Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[C:39]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=3[CH:33]=[CH:32][CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc2c1CCCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 15.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.38 g, 2.09 mmol) in acetonitrile (4.4 mL) was treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol). After addition was complete, the mixture was stirred at 60° C. for 1.3 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol) and acetonitrile (4.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (639 mg, 1.88 mmol) in acetonitrile (4.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded impure (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (102 mg, 15%) as an orange/red oil. The material was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[S:54][S:53][C:52](=[S:55])[CH:51]=2)=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[S:54][S:53][C:52](=[S:55])[CH:51]=4)=[CH:48][CH:49]=3)=[O:16])[CH:12]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(-c4cc(=S)ss4)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To the solution of 1 (naproxen, 595 mg, 2.58 mmol) in 20 mL of dimethylformamide, hydroxybenzotriazole (388 mg, 2.87 mmol) and DCC (593 mg, 2.87 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 650 mg, 2.87 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product was loaded on a silica gel open column and eluted with dichloromethane, from which 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl 2-(2-methoxynaphthalen-6-yl)propanoate (3) was obtained (406 mg, 36% yield).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH:2]=[CH2:3].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.N1C=CC=CC=1.Cl>CN(C1C=CC=CN=1)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCOCCOCCOCCOCCO
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)O
Temperature: 80 °C
Reaction time: 10 h
Yield: 103.7 %

Procedure:
2-{2-[2-(2-allyloxy-ethoxy)-ethoxy]-ethoxy}-ethanol (9) (3.6 g, 15 mmol), succinic anhydride (1.8 g, 18 mmol), pyridine (1.22 mL, 15 mmol), dimethylaminopyridine (183 mg, 10 mol %), and dry toluene (5 mL) were charged into a screw cap culture tube. The mixture was stirred at 80° C. for 10 hours. Next, the reaction was stopped by adding 10% HCl (6 mL) and the reaction mixture was extracted with CH2Cl2 (3×10 mL). An organic layer was collected and dried on MgSO4. AMBERLITE™ resin IR-120 (+) (2 g) was added and stirred to perform ion exchange. The resin was filtered off and the filtrate was concentrated to obtain yellow oil (5.2 g, 92%). The compound was used without further purification. The NMR analysis result of the compound is as follows.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:1])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:40]=1)#[N:24]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCN)CCC(c1ccccc1)c1ccccn1
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine and 0.89 g (2.3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=596 ([M+H]+ 7), 196 (100).
Reaction SMILES: [CH2:1]1[CH2:37][O:36][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3C=CC(OS(C(F)(F)F)(=O)=O)=CC=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1.[Cl-].[Li+].[CH2:40]([C:44]([Sn])=[C:45]([CH2:50]CCC)[CH2:46][CH2:47]CC)CCC.[CH3:55]N(C)C=O>C(OCC)(=O)C.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>[CH2:37]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:55][CH2:21][C@@H:16]4[C@@H:17]3[C@@H:8]([C:7]3[CH:6]=[CH:50][C:45]([CH:46]=[CH2:47])=[CH:44][CH:40]=3)[CH2:9][C@@:13]3([CH3:14])[C@H:15]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:36]1
Reactant: CN(C)C=O
Reactant: C[C@]12C[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)[C@H]3[C@@H](CC=C4CC5(CC[C@@H]43)OCCO5)[C@@H]1CCC2=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=Cc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CC=C4CC5(CC[C@@H]4[C@H]32)OCCO5)cc1
Temperature: 25 °C

Procedure:
1.7 g of 3,3-(ethylenedioxy)-11β-(4-trifluoromethylsulfonyloxyphenyl)-5-estren-17-one is dissolved in 25 ml of absolute dimethylformamide and mixed with 270 mg of lithium chloride and 190 mg of tetrakistriphenylphosphinepalladium. After five more minutes of stirring, the reaction mixture is mixed with 1.15 ml of tributylvinyltin, stirred for 1 hour at 110° C. under protective gas, cooled to room temperature and diluted with ethyl acetate. After filtration on Celite and washing of the filter residue with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. Chromatography of the residue on aluminum oxide (neutral, stage II) with a mixture of ethyl acetate/hexane yields 1.2 g of 3,3-(ethylenedioxy)-11β-(4-vinylphenyl)-5-estren-17-one as white foam.
Reaction SMILES: [NH:1]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:2]([C:10]([O:12]N1C(=O)CCC1=O)=O)[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[NH2:27][C@H:28]([C:40]([OH:42])=[O:41])[CH2:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN1CCOCC1.CN(C=O)C>C1COCC1>[NH:1]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:2]([C:10]([NH:27][C@H:28]([C:40]([OH:42])=[O:41])[CH2:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:12])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 62.6 %

Procedure:
BOC-Cys(Acm)-OSu (77.5 g, 198 mM) was dissolved in THF (400 ml). H-Asp(OBzl)-OH (44.64 g, 200 mM) was added thereto, and the mixture was adjusted to pH 7 by adding NMM (18 ml) at 0° C.; DMF (300 ml) was added and the mixture was stirred overnight. The DMF was removed in vacuo, and 5% sodium bicarbonate (150 ml) was added to the residue, which was then washed twice with ether. The aqueous layer was adjusted to pH 3 by adding 1 N HCl (200 ml) to precipitate an oily material, which was extracted three times with ethyl acetate (300 ml), and the ethyl acetate layer was washed three times with aqueous sodium chloride and water. After drying with anhydrous sodium sulfate, the solution was concentrated in vacuo. Ether and hexane were added to the residue to obtain a precipitate. Recrystallization was effected with ethyl acetate-ether to yield the substance [42] (61.98 g, yield: 62.9%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])=[O:2].[CH:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[OH:2][CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: CC(C)c1ccc(CCl)cc1
Product: Cc1c2c(c(C(O)Cc3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Yield: 92 %

Procedure:
Using N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 340 and 4-isopropylbenzyl chloride, the title compound was synthesized in the same manner as in Example 341. Yield: 92%. Amorphous substance.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[CH3:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-phenyl-1H-imidazole 41 (2.01 g, 13.9 mmol) in DMF (30 mL) containing cesium carbonate (6.05 g, 18.6 mmol) at room temperature was added iodomethane (0.950 mL, 15.3 mmol). The reaction mixture was stirred at room temperature for 5 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (70% to 100% EtOAc in hexanes) gave 1-methyl-4-phenyl-1H-imidazole 42. Mass spectrum: calculated for C10H10N 158.1; found 159.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[OH:17].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:18](=[O:19])[O:17][C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A solution of 4-amino-3′-nitro-biphenyl-3-ol (0.115 g, 0.5 mmol) in dry THF (2.5 mL) was treated with a solution of 1,1′-carbonyldiimidazole (0.098 g, 0.6 mmol) in dry THF (2.5 mL). The reaction mixture was stirred at room temperature under a blanket of nitrogen for 6 hours. A precipitate formed, was collected and washed with methylene chloride (50 mL) to give 6-(3-nitro-phenyl)-3H-benzooxazol-2-one (0.095 g, 74%) as a white solid: mp 280-281° C.; 1H-NMR (DMSO-d6) δ 11.7 (s, 1H), 8.43 (t, 1H, J=1.15 Hz), 8.2-8.13 (m, 2H), 7.79-7.72 (m, 2H), 7.59 (dd, 1H, J=8.08, 2.31 Hz), 7.21 (d, 1H, J=8.08 Hz), MS (ES) m/z 255([M−H−, 100%); Anal. Calc. For C13H8N2O4: C, 60.94, H, 3.15, N, 10.93. Found: C, 59.95, H, 3.17 N, 10.77.
Reaction SMILES: C1COCC1.C([O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:20])[N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)C.[OH-].[Li+]>O>[CH3:18][N:17]([CH3:19])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:21])=[O:8])=[CH:11][CH:12]=1)=[NH:20]
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
To a THF solution of ethyl-4(N,N-dimethylcarbamimidoyl)benzoate (Q) was added an aqueous solution of lithium hydroxide (2 eq.) and the reaction mixture was stirred for 6 hours. The completion of the reaction was confirmed by HPLC. To the reaction mixture was added water, followed by extraction with ethyl acetate. The aqueous layer was acidified with 6N HCl to pH between 3-4 at which point the desired 4-(N,N-dimethylcarbamimidoyl)benzoic acid precipitated as the white solid. The white solid isolated was washed with hexane to afford 4-(N,N-dimethylcarbamimidoyl)benzoic acid as an hydrochloride salt (A).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[NH:7][C:6]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: Cc1nc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Reactant: c1ccc(N2CCNCC2)cc1
Product: Cc1nc(N2CCN(c3ccccc3)CC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
A mixture of 2-methyl-4-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.51 g, 2.45 mmol) and 1-phenylpiperazine (Aldrich Chemical Company) (10 mL) was stirred at 140° C. for 4 h under a N2 atmosphere. After cooling the precipitate was removed by filtration and the filtrate was poured onto a mixture of CH2Cl2 (30 mL) and H2O (40 mL). The mixture was transferred to a separatory funnel where the organic solution was collected, washed with H2O (3×40 mL), saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 97:3 CHCl3/MeOH as eluant to give 483 mg (54%) of 2-methyl-6-phenyl-4-(4-phenylpiperazinyl)pyrrolo[3,2-d]pyrimidine as a tan colored solid. This compound (483 mg, 1.31 mmol) was dissolved in 5:1 EtOAc/MeOH (30 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.30 mL, 1.30 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (2×5 mL) and dried under vacuum at 60° C. to give 404 mg (41%) of the title compound as a beige powder. Mp: 232-234.5° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.55 (s, 3), 3.36 (br s, 4), 4.21 (br s, 4), 6.80 (t, 1, J=7.2), 6.88 (s, 1), 6.99 (d, 2, J=7.8), 7.22 (t, 2, J=7.5), 7.46 (q, 1, J=7.1), 7.51 (t, 2, J=7.3), 7.93 (d, 2, J=7.7), 12.06 (s, 1), 14.46 (s, 1). MS m/z: 370 (M+1 for free base). Anal. Calcd for C23H23N5.2.0HCl.2 .5H2O: C, 56.67; H, 6.20; N, 14.37; Cl, 14.55. Found: C, 56.67; H, 6.23; N, 14.19; Cl, 14.34.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.F[P-](F)(F)(F)(F)F.Cl.[CH:64]1[C:76]2[CH:75]([CH2:77][O:78][C:79](=[O:87])[NH:80][CH:81]3[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]3)[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1>C(OCC)(=O)C.CN(C)C=O>[CH:64]1[C:76]2[CH:75]([CH2:77][O:78][C:79](=[O:87])[NH:80][CH:81]3[CH2:82][CH2:83][N:84]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([NH:20][C:18]5[N:17]=[CH:16][C:7]6[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]7[CH2:4][CH2:3][CH2:2]7)[C:6]=6[N:19]=5)=[C:22]([O:30][CH3:31])[CH:23]=4)[CH2:85][CH2:86]3)[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1
Reactant: O=C(NC1CCNCC1)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A mixture of 0.200 g (0.46 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.186 g (1.84 mmole) of triethylamine, 0.220 g (0.51 mmole) of N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-methanaminium, hexafluorophosphate(1-) (1:1) and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.182 g (0.51 mmole) of 4-piperidinyl-carbamic acid 9H-fluoren-9-ylmethyl ester monohydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.210 g of {1-[4-(9-Cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.O[C:50]1[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=1>ClCCl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:50]2[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCO)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
1.7 g (10 mmole) 2-[4-(methylsulfanyl)phenyl]-1-ethanol, 5.24 g (20 mmole) triphenylphosphine and 5.05 g (20 mmole) 1,1-(azodicarbonyl)dipiperidine was added to a mixture of 2.47 g (20 mmole) 4-hydroxybenzaldehyde in 40 ml dichloromethane under argon atmosphere. Stirring at room temperature for 2 hours, (more dichloromethane was added after 20 minutes), gave a solid material that was removed by filtration. The filtrate was purified by chromatography on silica gel using dichloromethane as eluent to give 2.3 g (yield 84.4%) of 4-[2-(4-methylmercaptophenyl)ethoxy]benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[CH:13]=[CH:14]/[C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[CH:13]=[CH:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(/C=C/c1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(/C=C/c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
200 mg of (RS)-(E)-methyl 4-[3-(4,4-dimethyl-thiochroman-6-yl)-oct-1-enyl]-benzoate were dissolved in 10 ml THF/3 ml water/3 ml methanol and 200 mg of lithium hydroxide hydrate were added. The mixture was stirred at room temperature 4 hours. The mixture was diluted with 10 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 50 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 25 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (SiO2, 10% methanol/methylene chloride) followed by recrystalization from hexanes, yielding 185 mg of product as white solid. M.p. 146-146.5° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with cis-4-hydroxy-D-proline. A yellow solid 130 was obtained (0.038 g, 74%). 1H-NMR (CDCl3, 400 MHz) δ 2.34–2.42 (m, 1H), 2.64–2.68 (m, 2H), 3.73–3.82 (m, 1H), 3.94–4.00 (m, 1H), 4.28–4.34 (m, 4H), 4.68–4.74 (m, 1H), 6.92–7.12 (m, 6H), 7.52 (br, 1H), 7.80 (s, 1H), 8.04 (br, 1H); MS (APCI) m/z 519 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12](NCCCC)CCC.C(O)(=O)C.C=O>C1(C)C=CC=CC=1>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: CCCCNCCCC
Reactant: O=C1CCCc2ccccc21
Agent: C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A 100-ml pressure-proof glass reaction vessel was charged with 2.92 g (0.02 mole) of 1-tetralone, 2.59 g (0.02 mole) of di-n-butylamine, 1.20 g (0.02 mole) of acetic acid and 15 ml of toluene. To the mixture 0.974 g (0.012 mole) of an 37% aqueous formaldehyde solution was added and the vessel was sealed and heated up to 90° C. After maintaining the temperature at 90° C. for 30 minutes, the vessel was cooled to room temperature. The contents were separated by addition of 5 ml of water, and the water layer was washed off with a 50% aqueous acetic acid solution. The toluene layer was further washed with a 10% aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and saturated aqueous sodium chloride solution, to give a solution of 2-methylene-1-tetralone in toluene. The reaction mixture was analyzed by GLC and its composition was found to be 1.45 g of 2-methylene-1-tetralone and 1.16 g of unreacted 1-tetralone (the conversion of 1-tetralone: 60.2%; selectivity: 82.1%).