Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]1[CH2:23]C[CH:21](O)[CH2:20]1.CCOC(C)=O.CCO>CCCCCCC>[CH:1]1([C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH:10]2[CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(O)C1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCC1
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Yield: 72 %

Procedure:
A solution of 2 (2.20 g, 9.4 mmol) and N-methyl-3-pyrrolidinol (3, 1.30 g, 13 mmol) in 40 ml of n-heptane was heated until 20 ml of heptane had been distilled. About 0.003 g of sodium was added, and the solution was stirred and heated for 2 h as the distillation was continued. More heptane was added at such a rate as to keep the reaction volume constant. Additional sodium was added at the end of an hour. The solution was then cooled and extracted with 3N HCl. The acid extract was made alkaline with concentrated NaOH and extracted three times with ether. Removal of the dried ether solution gave a crude oil. Flash chromatography of the crude product on silica gel with 8:1 EtOAc:EtOH gave pure product 4 (2.053 g, 72%). Analysis for C18H25NO3. Calcd: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.55; H, 8.44; N, 4.68. 1H NMR (CDCl3, 500 MHz): 1.27-1.35, 1.40-1.47, 1.54-1.60, 1.75-1.90 [8H, m, (CH2)4], 2.12-2.30, 2.52-2.57, 2.64-2.81 (6H, m CH2NCH2CH2), 2.33, 2.36 (3H, 2s, NCH3), 2.93 [(1H, p, CHC(OH)], 3.83 (1H, bs, OH), 5.23 (1H, m, CO2CH), 7.23-7.36, 7.64-7.67 (5H, m, Ph) ppm.
Reaction SMILES: [CH2:1]([S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][C:10]=1[O:31][CH3:32])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[Mn+2]>[CH2:1]([S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:19]=2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][C:10]=1[O:31][CH3:32])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1CCCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1cc(C=O)ccc1CCCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.6 %

Procedure:
7.9 g (91 mmol) of manganese oxide is added to a solution of 4.2 g (9.1 mmol) of 4-[3-(2-butoxy-4-hydroxymethyl-phenyl)-propyl]-2-methoxy-phenyl 1-butane sulfonate in 300 ml of dichloromethane. The reaction mixture is stirred for 15 hours at room temperature and then filtered on Celite. The solvents are evaporated. 3.9 g (94%) of 4-[3-(2-butoxy-4-formyl-phenyl)-propyl]-2-methoxy-phenyl 1-butane sulfonate is obtained in the form of a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[O:23])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
Lithium bis(trimethylsilyl)amide solution in THF (1 M, 0.78 mL, 0.78 mmol) was added to a solution of 3-(2-methoxypyridin-3-yl)-4-phenoxybenzamide (Preparation 19, 0.1 g, 0.31 mmol) in THF (4 mL) at room temperature and the reaction allowed to stir for 30 minutes. Methanesulfonyl chloride (0.088 g, 0.78 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was then partitioned between EtOAc (40 mL) and water (10 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to afford a brown solid. The crude product was purified by preparative HPLC to afford the title compound as a white solid (20 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Product: Nc1nc(N)c2nc(CN3CCOCC3)nnc2n1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and 2.0 mL of morpholine were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 261 mg of yellow colored 3-Morpholin-4-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccccc3F)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(2-fluoro-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C22H25FN2O5 [M+H]+: 417.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:25]4[O:24][CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([CH3:11])=[N:9]2)[CH3:13])[C:25]2[O:24][CH2:23][CH2:22][CH2:21][N:20]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:19][C:18]=2[C:17]=1[F:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(S(C)(=O)=O)C3)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 10-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-8-chloro-7-fluoro-3,4-dihydro-2H-1,5-benzoxazocine-5(6H)-carboxylate (8 mg, 0.02 mmol) was stirred in methylene chloride (80 μL, 1 mmol) with N,N-diisopropylethylamine (8.5 μL, 0.049 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added and the mixture was stirred at 0° C. for 1 hr. The mixture was evaporated and diluted with methanol and purified by preparative LCMS (pH 10) to give Example 45. LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.65 (m, 1 H), 6.36 (m, 1 H), 4.58 (m, 2 H), 4.21 (m, 2 H), 3.52 (m, 2 H), 2.87 (s, 3 H), 2.60 (s, 3 H), 1.91 (m, 2 H), 1.80 (m, 3 H).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:25]#[N:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:10]1[C:9]2[C:8]([C:25]#[N:26])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C
Yield: 73 %

Procedure:
A solution of 2-(piperidin-1-yl)-4-(thiophen-2-yl)-9H-fluorene-1-carbonitrile (356 mg) in THF was added sodium hydride (29 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; yield 73%; mp 226-228° C.; ESMS 371 (M++1); IR (KBr) 1710 cm−1 (CO), 2220 (CN).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O>[Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[N:17]([C:24](=[O:25])[CH3:23])[N:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2Br)cc1C1CC1
Reaction time: 14 h
Yield: 67.3 %

Procedure:
To the mixture of 5-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (200 mg, 0.56 mmol, 1.0 eq) in THF (8 mL) and water (5 mL) was added a solution of Ac2O (0.18 mL, 1.68 mmol, 3.0 eq) in THF (2 mL). The reaction mixture was stirred for 14 hours and water was added. The mixture was filtered and the solid was washed with water and dried by co-evaporated with ethanol to give 1-(3-(5-bromo-2-phenylpyrimidin-4-ylamino)-5-cyclopropyl-1H-pyrazol-1-yl)ethanone (150 mg, 67%). LC-MS (m/z)=398.0, 400.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Reaction time: 5 h

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (12.5 g, 69.8 mmol) was combined in a flask with THF (125 mL) and placed in a room temperature water bath. Vinyl magnesium bromide (78 mL, 76.8 mmol) was added in three portions. The mixture was stirred for 5 h. Acetone was added to quench any remaining Grignard reagent. DDQ (19 g, 83.8 mmol) was added to the mixture, and the mixture was stirred overnight. The mixture was then concentrated to remove the THF. Dichloromethane (DCM) was added, triturated, and allowed to stand over the weekend before being filtered, concentrated, and purified by column chromatography on silica gel using a 5-30% ethyl acetate/hexane gradient. This produced the title compound (7.95 g), which was observed to be a light yellow solid that turned grey in light.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[C:10]1([CH3:23])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([O:21][NH2:22])(=[O:20])=[O:19].CCOCC>C(Cl)Cl>[C:10]1([CH3:23])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([O-:21])(=[O:20])=[O:19].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([NH2:22])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CCCCn1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC[n+]1ccn(N)c1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 1-butylimidazole (7.0 g, 16.30 mmol) in anhydrous CH2Cl2 (35 mL) was treated dropwise with a solution of O-mesitylene sulfonylhydroxylamine (17.8 g, 16.50 mmol) in CH2Cl2 (70 mL). After stirring for 6 hours in the ice-bath, ether (210 mL) was added with stirring over the course of 1 hour. The resulting mixture was allowed to stand at −16° C. overnight. The product was recovered by filtration, and washed with a mixture of CH2Cl2: ether (3:1 v/v) to yield a white amorphous powder; 16.70 g. The crude product was recrystallized from a mixture of CH2Cl2 (80 mL) and ether (80 mL) to give 12.40 g; mp 71–73° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][O:13]1)=[O:11].C(N(CC)C(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][C@@H:15]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:14][O:13]1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1C(=O)N1C[C@@H](O)CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1C(=O)N1C[C@@H](OS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
2-[(R)-4-Hydroxyisoxazolidine-2-carbonyl]benzoic acid methyl ester (prepared by the method of Martin et al., Tetrahedron Lett., 2007, 47, 7635) (3.50 g, 14.0 mmol) was dissolved in dichloromethane (100 mL) and N,N-diisopropylethylamine (3.55 mL, 20.3 mmol), then methanesulfonyl chloride (1.40 mL, 18.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was washed with 0.1M HCl solution (100 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil (5.00 g, 100%). δH (DMSO-d6) 7.92-7.46 (4H, m), 4.28 (1H, m) 4.17-4.14 (2H, m), 4.06-3.92 (2H, m), 3.82 (3H, s), 3.31 (3H, s). LCMS (ES+) RT 1.45 minutes, 330 (M+H)+ (pH 3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][N:46]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:52][CH2:51][C:48]3[CH:47]=[N:46][C:45]([CH3:44])=[N:50][CH:49]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: Cc1ncc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (45 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (2-methylpyrimidin-5-yl)methanamine (29 mg, 0.23 mmol) and N,N-diisopropylethylamine (54 μL, 0.31 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CCC1(O)CCCCCCC1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(CC)CCCCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a 500-mL 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 32.5 g (0.208 mol) of 1-ethyl-1-cyclooctanol and 100 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 150 mL (0.239 mol, 15% excess) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 25 g (0.239 mol) of freshly distilled methacryloyl chloride in 50 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 500 mL of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled twice from Na2CO3 and phenothiazine through a based-washed 15-cm Vigreux to yield 24 g (51%) of the title compound (bp 84° C. @ 1 mmHg) as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([NH2:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2.[N:15]([O-:17])=[O:16].[Na+].II>C(OCC)(=O)C.C(O)CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([NH2:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7]2
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Yield: 24 %

Procedure:
To a solution of 8-fluoro-2H-1-benzopyran-5-carboxamide (4.46 g, 23.1 mmol) in ethyl acetate (220 mL), ethylene glycol (4.0 mL) and a solution of sodium nitrite (6.52 g, 92.4 mmol) in H2O (11 mL) were added followed by iodine (9.0 g, 34.7 mmol). The reaction mixture was refluxed for 24 hours and during this time H2O (22 mL) and ethylene glycol (4.0 mL) were added portionwise. The reaction mixture was cooled, diluted with ethyl acetate, washed with a 5% solution of NaS2O3, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give a crude yellow solid. The solid was recrystallized from absolute ethanol to give 1.3 g (24% yield) of sparkly yellow crystals as the title compound (mp 227.8-228.2° C.). EIMS (70 eV) m/z (relative intensity) 238 (57, M+), 221 (100), 192 (71), 191 (46), 190 (10), 148 (14), 109 (16), 94 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: CN(C)CCCl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under ice cooling with stirring 1.2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 6.6 g of N,N-dimethyl-2-chloroethylamine over a period of 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is water washed and dried over magnesium sulfate, and the solvent is distilled off. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with benzene. The eluate is concentrated to obtain a crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The crude product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous isopropyl alcohol-acetone mixture to obtain 4.8 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCCl.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (100 mg) in 1,2-dichloroethane (4 ml) were successively added triethylamine (40 μl) and methanesulfonyl chloride (18 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (51.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH3:40])[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:39][CH3:40])[CH:35]=3)[CH:30]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:27][CH:28]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-methoxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (4.0 mg, 0.0072 mmol) in ethanol (1 mL) was added LiOH (2.0 N in water, 0.1 mL, 0.2 mmol), then the mixture was stirred for one hour The mixture was diluted with DCM, then acidified with 2.0 N HCl (aq). The layers were separated, then the organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% MeOH/DCM to obtain the title compound as a white solid. 1H NMR (600 MHz, CD3OD): δ 7.53-7.48 (m, 6H); 7.42 (d, J=8.5 Hz, 1H); 7.33-7.28 (m, 5H); 6.98-6.94 (m, 2H); 5.47 (s, 1H); 4.32 (d, J=11.7 Hz, 1H); 3.79 (s, 3H); 3.51-3.47 (m, 2H); 2.50 (s, 2H); 1.56 (t, J=7.6 Hz, 2H); 1.04 (d, J=9.5 Hz, 2H); 0.73 (t, J=7.3 Hz, 3H); LC3 2.61 min. [M+H]+ 531.