Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:32]1([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (90 mg, 0.276 mmol) (Example 11b) in chloroform (2 mL) was added triethylamine (0.115 mL, 0.827 mmol) followed by benzoyl chloride (0.053 mL, 0.414 mmol). The reaction mixture was stirred at room temperature for 1 hr. A saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone (45 mg, 0.128 mmol, 46.3% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.44-7.50 (m, 3H), 7.36-7.43 (m, 2H), 7.20-7.28 (m, 2H), 7.10-7.17 (m, 1H), 7.03-7.09 (m, 2H), 4.66 (d, J=12.88 Hz, 1H), 3.74 (d, J=12.63 Hz, 1H), 3.03-3.22 (m, 1H), 2.87 (t, J=12.51 Hz, 1H), 2.66 (dd, J=3.03, 6.32 Hz, 2H), 2.22-2.37 (m, 1H), 1.80-2.05 (m, 3H), 1.74 (d, J=13.14 Hz, 1H), 1.12-1.40 (m, 2H), 1.09 (dt, J=4.86, 9.47 Hz, 1H), 0.98-1.05 (m, 1H); LC-MS Rt=0.81 min; MS (ESI): 335.3 [M++H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[CH2:24]([C@@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:14]1[CH2:15][CH2:16][C:11]2([O:10][C:9]3[C:19]4[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=3[S:18][CH2:17]2)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)Cc3ccccc3)CC2)CS1

Procedure:
Compound 204 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H), 2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H), 1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])=O.[CH:13]([O-:15])=O.[NH4+:16].[OH-].[Na+]>C(O)=O>[CH3:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[CH:13][O:15][CH:2]=1
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: Cc1cc(O)ccc1C(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Cc1cc(O)ccc1-c1cocn1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone (18 g, 78 mmol), ammonium formate (17 g, 273 mmol) in formic acid (100 ml) was heated at reflux temperature for 3 hours. The mixture was cooled down to room temperature and made basic by addition of 50% NaOH aqueous solution at 0° c. The whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (1.8 g, 13% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Cl)nc[nH]1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1cnc(Cl)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 6-chloropyrimidin-4(3H)-one (5 g), methyliodide (2.6 mL) and K2CO3 (10.6 g) in acetone (100 mL) is stirred at room temperature over night. The mixture is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and concentrated. The residue is triturated with diisopropylether to give the title compound. Yield: 5.1 g; LC (method 11): tR=0.25 min; Mass spectrum (ESI+): m/z=145 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)cn1

Procedure:
Following the procedure of Example 1, 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.54 g. of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone were dissolved in 50 ml. of ethanol and the resulting solution heated at reflux temperature for about 1 week. The solvent was removed by evaporation and the residue purified by gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing the desired pyrimidone were combined and the solvents removed from the combined fractions. The resulting residue was crystallized from ethyl acetate to yield 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methoxy-3-pyridyl)methyl-4-pyrimidone melting at 137°-8° C.
Reaction SMILES: [C:1]([NH2:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CN(C)C=O>O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:10])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C#N

Procedure:
A mixture of anthranilamide (11.8 g), potassium carbonate (20 g), ethyl bromoacetate (18 g) and dimethylformamide (50 mL) was heated at reflux for 40 min. The reaction mixture was diluted with water and the product was extracted with ether. The organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from ethanol to afford N-(2-Cyanophenyl)glycine ethyl ester as a colorless solid.
Reaction SMILES: [CH2:1]1[N:9]2[C:5](=[N:6][C:7]([NH:10]C(C(F)(F)F)=O)=[CH:8]2)O[CH:3]=[C:2]1[Br:17].[CH2:18]1COCC1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Br:17][C:2]1[CH:3]=[CH:18][C:5]2[N:9]([CH:8]=[C:7]([NH2:10])[N:6]=2)[CH:1]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1cn2c(n1)OC=C(Br)C2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cn2cc(Br)ccc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a 250 mL round-bottomed flask was added N-(6-bromoH-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (3.50 g, 11 mmol), THF (15 mL), methanol (15 mL), water (15 mL) and potassium carbonate (16 g, 114 mmol). The mixture was stirred at 60° C. for 16 h. After cooling to rt, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (4×75 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH/CH2Cl2) afforded the title compound (1.01 g, 42%). MS (ESI, positive ion) m/z: 212 (M(79Br)+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][CH2:28][C:29](OC)=O)=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[NH:18]1[CH2:19][CH2:20][CH:21]([N:24]2[CH:29]=[CH:28][NH:27][C:25]2=[O:26])[CH2:22][CH2:23]1
Reactant: COC(=O)CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1[nH]ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M, 0.875 μL, 0.875 mmol) was added to a solution of methyl N-{[(1-(tert-butoxycarbonyl)piperidin-4-yl)amino]carbonyl}glycinate (230 mg, 0.729 mmol) in toluene (5 μL) and dichloromethane (5 mL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 30 min at room temperature, the reaction was quenched with 1 N saturated potassium sodium tartrate solution (15 mL) and extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, concentrated. The crude material was dissolved in dichloromethane (10 μL) and treated with trifluoroacetic acid (5 mL). After 25 min, the reaction was concentrated to give the title compound. MS 168.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=[O:20])[N:17]([CH3:19])[NH:18][C:11]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH:43](O)[CH2:44][CH2:45][CH3:46].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([O:20][CH:43]([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Reactant: CCCC(O)CCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 200 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydro-pyrazolo[3,4-b]pyridin-3-one (Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of dry tetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg of diethylazodicarboxylate. The mixture was stirred under an atmosphere of nitrogen at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel eluting with 15% ethyl acetate/hexane to afford 84 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine as a colorless oil: ms (MH+)=390.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[CH2:7][CH:8]=[CH2:9].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:6]([C:10]1([CH2:23][O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CCCC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Ms-Cl (5.59 mL, 71.7 mmol) was added dropwise at 0° C. to a stirred solution of tert-butyl 4-(but-3-en-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (16.1 g, 59.8 mmol) TEA (16.66 mL, 120 mmol) and DMAP (0.365 g, 2.99 mmol) in CH2Cl2 (300 mL) and the mixture was stirred at room temp for 2 h. Water was then added and the mixture was extracted with methylene chloride (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage (0-40% Hex/EtOAc) to afford tert-butyl 4-(but-3-en-1-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (18 g, 51.8 mmol, 87% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.88-5.75 (m, 1H), 5.11-4.90 (m, 2H), 4.09 (s, 2H), 3.58-3.44 (m, 2H), 3.40-3.32 (m, 2H), 3.05 (s, 3H), 2.07-2.02 (m, 2H), 1.59-1.54 (m, 2H), 1.53-1.49 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@:8]1([C:18]([OH:20])=[O:19])[C@@H:13]([F:14])[CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([OH:17])=[O:16])=[O:6])[CH:2]=[CH2:3].[CH2:21](O)[CH:22]=[CH2:23].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl>[CH2:23]([O:16][C:15]([C@@H:10]1[C@@H:9]2[C@H:11]1[CH2:12][C@H:13]([F:14])[C@@:8]2([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:18]([OH:20])=[O:19])=[O:17])[CH:22]=[CH2:21]
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Reactant: C=CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCC=C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of a mixture of (1S,2S,3S,5R,6S)-2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 1.41 g), allyl alcohol (336 μL), N,N-diisopropylethylamine (837 μL) and N,N-dimethylaminopyridine (60 mg) in chloroform (30 mL) was cooled to 0° C. To this solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (837 mg) was added, and then the mixture was heated to room temperature and stirred for 2 days. To the reaction solution, chloroform was added, and the organic layer was washed twice with 0.25 mol/L hydrochloric acid, once with water, and once with brine, sequentially. After the organic layer was dried over anhydrous magnesium sulfate, the insoluble was filtered and the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-6-((allyloxy)carbonyl) 2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2-carboxylic acid (B-1-1, 1.30 g) as a colorless amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1.Br[C:24]1[CH:25]=[C:26]([CH:31]([OH:33])[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:30][C:29]1[CH:28]=[CH:27][C:26]([CH:31]([OH:33])[CH3:32])=[CH:25][C:24]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: CC(O)c1ccc(F)c(Br)c1
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C(C)O)ccc4F)cn3)c2c1

Procedure:
Synthesized from methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (1.0 g, 2.65 mmol) and 1-(3-bromo-4-fluorophenyl)ethanol (0.87 g, 3.98 mmol) analogously to the experimental procedure 289a). Yellow solid. Yield: 1.0 g (89% of theory)
Reaction SMILES: CC(O)=O.OS(O)(=O)=O.[CH2:10]([N:12]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)[CH3:11].ClC[C:37]([NH:39]CO)=O>O>[NH2:39][CH2:37][C:21]1[CH:20]=[C:19]([CH:16]2[CH2:17][CH2:18][CH:13]([N:12]([CH2:10][CH3:11])[CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)c(CN)c2)CC1
Temperature: 10 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A mixture of HOAc and H2SO4 (1 mL, 9:1, v:v) was cooled to 10° C. 4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (200 mg, 0.53 mmol) and 2-chloro-N-(hydroxymethyl)acetamide (66 mg, 0.53 mmol) were added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured onto ice (1 g) and water (10 mL) was added. After concentration under reduced pressure, a mixture of EtOH and HCl (6.5 mL, 10:3, v:v) was added, and the mixture was heated under reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10:0.5 CH2Cl2:MeOH:NH4OH), followed by formation of the HCl salt, gave 2-aminomethyl-4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (65 mg, 28%), as a yellow solid: mp 168-173° C.; IR (KBr): 2940, 1510, 1453 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br s, 1H), 9.96 (s, 1H), 8.1 (br s, 2H), 7.35-7.17 (m, 6H), 7.06 (dd, J=8 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 3.90 (br d, J=5 Hz, 2H), 3.45-2.98 (m, 4H), 2.71-2.65 (m, 2H), 2.52-2.39 (m, 2M), 2.19-2.10 (m, 2H), 2.10-2.05 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.49 (m, 4H), 1.27 (t, J=7 Hz, 3H) API-MS (methane) (m/z): 367 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C24H34N2O, 367.2749. found: 367.2741. Anal. Calcd for C24H34N2O.02HCl.H2O: C, 64.93; H, 8.29; N, 6.31. Found: C, 64.90; H, 8.53; N, 6.09.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[C:37](#N)C>O.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:33]([CH3:37])(=[O:35])=[O:32])[N:3]=1
Reactant: O=S([O-])OO
Reactant: CC#N
Reactant: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round-bottomed flask was added (S)-4-amino-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (200 mg, 0.477 mmol) in acetonitrile (5418 μL) and water (5418 μL). The mixture was cooled to 0° C. Oxone® (733 mg, 1.192 mmol) was added to give an orange solution. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature. After 2 h, LCMS showed the reaction to be complete. The reaction mixture was subsequently diluted with EtOAc and washed with brine (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C20H21N9O2S, 452.15; found 452.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20]C(O)=O)#[N:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[CH:20][C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
3,5-di tert.butyl-4-hydroxycinnamonitrile was prepared by heating a mixture of 85.5 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 62 grams of cyanoacetic acid, 360 milliliters of pyridine, and 18 milliliters of piperidine at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and poured into a mixture of 200 milliliters of concentrated hydrochloric acid and 350 grams of ice. The sticky solid tht precipitated was separated and recrystallized from petroleum ether. The yield was 48.8 grams of product which melted at 109° to 113° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCc3ccccc3)cc2CC1
Yield: 100 %

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (790 mg, 3 mmol), potassium carbonate (1.24 g, 9 mmol) and catalytic potassium iodide were suspended in 2-butanone (20 ml). Benzyl bromide (536 μL, 4.5 mmol) was added and the mixture heated at reflux for 24 hours. The solids were filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude oil purified by column chromatography, eluting with a mixture of ethyl acetate and hexane (1:4) to afford the title compound (D1) (1.06 g, 100%), 1H NMR (CDCl3) 7.44 (5H, m), 7.03 (1H, d, J 8.1 Hz), 6.77 (1H, s), 6.74 (1H, dd, J 8.1 & 2.4 Hz), 3.49 (4H, m), 2.84 (4H, m), 1.48 (9H, s).
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:9]1.Cl.[O:16]1[C:20]2([CH2:25][CH2:24][CH:23](N3CCOCC3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([N:10]3[CH2:9][CH2:8][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CN(C2CCC3(CC2)OCCO3)CCO1
Reactant: C1CNCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C1COCCN(C2CCC3(CC2)OCCO3)C1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Et3N (96.9 mL, 0.695 mol) was added in one portion to a stirred suspension of homomorpholine hydrochloride (79.76 g, 0.579 mol) and ketone 1 (90.5 g, 0.579 mol) in 1,2-dichloroethane (1.81 L). Then glacial acetic acid (34.8 mL, 0.607 mol) was added in one portion followed by solid NaBH(OAc)3 (154 g, 0.727 mol) in one portion as well. This was accompanied by 5° C. increase in the temperature of the reaction mixture. After 2 h 45 min the reaction was quenched by addition of 10% aqueous NaOH (800 mL). The mixture was stirred for 10 min. The organic layer was separated, washed with brine (100 mL), dried (MgSO4) and concentrated to afford an oil (142.36 g) with some suspended solid, which was filtered off (3.00 g). The aqueous part of the reaction mixture was combined with the brine washings and extracted with AcOEt (4×500 mL). Combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to afford additional portion of oil (16.82 g). The two oily products were combined and distilled in vacuum to give 3 (101.07 g, 72%) as colorless liquid, b.p. 122° C./8.9·10−3 mbar. 1H NMR (400 MHz, CDCl3) δ 1.48-1.64 (m, 4H), 1.70-1.88 (m, 6H), 2.50-2.63 (m, 1H), 2.71-2.81 (m, 4H), 3.66-3.72 (m, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.93 (s, 4H).