyl)(phenyl)methanone (100 mg, 0.325 mmol) in 0.22 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (0.25 mL, 10 eq) and triethylsilane (0.21 mL, 4 eq). After 17 h of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL) The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted twice with DCM (2×5 mL). The combined organic phase was washed twice with a saturated NaHCO3 solution (2×20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (Cyclohexane/AcOEt 97:3) to afford the desired product in 72% yield (68.5 mg) as an uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 2H), 7.28-7.20 (m, 3H), 7.01 (s, 1H), 6.70 (s, 1H), 4.89 (s, 1H), 3.96 (s, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.3 (C), 148.1 (C), 139.4 (C), 128.8 (CH), 128.7 (CH), 127.5 (C), 126.6 (CH), 120.7 (CH), 115.0 (CH), 109.4 (C), 57.0 (OCH3), 36.4 (CH2Bn); MS (ESI) m/z: 310.1, 312.1 [M+NH4, 79Br, 81Br]+; 602.0, 604.3, 606.1 [2M+NH4, 79Br, 81Br]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[N:14](C)[CH2:15][CH2:16][C:17]#N.[Na].[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[NH2:23][C:22]1[N:24]=[C:15]([NH2:14])[C:16]([CH2:1][C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:17][N:21]=1
Reactant: N=C(N)N
Reactant: COc1ccc(C=O)cc1OC
Reactant: CN(C)CCC#N
Agent: [Na]
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OC
Yield: 32 %

Procedure:
The aforesaid British Patent Specification No. 957,797 also describes (Example 14) the reaction of veratraldehyde with β-dimethylaminopropionitrile in the presence of sodium in ethanol to give a mixture of β-dimethylaminoveratralnitrile (III) and β-ethoxyveratralnitrile (IV) in a 32% yield. ##EQU3## It is stated in the Example that this mixture was subsequently cyclised with guanidine to give 2,4-diamino-5-(3',4'-dimethoxybenzyl)-pyrimidine. It is to be noted that both the compounds (III) and (IV) above are `benzal` derivatives.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].Cl.CN(C)[CH:21]=[O:22]>C(OC)=O>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:21][OH:22])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1csc2ccc(C)cc12
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC=O
Product: COC(=O)C(=CO)c1csc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 79.7 g of methyl 5-methyl-3-benzo[b]thienylacetate in 200 ml of dimethylformamide and 200 ml of methyl formate is slowly added dropwise to a suspension of 10.4 g of sodium hydride in 100 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at room temperature and then acidified with dilute hydrochloric acid, and this is then extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this manner, methyl α-(5-methyl-3-benzo[b]thienyl)-β-hydroxyacrylate is obtained as the crude product which is used unpurified as the starting material in the next process step.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([O:24]CC)=O)=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C(O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:24])[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[NH:16][C:14]2=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 118.0 g of ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate in 800 ml of absolute 1,2-dimethoxyethane, is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 7.7 g of sodium hydride in 800 ml of absolute 1,2-dimethoxyethane. The reaction mixture is subsequently stirred for 1 hour, treated with 20 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 2 l of methylene chloride and washed twice with 1 l of water. The organic phase is dried over anhydrous sodium sulphate and evaporated up to crystallization. The residue is treated with 1 l of n-hexane and the crystals are filtered off under suction and rinsed with n-hexane. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 178°-180° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]>C(OCC)(=O)C.C(O)C>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(NCCCCc2ccccc2)c(N)c1

Procedure:
The same procedure is used as in (2). Rf value: 0.68 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=O)=[CH:5][CH:4]=1.C(O)CC.CC1C=CC(S([NH:44][NH2:45])(=O)=O)=CC=1.N1CCOCC1>O1CCOCC1.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:44]=[N:45][N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:21])=[O:22])[C:14]=4[N:15]=[CH:16][C:11]=23)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1COCCN1
Solvent: CCCO
Product: COc1ccc(-c2nnn3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
The (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanone (2.25 g, 5.52 mmol, prepared using AT from Preparation #AF.1) was dissolved in 1,4-dioxane (25 mL) and PrOH (5 mL) then treated with 4-methylbenzenesulfonohydrazide (1.08 g, 5.80 mmol). The mixture was heated to about 100° C. for about 2 h then it was treated with 1 drop concentrated HCl. The mixture was stirred about 1 h at about 100° C. and then the mixture was concentrated under reduced pressure. The material was dissolved in morpholine (15.0 mL, 172 mmol) then the mixture was heated to about 100° C. for about 15 min. The mixture was cooled to rt and concentrated on the under reduced pressure. The material was treated with water (100 mL) and EtOAc (˜40 mL). The mixture was stirred for about 10 min then filtered. The solids were washed with EtOAc (˜7 mL) then dried to a constant weight under vacuum at about 70° C. to give 3-(4-methoxyphenyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyrazine (0.760 g, 33%): LC/MS (Table 2, Method a) Rt=2.74 min; MS m/z 420 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (8.2 mg, 28%), MS (ISP) m/z=416.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methylbutanoic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:14]2[O:13][CH2:12][O:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(OC(=O)C)(=O)C>[N+:1]([C:8]1[CH:7]=[C:6]([CH3:5])[C:14]2[O:13][CH2:12][O:11][C:10]=2[C:9]=1[CH3:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2c1OCO2
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c2c1OCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.92 mL of concentrated nitric acid in 17 mL of acetic arthydride is added dropwise to a stirred solution of 2.20 g of 4,7-dimethyl-1,3-benzodioxole in 60 mL of acetic anhydride at -5° C. After 30 minutes, the mixture is poured over 100 g of crushed ice and allowed to stir for 30 minutes as a white precipitate falls out of solution. The solid is filtered, taken up in ether, dried over magnesium sulfate and concentrated under reduced pressure to afford 2.1 g of 5-nitro-4,7-dimethyl-1,3-benzodioxole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1F)[C:20]#[N:21].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:24]1[C:17]([F:16])=[CH:18][C:19]([C:20]#[N:21])=[CH:22][C:23]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1c(F)cc(C#N)cc1F
Yield: 7.2 %

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.36 g) and 3,4,5-trifluorobenzonitrile (1.00 g) were heated under argon in xylene (10 ml) containing diisopropylethylamine (3.3 ml) for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to give a solid which was triturated with pentane-ether to afford the title product (0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum (API+): Found 252 (MH+-tBoc). C18H23F2N3O2 requires 351.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:38])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:37])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:40])[CH3:39].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:37][C@:8]12[C@@:7]3([CH3:38])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:39])([CH3:40])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-benzyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (7.1 g, 12.98 mmol) in dichloromethane (100 mL) was added PCC (4.20 g, 19.48 mmol). After stirring for five minutes, the mixture turned a deep crimson color. The mixture was further stirred for 5.5 h. The mixture was filtered through a pad of celite and silica gel which was washed with dichloromethane and then a 1:1 mixture of ethyl acetate:hexanes. The filtrate was concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (6.92 g, 12.7 mmol, 98% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.38-7.28 (m, 5H), 5.17-5.06 (m, 2H), 4.72 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.01 (td, J=10.99, 4.88 Hz, 1H), 2.51-2.43 (m, 1H), 2.42-2.34 (m, 1H), 2.28 (dt, J=12.59, 3.17 Hz, 1H), 2.21 (td, J=12.28, 3.51 Hz, 1H), 1.94-1.82 (m, 3H), 1.67 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 1.73-0.95 (m, 17H), 0.94 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H).