Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:35])[CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[O:25][CH2:24][C:23]3[CH:22]=[CH:21][S:20][C:19]=3[C:18](O)([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[C:17]=2[CH:34]=1.Cl.O1CCOCC1>ClCCl>[CH3:8][O:9][C:10](=[O:35])[CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[O:25][CH2:24][C:23]3[CH:22]=[CH:21][S:20][C:19]=3[CH:18]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[C:17]=2[CH:34]=1
Reactant: COC(=O)CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1sccc1CO2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSc1ccc2c(c1)C(C1CCN(C)CC1)c1sccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a dichloromethane solution of the compound obtained in Example 23 (5.7 g, 14 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give a free compound. Thereafter, 4 mol/L hydrogen chloride-dioxane (8.0 mL, 32 mmol) was added thereto, and the mixture was stirred for 1 hour. The solvents were distilled off under a reduced pressure, and ether was added to the residue to allow crystallization. The precipitated crystals were separated by filtration and dried, to give 4.1 g (69%) of the captioned compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH:2]=[CH2:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C([O-])=O.[CH2:37]([O:40][C:41]1[CH:42]=[C:43]([CH:70]=[C:71]([F:73])[CH:72]=1)[CH2:44][CH:45]([NH3+:69])[CH:46]([OH:68])[CH2:47][N:48]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][CH3:57])[CH:51]=1)[CH:38]=[CH2:39]>C(Cl)Cl.CCOC(C)=O>[CH2:61]([O:60][C:58](=[O:59])[N:48]([CH2:47][CH:46]([OH:68])[CH:45]([NH:69][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5](=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH2:14][CH3:15])[CH2:44][C:43]1[CH:70]=[C:71]([F:73])[CH:72]=[C:41]([O:40][CH2:37][CH:38]=[CH2:39])[CH:42]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][CH3:57])[CH:51]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: C=CCN(CCC)C(=O)CCCC(=O)O
Reactant: C=CCOc1cc(F)cc(CC([NH3+])C(O)CN(Cc2cccc(CC)c2)C(=O)OCc2ccccc2)c1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCOc1cc(F)cc(CC(NC(=O)CCCC(=O)N(CC=C)CCC)C(O)CN(Cc2cccc(CC)c2)C(=O)OCc2ccccc2)c1

Procedure:
A solution of [4-(3-Allyloxy-5-fluoro-phenyl)-3-tert-butoxycarbonylamino-2-hydroxy-butyl]-(3-ethyl-benzyl)-carbamic acid benzyl ester (1.84 g, 3.03 mmol) in 20% TFA/DCM (30 mL) is prepared and stirred for 1 hour. The reaction mixture is concentrated in vacuo yielding a white solid (2.12 g). Peptide coupling is performed by preparing a solution of 4-(allyl-propyl-carbamoyl)-butyric acid (0.060 g, 2.82 mmol) in CH2Cl2 to which is added EDC (0.74 g, 3.84 mmol) and HOBT (0.52 g, 3.84 mmol) under N2, with stirring. To this solution is added a solution of TEA (1.43 mL, 10.24 mmol), 1-(3-Allyloxy-5-fluoro-benzyl)-3-[benzyloxycarbonyl-(3-ethyl-benzyl)-amino]-2-hydroxy-propyl-ammonium trifluoro-acetate (1.59 g, 2.56 mmol) dissolved in CH2Cl2 (15 mL). Upon complete reaction the mixture is diluted with EtOAc, washed with NaHCO3 and then 1N HCl. The mixture is then neutralized with NaHCO3, and then 0.5N NaOH, treated with activated charcoal, dried with MgSO4, filtered, concentrated in vacuo, yielding a yellow oil. Purification is achieved via flash chromatography using 75% EtOAc/Hexanes. Calculated mass for C41H52FN3O6+H1: 702.3918. Accurate mass found for C41H52FN3O6+H1: 702.3916.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1.[OH:22][CH:23]1[CH2:26][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:24][CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of tert-butyl (3-hydroxycyclobutyl)carbamate (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M−tBu+H)+.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[CH:8][CH:7]=1.O>C(#N)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]=2[CH:4]=[CH:3][CH:1]=[O:2])=[CH:8][CH:7]=1
Reactant: C=CC=O
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Use of the crude acrolein coming from Example 3a. To a suspension of 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) phosphorus oxychloride (31.4 g) in acetonitrile (35 ml) cooled at 5° C. a solution of crude acrolein (32.3 g from Example 3a) in acetonitrile (40 ml) is added dropwise in 30 minutes. The reaction mixture is then warmed to 60° C. and kept under stirring at 60° C. for 4 hours; water (300 ml) is added and after 1 hour at 60° C. the formed solid is filtered on Buchner and washed with 75 ml of water. The wet solid (49.7 g) is dissolved in toluene (250 ml), celite (1 g) and charcoal (0.5 g) are added and the mixture is stirred at room temperature for 30 minutes. After filtration of the solid, the solvent is distilled off at reduced pressure and the residue is dissolved at 75° C. with isopropanol (72 ml). The solution is cooled at 20° C. and stirred at room temperature for 1 hour. The precipitate is filtered on Buchner, washed twice with isopropanol (15 ml) and dried at 60° C. under vacuum. 30.2 g (70% molar yield) of the product are obtained.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].O1CCCC1.[CH3:38][NH:39][CH3:40]>>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[N:39]([CH3:40])[CH3:38])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: CNC
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 70 °C
Yield: 96 %

Procedure:
2-Chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (50 mg, 0.10 mmol) was dissolved in 2M dimethylamine in tetrahydrofuran (2 ml, 4 mmol) and heated in a sealed tube at 70° C. for 2 hours. The mixture was allowed to cool to ambient temperature then evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band, followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a white foam (49 mg, 96%). 1H NMR δ (ppm)(CDCl3): 8.18 (1H, d, J=7.7 Hz), 7.65 (1H, s), 7.26 (1H, d, J=7.7 Hz), 3.63 (2H, d, J=6.2 Hz), 2.94-2.89 (9H, m), 2.07-1.81 (6H, m), 1.39-1.31 (2H, m), 1.28-1.14 (3H, m), 0.79-0.67 (3H, m), 0.55-0.49 (2H, m), 0.42 (2H, q, J=5.3 Hz), 0.06 (2H, t, J=4.2 Hz). MS (m/e)=503.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCN)cc34)cc2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a suspension of (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (1.22 g, 2.46 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL) dropwise. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH2Cl2 (30 mL) and aqueous saturated sodium bicarbonate. Phases were separated and the aqueous layer was extracted with CH2Cl2 (30 mL). Organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (0.85 g, 88%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:42])[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:33](=[O:42])/[CH:34]=[CH:35]/[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)/C=C/c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D25(iii) in pyridine (4 mL) was added cinnamoyl chloride (141 mg, 845 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (108 mg, 56%) as pale-yellow crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:15]1[C:16]2[CH2:39][NH:38][CH2:37][CH2:36][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:15]1[C:16]2[CH2:39][N:38]([C:1](=[O:3])[CH3:2])[CH2:37][CH2:36][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(C)=O)CC3)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Acetic anhydride (0.039 mL, 0.41 mmol) was added to a solution of 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (175 mg, 0.41 mmol, example 109) in THF (3 mL) and stirred for one hour. The solvent was evaporated under reduced pressure and the crude product purified on prepHPLC yielding 1-(4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (64.0 mg, 33.3%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.CO.[NH3:15].N.CO>C(Cl)Cl>[NH2:15][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: N
Reactant: COc1cc(CBr)ccc1C#N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN)ccc1C#N
Reaction time: 2 h

Procedure:
2.5 g of the bromide (b) were introduced into 10 ml of MeOH, and NH3 was passed in during dropwise addition of 38 ml of conc. ammonia/MeOH 1:1. After 2 h, the solvent was stripped off, the product was taken up in DCM and washed with water, and the organic phase was dried over Na2SO4. The product was precipitated as hydrochloride with ethereal HCl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: BrCCCBr
Reactant: Oc1c(F)cccc1F
Product: Fc1cccc(F)c1OCCCBr

Procedure:
Analogously to Example 91b. 2.00 g of 2,6-difluorophenol and 30.7 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.70 (1:6 EtOAc-heptane); Rt=4.97.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:14])[F:15])=[CH:7][CH:8]=1)=[O:21]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Nc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)ccn1
Yield: 29 %

Procedure:
The title compound is prepared in 29% yield (182 mg, a white solid) from (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (473 mg, 1.95 mmol) and 2-aminoisonicotinic acid (269 mg, 1.95 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: N(C(C)=O)(CNC(C)=O)CNC(C)=O.C=O.O.[C:18]([OH:21])(=[O:20])[CH3:19].N(CC(O)=O)CC(O)=O.[C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:33])[CH3:32]>COCCOC>[C:31]([N:34]([CH2:35][C:36]([OH:38])=[O:37])[CH2:19][C:18]([OH:21])=[O:20])(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(=O)NCC(=O)O
Agent: C=O
Agent: CC(=O)NCN(CNC(C)=O)C(C)=O
Agent: O=C(O)CNCC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 91 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (10.8 g, 0.60 mole), acetic acid (16.8 g, 0.28 mole, 0.19 g/mL of DME), DME (90 mL) and Co2(CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 125° C. for 30 min. HPLC analysis of this stream indicated a 91% yield of (XVI), 1% (XIV), and 3% (XVIII).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[CH:19]=2)[C:15](=[O:30])[CH2:14][CH2:13][CH2:12]1.C1C(=O)N([Cl:38])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[Cl:38][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH:11]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[C:26]([CH3:29])[S:27][CH:28]=4)[CH:19]=3)[C:15](=[O:30])[CH2:14][CH2:13][CH2:12]2)[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6-(2,6-dimethoxyphenyl)-1-(3-(2-methylthiazol-4-yl)benzyl)piperidin-2-one (60 mg; 0.14 mmol; compound corresponding to example 16), and NCS (21 mg; 0.15 mmol) in anh. DMF (1.5 ml) was stirred at rt, under nitrogen, for 24 h. Water (5 ml), and AcOEt (10 ml) were added, and the separated organic layer was washed with brine (5 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])CC1C2C(=CC=CC=2)NC=1)=[O:7])([CH3:4])[CH3:3].[NH2:23][C@H:24]([C:29]([N:31]([CH3:43])[C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].ClC(OCC(C)C)=O.CN1CCOCC1>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:40][C:32]1[NH:31][C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:33]=1)=[O:7])([CH3:1])[CH3:3].[NH2:23][C@H:24]([C:29]([N:31]([CH3:43])[C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[C@H](N)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Yield: 78 %

Procedure:
Condensation of Boc-trp-OH (1.81 g.) and H-Leu-MePhe-NH2 and H-Leu-Mephe-NH2 (mixture of isomers) hydrochloride salt (1.95 g.) by the mixed anhydride method using isobutyl chloroformate (813 mg.) and N-methylmorpholine (two 685 mg. portions) in tetrahydrofuran (35 ml.) at -20° C. for 20 min. and then at room temperature briefly, isolation by ethyl acetate extraction, and purification by filtration through silica gel with ethyl acetate gave Boc-trp-Leu-MePhe-NH2 and Boc-trp-Leu-Mephe-NH2 (mixture of isomers) as white foam (2.70 g., 78% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH2:18][C:19](=[O:22])[CH2:20][CH3:21].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (7.1 g, 0.03 M) was reacted with 1-bromo-2-butanone (5 g) and triethylamine (4.2 ml) in ethyl ether (25 ml) by the method of Example 8 to give the title compound, m.p. ca. 55-57° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])=[CH:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][C:4]([CH3:18])=[CH:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: Clc1ccccn1
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)=CCOc1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (0.13 g) in 5 ml of THF and 5 ml of HMPA, cooled in an ice bath, is added, dropwise, 2-[4-(3-methyl-2-butenoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 1 hour, after which 2-chloropyridine (0.61 g) is added and the mixture is stirred at 60° for 2 hours. The solvent is removed by rotoevaporation. The residue is taken up in ether, washed with water, dried and concentrated, and the remaining oil is purified by column chromatography to give 2-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethoxy}pyridine, MS m/e 300 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0 ° C. was treated with ] .OM BH3THF (50 mL), stirred overnight at room temperature, treated with an additional 130 mL 1.0 M BH3THF, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, the product partitioned between aqueous sodium bicarbonate/methylene chloride, the organic layer dried (sodium sulfate), filtered and solvent evaporated. The product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2O)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[N:43]=[N+:44]=[N-:45])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)C(O)CC2)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(N=[N+]=[N-])CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-tert-butyldiphenylsilyloxy-1-indanol, as described above in Step B, (5.80 g, 14.9 mmol) and diphenylphosphoryl azide (4.98 g, 18.1 mmol) in toluene (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.50 mL, 16.4 mmol), dropwise. The mixture was allowed to slowly warm to ambient temperature and was stirred for 18 hours, then washed with H2O (10 mL), then dilute HCl (10 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—1% EtOAc, to yield the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4cccnc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.