Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][CH2:4][O:5][C:6](=[O:47])[C@@H:7]([NH:39]C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:26][CH:25]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:48][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:47])[C@@H:7]([NH2:39])[CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CN(C)CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOC(=O)[C@@H](N)CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h
Yield: 137.2 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-4-(3-{3-[4-(pyridin-2-yloxymethyl)-benzyl]-isoxazol-5-yl}-pyridin-2-ylcarbamoyl)-butyric acid 2-dimethylamino-ethyl ester (53 mg, 0.060 mmol; purity of 75%) described in Manufacturing Example 3-2 and dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, which was stirred overnight at the same temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and the residue thus obtained was washed with diethyl ether, so as to obtain the titled compound (46 mg) as di-(trifluoroacetic acid) salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.Br[CH2:29][CH2:30][OH:31].CCN(C(C)C)C(C)C>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:29][CH2:30][OH:31])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(CCO)C1
Temperature: 70 °C
Reaction time: 20 h
Yield: 4.8 %

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-bromoethanol (30 μL, 0.414 mmol) and DIPEA (215 μL, 1.24 mmol) in IMS (2 mL) was stirred in a sealed vial at 70° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) followed by sonication in cyclohexane and HPLC purification (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-50% 0.1% NH4OH in acetonitrile/water). The product containing fractions were concentrated in vacuo affording 150 as a white solid (8 mg, 5%). LCMS: RT 1.72 min [M+H]+ 407.1. 1H NMR (DMSO, 400 MHz): 8.30-8.07 (2H, m), 7.95 (1H, bs), 7.73-7.68 (1H, m), 7.63-7.58 (1H, m), 7.20-7.11 (2H, m), 5.93 (1H, bs), 4.68-4.57 (1H, m), 4.36 (1H, bs), 3.48 (2H, bs), 3.03-2.97 (1H, m), 2.89-2.77 (2H, m), 2.52-2.39 (3H, m), 2.14-2.98 (2H, m), 1.74-1.66 (4H, m), 1.61-1.53 (1H, m), 1.24-1.10 (1H, m)
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:6])[C:4]#[CH:5].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C:18]([CH3:20])=[O:19])[CH3:14])[CH3:9].S(=O)(=O)(O)O>O1CCCC1>[CH3:20][C:18]([OH:19])([CH2:17][CH2:16][CH2:15][CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[C:5]#[C:4][CH2:3][OH:6]
Reactant: C#CCO
Reactant: CC(=O)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CCO
Temperature: 0 °C
Yield: 70.9 %

Procedure:
Into a 2-liter, three-neck, round-bottom flask fitted with a mechanical stirrer, a reflux condenser, and an addition funnel was added 210 g (3.60 mol) of finely powdered potassium hydroxide and 500 ml of anhydrous tetrahydrofuran. The resulting reaction mixture was heated to reflux and then 30.0 g (0.54 mol) of propargyl alcohol was slowly added over a 30 minute period with rapid stirring. The mixture was refluxed for 3 hours before 100 g (0.51 mol) of hexahydropseudoionone in 140 ml of tetrahydrofuran was slowly added over a 2-hour period. After an additional 2 hours at reflux, the reaction was cooled to 0° C. and poured onto 1000 g of ice and 360 g of concentrated sulfuric acid with efficient mixing. The resulting aqueous layer was rinsed with 3×100 ml of ether and the combined organic layers were rinsed with 50 ml of water, 3×50 ml of saturated aqueous sodium bicarbonate, and 50 ml of brine. The resulting ethereal solution was dried with 50 g of magnesium sulfate, and the solvent was removed at aspirator pressure with the aid of a rotary evaporator, leaving 110 g of crude product. Vacuum distillation at 40 μHg and 140° C. afforded 92 g (73%) of pure product, i.e. 4,8,12-trimethyltridec-2-yn-1,4-diol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][S:23][CH:24]([CH3:26])[CH3:25])[CH:7]=1)[CH3:2].C(N(CC)CC)C>CN(C=O)C.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]>[CH3:1][O:3][C:4](=[O:27])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[C:16]([CH2:22][S:23][CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)OC)cc2CSC(C)C)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.5 g, 1.1 mmol) and triethylamine (0.5 mL) were dissolved in DMF (10 mL) and MeOH (10 mL) and degassed for 10 minutes with N2. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09 g, 0.11 mmol) was added, and then carbon monoxide was bubbled through the solution for 10 minutes. The reaction was stirred under a balloon of carbon monoxide at 65° C. overnight, and then concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 2-bromo-5-(trifluoromethyl)benzaldehyde (7.5 g, 29.6 mmol) in MeOH (80 mL) was added ethylamine (2M in MeOH; 30 mL, 60 mmol), sodium cyanoborohydride (3.7 g, 58.9 mmol), and acetic acid (1.7 mL, 26.2 mmol), and the reaction was stirred at room temperature for 4 days. The mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-4% MeOH in CH2Cl2) to give (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C@@H:7]1[C@@H:14]2[C@@H:10]([CH2:11][NH:12][CH2:13]2)[CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([N:12]1[CH2:13][C@@H:14]2[C@@H:7]([NH:6][C:4](=[O:5])[CH:3]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:2]([CH3:21])[CH3:1])[CH2:8][CH2:9][C@@H:10]2[CH2:11]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(C(=O)c3ccccc3)C[C@@H]21)c1ccccc1
Reaction time: 0.08 h

Procedure:
3-Methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A (25 mg, 0.087 mmol), triethylamine (0.018 mL, 0.131 mmol), and benzoyl chloride (10.12 μL, 0.087 mmol) were combined in dichloromethane (5 mL). After 5 minutes, tlc shows no more starting material. The crude reaction mixture was concentrated and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.49-7.42 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.27 (m, 3H), 5.43 (d, J=6.7, 1H), 3.97 (m, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.39 (m, 1H), 2.74 (m, 2H), 2.48 (m, 1H), 2.38 (m, 2H), 2.07 (dd, J=4.6, 10.8, 1H), 1.94 (m, 1H), 1.52-1.31 (m, 2H), 1.01 (d, J=6.3, 3H), 0.68 (d, J=6.6, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[C:3]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesised in analogy to the Suzuki reaction procedure described for the preparation of Example 1, from 5-bromo-N-(trans-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide and 4-trifluoromethyl-phenylboronic acid (commercially available). MS (m/e): 439.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH:22]CC=C)[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: C=CCNCC=C
Reactant: Cc1csc2c(N3CCC(C)CC3)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(N2CCC(C)CC2)c2scc(C)c2n1
Yield: 43.6 %

Procedure:
In a sealed tube were heated 422 mg (1.5 mmol) of 2-chloro-7-methyl-4-(4-methylpiperidino)thieno[3,2-d]pyrimidine and 1.37 g (24.0 mmol) of diallylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 198 mg (yield: 43.9%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:22][NH:23][C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)=[O:25]
Reactant: CN=C=O
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 83.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (500 mg, 1.68 mmol) in chloroform (20 ml) was added methylisocyanate (0.10 mg, 1.75 mmol) in chloroform (10 ml) under cooling with ice. After the mixture was stirred, methylisocyanate (0.15 mmol, 2.63 mmol) was added to the mixture, and then the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure to a residue, which was crystallized to afford N-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)urea (0.499 g, 84% yield) as crystalline material: mp 208.5°-209.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C.O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is dissolved in DMF (25 ml) in a dry flask under nitrogen. Allyl bromide (0.65 ml, 7.55 mmol) is added drop-wise, followed by the careful addition of 60% NaH (303 mg, 7.55 mmol). The reaction is stirred overnight at RT and then is diluted with H2O (30 ml). The mixture is extracted with EtOAc (3×30 ml), and the combined organics are washed with 50% saturated NaCl (4×25 ml), dried (MgSO4), filtered, and concentrated under high vacuum to an oil that solidified upon standing. The volatiles are removed in vacuo to obtain 2.28 g (100%) of methyl 3-(allyloxy)-4-iodobenzoate as a tan solid. HRMS (FAB) calcd for C11H11IO3+H: 318.9833, found 318.9831 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](Cl)(=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:32](=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chloro-phenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrmidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 81.5 mg (0.37 mmol) of lauric acid chloride in 10 ml of dioxane and extracted. Column chromatography (SiO2; methylene chloride/ethyl acetate/acetic acid=50:50:1) yields 4-(3-chloro-phenylamino)-3-(4-[n-dodecanoyl]-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=22.6; FAB-MS: (M+H)+=512.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-fluoro-5-nitropyridine (30 g, 18.9 mmol) was added to a stirred solution of 1H-1,2,4-triazole (1.566 g, 22.7 mmol) and K2CO3 (5.14 g, 37.8 mmol) and stirred for 16 hrs at 25° C. Reaction mass was diluted with ice cold water and stirred for 15 min. The solid obtained was filtered and dried under vacuum to afford the desired product. MS (ESI): m/z 192 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2].[OH-].[Na+].Cl>C(O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)CC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate (0.5 g, 1.797 mmol) in ethanol 10 ml, sodium hydroxide (aq) (5 ml, 25.00 mmol) was added and stirred at room temperature for 10 hr. Reaction mixture was diluted with water (20 ml), and acidified by adding 5N HCl. Obtained white precipitates were filtered. The residue was dried by azetrope with toluene (0.38 g, 85%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[CH2:10](I)[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: OCCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCCCC1CCO
Yield: 72.9 %

Procedure:
2-Piperidineethanol (15 g, 0.12 mol), n-butyl iodide (23.5 g, 0.13 mol) and potassium carbonate (32.1 g, 0.23 mol) in actonitrile (250 ml), as described in example 3 above, gave 1-butyl-2-piperidineethanol (16.2 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].CI.[CH2:14]1CCCCC1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[NH:11])[S:10][CH3:14]
Reactant: C1CCCCC1
Reactant: NC(=S)Nc1ccccc1F
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=N)Nc1ccccc1F

Procedure:
To a stirred solution of 3.0 g (0.017 mol) of N-(2-fluorophenyl)thiourea in 75 ml of acetone was added an excess of methyl iodide. The reaction was allowed to stir over night. To the solution was then added 20 ml of cyclohexane; a white solid crystallized and was collected by filtration to yield 4.3 g of N-(2-fluorophenyl)-S-methylisothiourea.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CN(C)P(N(C)C)(N(C)C)=O>C(OCC)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: Cc1c(O)cccc1Br
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: Cc1c(Br)cccc1OC12CC3CC(CC(C3)C1)C2
Temperature: 250 °C

Procedure:
3-Bromo-2-methylphenol (1000 mg) and 1-bromoadamantane (2013 mg) were added to hexamethylphosphoramide (8 mL) and the mixture was heated in a microwave reactor (Biotage) at 250° C. for 35 minutes. The solution was taken up in diethyl ether, washed with water two times, washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 2% ethyl acetate (hexanes) increasing to 5% ethyl acetate (hexanes) to yield the title compound.
Reaction SMILES: NN.O=[C:4]1[C:12]2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.[CH2:43](O)C>>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:4]([CH3:43])[CH3:12])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:18]=2[C:23]=1[CH3:24]
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Reactant: CCO
Agent: NN
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.47 mL, 15 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide (2.8 g, 5.0 mmol) in ethanol (50 mL). After two hours, a solid was isolated by filtration and the filter cake was washed with ethanol. Acetone (25 μL) and methanol (25 mL) were added to the solid and the mixture was stirred overnight. The volatiles were removed under reduced pressure to afford a solid that was triturated with 1 M aqueous sodium hydroxide (10 mL) and 1:1 methanol/acetone (4 mL). The solid was isolated by filtration, washed with water, and dissolved in chloroform (100 mL). The solution was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1.9 g of a N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[CH:10][C:9]=2[CH:8]=[C:7]([O:23][CH3:24])[CH:6]=1)=O.[Li]>C1COCC1>[F:22][C:16]1[CH:15]=[C:14]([C:11]2[O:12][C:13]3[C:5]([CH2:3][OH:2])=[CH:6][C:7]([O:23][CH3:24])=[CH:8][C:9]=3[CH:10]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc(OC)cc2cc(-c3ccc(OC)c(F)c3)oc12
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(CO)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 72.9 %

Procedure:
Fluoro ester 40 (1.00 g, 3.63 mmole), was dissolved in 40 mL THF and stirred under nitrogen. To this solution was added lithium aluminumhydride (1M in THF, 3.81 mL, 3.81 mmole) dropwise over fifteen minutes. After stirring at rt for one half hour, the solvent was removed and the mixture was poured into 2N HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 4:1) to afford 0.800 g (73%) of benzyl alcohol 41 as a tan solid: Mp=128-130° C.; 1H NMR (DMSO-d6) δ 7.78 (dd, 1 H, J=12.5 Hz, 2.0 Hz), 7.69 (dd, 1 H, J=8.7 Hz, 1.1 Hz), 7.29 (t, 2 H, J=8.1 Hz), 7.01 (d, 1 H, J=2.5 Hz), 6.90 (d, 1 H, J=2.5 Hz), 5.37 (br s, 1 H), 4.81 (d, 2 H, J=3.1 Hz), 3.90 (s, 3 H), 3.81 (s, 3 H); MS 303 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C)nc1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)acrylate (60.36 g) was hydrogenated in ethanol at 35° and 355 kPa using palladium-on charcoal catalyst (10%, 1.0 g). The mixture waas filtered and the filtrate was evaporated to give ethyl 3-(6-methyl-3-pyridyl)propionate as an oil.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([S:12](Cl)(=[O:14])=[O:13])[CH2:3][CH2:2]1.[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1>>[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37][S:12]([N:4]3[CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[O:1][CH2:2][CH2:3]3)(=[O:14])=[O:13])[C:28]([N:30]3[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: O=S(=O)(Cl)N1CCOc2ccccc2C1
Product: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)N2CCOc3ccccc3C2)CC1

Procedure:
This compound was prepared from 200 mg of 2,3-dihydro-5H-benzo[f][1,4]oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 80 mg (oil), (+)-FAB-MS: 530 (MH+).