Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=O)[NH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([Cl:30])=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24][C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)nc2Cl)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4-(3,4-Dihydro-4-oxo-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate (6.8 g) (18.7 mmol) are dissolved in 150 ml of phosphorus oxychloride. After stirring at 100° C. for 6 hours the mixture is concentrated in a vacuum at 50° C. and the residue is dried in a vacuum. Now, dichloromethane and ice/water are added thereto and, after good intermixing, the dichloromethane phase is separated. After drying over sodium sulphate and distilling off the solvent the product is crystallized from ethanol. The product is filtered off and washed with ethanol/diethyl ether. There are obtained 6 g of 4-(4-chloro-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate as white crystals of m.p. 152°-153° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.C1COCC1.O.CN(C=O)C>[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([CH2:20][O:19][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH2:18][CH:9]([CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:10][CH2:11]4)=[CH:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: COc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(COc3ccc4c(c3)CCC(CCN3CCCCC3)C4)cc2)cc1
Reaction time: 12 h
Yield: 65.2 %

Procedure:
WSCD (0.11 ml) was added to DMF solution (2 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (170 mg), 4-methoxyaniline (53 mg), HOBt (70 mg) and DMAP (60 mg) at room temperature, which was stirred for 12 hours. 10% aqueous potassium carbonate solution and water was added to the reaction mixture, and extraction was conducted using a mixed solution of THF and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (THF-IPE) to give the titled compound (140 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]C(=O)CC#N)=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1.NN>CCO>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:24]2[CH:25]=[C:21]([NH2:20])[NH:22][N:23]=2)=[CH:11][CH:12]=1
Reactant: Nc1cc[nH]n1
Reactant: CN(C)CCCOc1ccc(CC(=O)CC#N)cc1
Agent: NN
Solvent: CCO
Product: CN(C)CCCOc1ccc(Cc2cc(N)[nH]n2)cc1
Temperature: 65 °C

Procedure:
The 4-[4-(3-dimethylamino-propoxy)-phenyl]-3-oxo-butyronitrile is then converted to the appropriate aminopyrazole by the following method: Under Ar(g), 0.285 gms. of the 4-[4-(3-dimethylamino-propoxy)-phenyl]-3-oxo-butyronitrile is dissolved in 5 mL of anhydrous EtOH and then is treated with 0.100 mL anhydrous hydrazine. The reaction mixture is then heated overnight at 65° C., subsequently, cooled to room temperature and concentrated in vacuo providing 5-[4-(3-dimethylamino-propoxy)-benzyl]-2H-pyrazol-3-ylamine which is use in crude form in the reactions of Examples 56 and 57.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([N:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:15]/[C:14]/1=[N:22]\[C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1F)[CH2:10][CH2:11][CH3:12]>C1COCC1>[CH2:9]([N:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:15]/[C:14]/1=[N:22]\[C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:4][CH2:3][C:2]([OH:6])([CH3:5])[CH3:1])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Reactant: CC(C)(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCC(C)(C)O)sc2ccncc21
Reaction time: 4 h
Yield: 35.3 %

Procedure:
The product from Example 21A (91 mg, 1.01 mmol) in THF (2 mL) was treated with NaH (60%) (40.3 mg, 1.01 mmol) at room temperature for 20 minutes. To the above mixture was added the product from Example 20B (200 mg, 0.5 mmol) in THF (2 mL). After 4 hrs, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 82.4 mg (35%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.63 Hz, 3H) 1.38 (s, 6H) 1.48-1.55 (m, 2H) 1.89-1.97 (m, 2H) 4.03 (s, 2H) 4.54 (t, J=7.32 Hz, 2H) 4.62 (brs, 1H) 7.08 (d, J=8.85 Hz, 1H) 7.66 (d, J=4.58 Hz, 1H) 7.70 (dd, J=8.54, 2.14 Hz, 1H) 8.51 (d, J=5.19 Hz, 1H) 8.51 (s, 1H) 8.74 (s, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [CH:1]([N:14]=[C:15]=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:20][C:21](=O)[CH2:22][NH:23][CH3:24])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:14]1[C:21](=[O:20])[CH2:22][N:23]([CH3:24])[C:15]1=[S:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(C(c2ccccc2)c2ccccc2)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 1 using 11.25 g of benzhydryl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chloroform. The title compound was obtained (7.40 g) as an off-white solid, m.p. 139°-141° C. Anal. Calcd. for C17H16N2O S: C, 68.89; H, 5.44; N, 9.45. Found: C, 68.92; H, 5.43; N, 9.58. Mass spectrum (El, M.+) m/z 296.
Reaction SMILES: C(C1NC2C=CSC=2C(O)=N1)C.[CH2:13]([CH:15]1[NH:20][C:19]2=[CH:21][S:22][CH:23]=[C:18]2[C:17]([OH:24])=[N:16]1)[CH3:14]>CS(C)=O>[CH2:13]([CH:15]1[N:16]=[C:17]([OH:24])[C:18]2[CH:19]=[CH:21][S:22][C:23]=2[NH:20]1)[CH3:14]
Reactant: CCC1N=C(O)c2cscc2N1
Agent: CCC1N=C(O)c2sccc2N1
Solvent: CS(C)=O
Product: CCC1N=C(O)c2ccsc2N1

Procedure:
The aqueous filtrate was extracted with four 75 ml portions of chloroform. The organic extracts were washed once with brine, dried (MgSO4) and concentrated under vacuum. The residual oil was diluted with ether (15 ml) and hexane (15 ml). The solid that crystallized was filtered, washed with four 3 ml portions of ether and combined with the solid obtained earlier from the aqueous solution. The 2.3 g of colorless solid was shown by NMR in DMSO to be a 1:1 mixture of 2-ethyl-4-hydroxy-dihydrothieno-[3,2-d]pyrimidine and 2-ethyl-4-hydroxy-dihydrothieno-[3,4-d]pyrimidine.
Reaction SMILES: [CH:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]1[CH:4]=[CH:3][CH2:2]2.N12CCCN=C1CCCCC2.[N+:27]([CH3:30])([O-:29])=[O:28]>Cl>[N+:27]([CH2:30][C:6]1([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH:1]2[CH:5]1[CH:4]=[CH:3][CH2:2]2)([O-:29])=[O:28]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)C=C1CC2CC=CC12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CC1(C[N+](=O)[O-])CC2CC=CC21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl bicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.73 g, 8.39 mmol) was dissolved in nitromethane (10 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then heated with stirring at 50 to 60° C. for 5 hours. The mixture was allowed to cool and then diluted with 1 N hydrochloric acid and saturated saline, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.98 g, 89%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]3[C:11](I)=[N:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:10]=[C:11]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)[C:12]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CCCn3ccnc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.086 g, 0.233 mmol) in ethylene glycol dimethyl ether (4 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.104 g, 0.256 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.059 g, 0.56 mmol) in water (2 mL). The reaction mixture was stirred for 24 h at 80° C. The organic solvent was removed under reduced pressure and dichloromethane (25 mL) was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 10 g ISCO column. The column afforded 0.06 g (49%) of pure N2-(4-{4-amino-1-[3-(1H-1-imidazolyl)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.443 (s, 1H), 8.278 (s, 1H), 8.1324-8.1121 (d, 1H, J=8.12 Hz), 7.744-7.699 (m, 2H), 7.6-7.579 (d, 1H, J=8.4 Hz), 7.365-7.283 (m, 5H), 7.172-7.135 (m, 1H), 6.939 (s, 1H), 4.36-4.326 (m, 2H), 4.079-4.019 (m, 5H), 3.964 (s, 3H), 2.324-2.309 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.25 min (100%), MH+ 522.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[CH:15]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]3)[CH:17]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(C#N)c3)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (3-cyano-4-fluorophenyl)boronic acid (0.983 g, 5.96 mmol) in DME (40 mL) was added 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazinecarboxylate (2.20 g, 5.96 mmol) followed by Na2CO3 (17 mL, 2M in H2O, 34.0 mmol). The reaction vessel was flushed with Ar, and tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.78 mmol) was added. The reaction mixture was placed in an oil bath at 78° C. under Ar for overnight. The reaction was diluted with EtOAc (600 mL) and washed with H2O (250 mL). The water layer was extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (20% EtOAc/80% hexane) on silica gel gave the title compound (1.77 g, 73.1%). EI-MS m/z 410 (M−H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[NH:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:30][C:29]2[CH:31]=[CH:32][C:26]([C:25]([F:24])([F:33])[F:34])=[CH:27][CH:28]=2)=[CH:6][C:5]=1[NH:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(C(F)(F)F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of N-(6-nitro-1-oxo-indan-5-yl)-3-cyclopentyl-propionamide (0.57 g, 1.8 mmol), 4-trifluoromethylaniline (0.35 g, 2.2 mmol), and decaborane (200 mg) in 20 ml of anhydrous methanol was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column (hexane/EtOAc, 5:1) to give a pure product (0.65 g, 90%).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1)=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc2c(c1)OCO2
Yield: 43.5 %

Procedure:
1,2-Methylenedioxybenzene (1.18 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 1.22 g of 6-bromo-1-(3,4-methylenedioxyphenyl)-1-hexanone.
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH3:23])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH3:23])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCCCC(=O)/C=C/c1oc(C)cc(=O)c1OCCCCCC(=O)OCC
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1oc(C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 1.8 g (4.6 mmol) of 2-(3-oxo-trans-1-octenyl)-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone in 20 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 30 ml (4.6 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 3.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.5 g (26%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ0.90 (3H, t, J=4.5 Hz), 2.33 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[NH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]#[N:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:36]([CH2:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])#[N:37]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: N#CCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCC#N)ccc21
Yield: 53.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-cyano-ethoxy)-ethyl]-amide (54 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (60 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 506.0.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.O>C(O)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(OCc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 7.9 grams (0.025 mole) of 8-(3-trifluoromethylphenylmethoxy)-1,4-dioxaspiro[4.5]decane. and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenylmethoxy)cyclohexanone.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH2:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:24]
Reactant: CCc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Yield: 18.7 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-ethylpyrimidine (Intermediate 12, 49.7 mg, 0.349 mmol) and DIPEA (0.122 mL, 0.697 mmol) in N-methyl-2-pyrrolidone (1 mL) were stirred in a microwave reactor at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (0.9 mL) and purified by MDAP (2 injections). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (21 mg);
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:10](=[O:17])[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:26]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[CH2:27][CH2:28][CH2:29][C:30]#[CH:31].C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C.CCCCCC.C(OCC)(=O)C.[Cu]I.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]>[C:21]([O:20][C:19]([NH:18][C@H:9]([C:10](=[O:17])[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][C:26]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:3][CH:4]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C#CCCCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCC#Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (S)-(3-(4-iodophenyl)-1-oxo-1-(piperidin-1-yl)propan-2-yl)carbamate (Compound SP413, Boc-Phe(4-I)-pip) (6.00 g, 13.09 mmol), tert-butyl hex-5-ynoate (Compound SP423) (4.40 g, 26.2 mmol) and triethylamine (5.47 ml, 39.3 mmol) were dissolved in DMF (60.0 ml), CuI (0.125 g, 0.655 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.538 g, 0.655 mmol) were added and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with hexane/ethyl acetate (1/1) and washed with a saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-60:40) to afford the title compound SP425 (6.19 g, 95%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([NH2:28])([CH2:26][CH3:27])[CH3:25].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:28][C:24]([CH2:26][CH3:27])([CH3:25])[CH3:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCC(C)(C)N
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 70 °C
Yield: 51.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48.0 mg, 0.162 mmol) and 2-methylbutan-2-amine (Aldrich; 0.047 mL, 0.405 mmol) in DMSO (1.0 mL), heating 70° C. for 9 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(tert-pentylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30.5 mg, 0.084 mmol, 52% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.51 (1H, br. s.), 7.94 (1H, dd, J=7.5, 0.8 Hz), 7.65 (1H, dd, J=8.1, 0.7 Hz), 7.38 (1H, t, J=7.8 Hz), 7.11 (1H, d, J=2.0 Hz), 5.38 (1H, br. s.), 4.77 (1H, s), 3.66 (2H, td, J=6.8, 1.9 Hz), 2.99 (2H, t, J=6.8 Hz), 2.57 (3H, s), 2.03 (2H, q, J=7.4 Hz), 1.61 (6H, s), 0.97 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 364.2 (M+H)+.