Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:29]=[N:30][CH:31]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: COc1cncc(B(O)O)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.15 mmol), 5-methoxypyridin-3-ylboronic acid (0.028 g, 0.18 mmol), Pd(dba)2 (0.02 g, 0.035 mmol), X-Phos (0.02 g, 0.042 mmol) and Na2CO3 (0.032 g, 0.3 mmol) in dioxane/H2O (20 mL/2 mL) was stirred at 95° C. for 18 h under N2 atmosphere. The solvent was removed in vacuo and the residue purified by chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to give 6-(5-methoxypyridin-3-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.03 g, 49%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.28 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.49 (t, 1H, J=7.9 Hz), 6.34 (d, 1H, J=7.8 Hz), 6.17 (d, 1H, J=7.8 Hz), 4.31-4.27 (m, 1H), 4.01 (s, 3H), 3.68-3.63 (m, 1H), 3.51-3.43 (m, 1H), 2.20-2.07 (m, 3H), 1.81 (brs, 1H), 1.23 (d, 3H, J=6.0 Hz). LC/MS: 402 [M+H]+, tR=1.73 min. HPLC: 99.91% at 214 nm, 99.92% at 254 nm, tR=5.59 min.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:19][C:20](=[O:37])[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32](C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].ClC(OC)=O.O>Cl.O1CCOCC1>[CH3:32][O:31][C:30](=[O:36])[NH:29][C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C@H:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:37]
Reactant: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Agent: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-butyl (S)-1-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-1-oxo-3-phenylpropan-2-ylcarbamate, 8, (0.460 mg, 0.881 mmol) is dissolved in a solution of 4M hydrogen chloride in 1,4-dioxane (4 mL). The reaction mixture is stirred 1 hour, and the solvent is removed under reduced pressure. The resulting crude amine is dissolved in CHCl3 (8 mL) and pyridine (1 mL) is added. The temperature is cooled to 0° C. and methyl chloroformate (0.083 g, 0.881 mmol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 2 days. Water is added, the solution stirred for 15 minutes and then extracted several times with CHCl3. The combined organic layers are washed with 1N HCl, 5% NaHCO3, and brine, dried over Na2SO4, and filtered. The solvent is removed in vacuo to afford 0.297 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+].[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH2:11][CH2:10][CH2:9]2
Reactant: O=[N+]([O-])c1cccc2cccnc12
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cccc2c1NCCC2
Yield: 79.4 %

Procedure:
A mixture of 8-nitroquinoline (1.035 g, 5,94 mmol) and platinum oxide (35 mg, 0.15 mmol, 2.5 mol %) in glacial acetic acid was hydrogenated (20 psi) on a Parr Shaker at room temperature for 20 hours. The mixture was filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate to afford a red oil. The oil was dissolved in a mixture of CH2Cl2 (25 mL) and saturated aqueous NaHCO3 (10 mL) and a 10 M aqueous solution of sodium hydroxide was added dropwise until the aqueous phase was basic (pH ˜14) to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed once with water (10 mL), dried (Na2SO4), and concentrated. The residue was filtered (100:1 CH2Cl2-CH3OH) through a short pad of silica gel (30 g) and afforded 0.699 g (79%) of 8-amino-1,2,3,4-tetrahydroquinoline as an oil. 1H NMR (CDCl3) δ 1.89-1.97 (m, 2H), 2.79 (t, 2H, J=6.3 Hz), 3.34 (t, 2H, J=5.4 Hz), 3.20-3.60 (br signal, 3H, NH & NH2), 6.55-6.64 (m, 3H); 13C NMR (CDCl3) δ 22.79, 27.44, 42.98, 114.50, 118.47, 121.56, 123.70, 134.24 (2 carbons).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH:15]2[CH2:16][CH2:17][CH2:18]2)[CH3:14])[N:12]=1
Reactant: CN(C)C=O
Reactant: CN(c1cncc(Cl)n1)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reaction time: 0.33 h
Yield: 66 %

Procedure:
Phosphoryl chloride (4.3 mL) was added dropwise to DMF (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 6-chloro-N-cyclobutyl-N-methylpyrazin-2-amine (4.61 g) in DMF (5 mL), and the mixture was stirred at 50° C. for 15 hr. Water was added to the reaction mixture and the mixture was stirred for 2 hr and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) and recrystallized from hexane-diisopropyl ether to give the title compound (3.46 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[OH-].[Na+].O>CN(C)C=O>[CH2:20]([O:11][C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(O)cc1
Yield: 99.6 %

Procedure:
A solution of N-tert-butoxycarbonyl-2-(4-hydroxyphenyl) glycine (9.18 g.), phenacyl bromide (6.86 g.) and sodium hydroxide (1.37 g.) in N,N-dimethylformamide (100 ml.) was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water (500 ml.) and extracted three times with every 50 ml. portions of ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to give an oily N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine phenacyl ester (13.19 g.).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17]C(=O)[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[K+].CCOC(C)=O>CCO>[F:1][C:2]([F:42])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:17])[C@@H:14]([NH:15][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=2[C:30]2[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[CH:32][C:31]=2[O:39][CH3:40])[CH3:41])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
To a solution of (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (147.7 mg, 0.239 mmol) in EtOH (7.5 mL) was added H2O (1.5 mL) and KOH (150 mg, 2.67 mmol). The solution was heated to 75° C. for 30 h and then cooled to room temperature. EtOAc (75 mL) was added and the organic layer was washed with H2O (15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to afford (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol. Rf=0.44 (40% EtOAc/hexanes). LCMS=594.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 6.93-7.78 (m, 9H), 3.51-4.20 (m, 6H), 2.91 (m, 1H), 2.49 (m, 1H), 1.22-1.26 (m, 6H), 0.79-0.81 (m, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13].FC(F)(F)C(O)=O>>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1

Procedure:
The title compound was prepared by a similar method to Example 8 from tert-butyl (2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinecarboxylate [see Preparation 14] and trifluoroacetic acid, to afford (2S)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-2-piperidinecarboxamide as a gum.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[C:27]1([CH:33]2[CH2:35][O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl([O-])(=O)(=O)=O.[Li+].[NH4+].[Cl-]>C(#N)C.CCOCC>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:19][Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[CH2:23][CH3:24])([C:15]([F:16])([F:17])[F:18])[C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=1)[CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:35][OH:34])[CH3:2]
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Reactant: c1ccc(C2CO2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Product: CCN(c1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1)C(CO)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of 4 g (10 mmol) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine (example 1.1) in 12 mL of acetonitrile was treated with 2.3 mL (20 mmol) of racemic phenyloxirane and 2.12 g (20 mmol) of lithiumperchlorate. The mixture was stirred overnight at 80° C. in a sealed tube. The crude was distributed between saturated aqueous NH4Cl and Et2O and the combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 9:1 yielded 3.5 g (66%) of 2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-2-phenyl-ethanol, light yellow oil, MS: 522 (MH+) and 0.475 g (9%) of 2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-1-phenyl-ethanol, light yellow oil, MS: 522 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[F:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:5]([B:19]([OH:22])[OH:20])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COB(OC)OC
Reactant: COc1cc(F)c(C(C)C)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (2.61 g, 8.88 mmol) in THF at −78° C., n-butyl lithium (2.5 M, 4.26 mL, 10.65 mmol) was added dropwise. The solution was stirred at −78° C. for 30 min. Trimethyl borate (2.98 mL, 26.6 mmol) was added. The solution was then stirred at −78° C. for 3 h. The reaction was quenched at −78° C. with saturated NH4Cl and the mixture was warmed to room temperature. The organic was extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine and dried over Na2SO4. The title compound was obtained as a solid pure enough for next step. Further purification with silica gel caused decomposition of product. 1H NMR (CDCl3, 500 MHz) δ 7.74 (d, J=10.0 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H), 3.20 (m, 1H), 1.22 (m, 6H).
Reaction SMILES: C1([O:6][C:7](=[O:40])[C@@H:8]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:38])[NH:36][OH:37])[CH:22]=2)=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)CCCC1.[OH-].[Na+]>C1COCC1>[OH:37][NH:36][C:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]([NH:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:40])=[O:6])=[O:18])=[O:39])=[O:38]
Reactant: O=C(CCCCCCC(=O)Nc1cccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)c1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCC(=O)Nc1cccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1)NO
Yield: 70.9 %

Procedure:
Compound (94) (100 mg, 0.18 mmol) was dissolved in THF (1 ml) and 2M NaOH (1 ml) added. The reaction vial was shaken for 4 h before THF removal via a stream of nitrogen. The aqueous residue was purified by preparative HPLC to yield compound (95) (62 mg). LCMS purity 95%, m/z 486 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.35 (4H, m, 2×CH2), 1.55-1.75 (4H, m, alkyl), 2.10 (2H, t, CH2), 2.35 (2H, t, CH2), 2.95 (2H, dd, CH), 3.20 (1H, dd, CH), 4.45 (1H, dd, NHCHCO), 5.00 (2H, s, CH2), 7.05 (1H, d, Ar), 7.20-7.35 (6H, m, Ar), 7.55 (2H, m, Ar).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].CN1C(=O)CCC1.O.[OH-].[Li+]>O>[C:16]([C:17]1[S:18][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[NH2:7])([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1N
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
Equip a 22-L, 3-necked, round-bottom flask with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, charge with 1.20 kg (5.55 mole) of 2-nitro-4-trifluoromethylbenzonitrile, 589.3 g (496 mL, 5.55 mole) of methyl thioglycolate, and 4.3 L of NMP. Cool the resulting yellow solution to 2° C., and add slowly, over a period of 78 min a solution prepared from 466.0 g (11.11 mole, 2.0 eq) of lithium hydroxide monohydrate in 3.36 L of water while maintaining the temperature between 2–20° C. Allow the brown slurry to warm to 21° C. over a 2 h period, and then dilute with 8.0 L of water (observe exotherm->27° C.). Stir for 40 min and cool to 18° C., collect the product by filtration, rinsing with 10 L of water, then air-drying at ambient temperature to give 1.295 kg (84.7% yield) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene, as a light-yellow solid, 99.8% pure by HPLC assay.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH2:31][CH3:32]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[O:14]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:13]([C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])[OH:14])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=Cc1c(F)cccc1F
Product: OC(c1cnc(Cl)nc1Cl)c1c(F)cccc1F
Yield: 88 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 2,6-difluorobenzaldehyde (Aldrich) in 88% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.35 (m, 1H, 7.92 (m, 2H), 6.35 (s, 1H), 2.67 (br. s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:14]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]2)[C:6]2=[C:7]3[S:13][CH:12]=[CH:11][C:8]3=[N:9][CH:10]=[C:5]2[N:4]=1.[CH3:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([N:14]2[C:6]3=[C:7]4[S:13][CH:12]=[CH:11][C:8]4=[N:9][CH:10]=[C:5]3[N:4]=[C:3]2[CH2:2][N:28]([S:25]([CH3:24])(=[O:26])=[O:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:16][CH2:17]1)#[N:23]
Reactant: N#CC[C@H]1CC[C@H](n2c(CCl)nc3cnc4ccsc4c32)CC1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of {trans-4-[2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile (from example 17, 22.2 mg, 0.0644 mmol) dissolved in N,N-dimethylformamide (0.2 mL) was added tert-butyl (methylsulfonyl)carbamate (19 mg, 0.096 mmol) and potassium carbonate (18 mg, 0.13 mmol). The reaction was stirred at 50° C. overnight. The mixture was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl ({1-[trans-4-(cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C23H30N5O4S2 (M+H)+: m/z=504.2. Found: 504.1. This crude intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.1 mL) at room temperature for 30 min, and then the solvent was removed in vacuo. The residue was then dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (9.5 mg, 36%). LCMS calculated for C18H22N5O2S2 (M+H)+: m/z=404.1. Found: 404.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:3][CH:2]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].N.CO.CCOC(C)=O>ClCCCl.CCCCCC>[CH3:14][S:15]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1-c1ccncc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CS(=O)(=O)Nc1ccccc1-c1ccncc1
Temperature: 50 °C
Yield: 66.7 %

Procedure:
A solution of 2-(4-pyridyl)phenylamine (Step b) (500 mg, 2.9 mmol) in 1,2-dichloroethane (35 mL) was stirred magnetically under N2 in a 100 mL round-bottomed flask at 25° C. The solution was treated with TEA (Aldrich) (400 μL, 2.9 mmol) followed by methanesulfonyl chloride (Aldrich) (230 μL, 335 mg, 2.9 mmol). The vessel was heated in a 50° C. oil bath for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (100 mL) and satd NaHCO3 (50 mL). The organic layer was washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford a yellow oil. To the oil was added 5:25:75 1 M NH3/MeOH:EtOAc:hexane (10 mL). A yellow precipitate formed which was collected by filtration and dried in vacuo at 40° C. to afford the title compound as a yellow solid (480 mg). MS (ESI, pos. ion) m/z: 249 (M+1); (ESI, neg. ion) m/z: 247 (M−1). Calc'd for C12H12N2O2S: 248.30.
Reaction SMILES: [N+:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1)([O-])=O>CCO.[Pd]>[O:8]1[C:7]2([CH2:12][CH2:13][CH2:14][C@H:5]([CH2:4][NH2:1])[CH2:6]2)[O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])C[C@H]1CCCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: NC[C@H]1CCCC2(C1)OCCO2
Reaction time: 19 h
Yield: 102.5 %

Procedure:
A solution of (S)-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (5.00 g, 24.9 mmol) in EtOH (150 mL) in a 1000 mL Parr bottle was flushed with nitrogen before Pd/C (1.32 g, 1.24 mmol) was added in one portion under nitrogen. The reaction flask was evacuated, charged with hydrogen (56 psi), and shaken for 19 h on the Parr shaker. The reaction mixture was filtered through celite under a stream of nitrogen, and the filtrate was concentrated to afford the crude title compound (4.37 g, 103% crude yield) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][CH:5]=1)=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][CH:2]([OH:3])[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][CH:5]=1
Reactant: CC(=O)C1=CCCC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)C1=CCCC(C)(C)C1
Yield: 84.6 %

Procedure:
A solution of 1-(5′,5′-dimethylcyclohex-1′-enyl)ethanone (13.1 g, 85.8 mmol) in Et2O (50 ml) was added dropwise with stirring within 50 min. to a suspension of LAH (895 mg, 23.6 mmol) in Et2O (150 ml). The reaction mixture was refluxed for 1 h prior to quenching at 0° C. by careful addition of water (50 ml) followed by 5 N aq. HCl (50 ml). The organic layer was separated and the aqueous one extracted with Et2O. The combined ethereal solutions were washed with water and brine, dried (Na2SO4), and concentrated in a rotary evaporator. Silica-gel FC (pentane/Et2O, 9:1, Rf=0.14) of the resulting residue (14.7 g) gave 11.2 g (85%) of 1-(5′,5′-dimethylcyclohex-1′-enyl)ethanol.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.IC(C)C.[OH:16][C@H:17]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33](=[O:34])[CH2:32][O:31][C@@H:30]2[CH2:35][CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([OH:45])=[O:44])=[CH:40][CH:39]=2)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[OH:16][C@H:17]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:33](=[O:34])[CH2:32][O:31][C@@H:30]2[CH2:35][CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([O:45][CH:3]([CH3:4])[CH3:2])=[O:44])=[CH:40][CH:39]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@H](O)c1ccc(N2C(=O)CO[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CC(C)I
Product: CCCCC[C@H](O)c1ccc(N2C(=O)CO[C@@H]2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Reaction time: 72 h
Yield: 72.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.5 μL, 0.037 mmol) and 2-iodopropane (65 μL, 0.65 mmol) were added to a solution of acid 12i (8 mg, 0.019 mmol) in acetone (0.19 mL) at rt under nitrogen. After 3 d at room temperature, the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (1 mL), acidified with 1.0 N HCl (1 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on 4 g silica (hexanes→EtOAc, gradient) afforded 6.5 mg (74%) of 12j.