Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[N:4][CH:5]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:30].C(OC(C)C)(C)C>CCO.O1CCOCC1>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCNC2)c(Cl)c1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.3 g) in EtOH (19.3 ml) was added solution of 4N HCl in dioxane (19.3 ml) at ambient temperature and the mixture was stirred at same temperature for 1.5 hr. Diisopropylether was added to the mixture and precipitate was collected by filtration to give ethyl (2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (2.98 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=C[CH:21]=[CH:20][C:19]=1O.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C=O)C.CO>[NH2:17][C:18]1[CH:23]=[C:25]([CH:21]=[CH:20][CH:19]=1)[O:28][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 2-aminophenol (43 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, and filtered through a membrane. The crude product was purified via prep-LC-MS to provide 133 (5 mg, 12% yield) as a solid. LC-MS (M+H=304, obsd.=304). 1H NMR (400 MHz, d6-DMSO): δ 11.72 (s, 1H), 9.68 (s, 2H), 8.88 (d, 1H), 8.35 (d, 1H), 8.18 (m, 1H), 8.01 (d, 1H), 7.76 (t, 1H), 7.58 (t, 1H), 7.02 (m, 2H), 6.78 (t, 1H), 6.48 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](O)[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].ClC1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.[C:24](=O)([O-])[O-:25].[K+].[K+]>CS(C)=O.O>[Cl:19][C:18]1[C:1]([O:2][C:3]2[CH:8]=[CH:7][C:6]([O:25][CH3:24])=[CH:5][CH:4]=2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(O)c1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
P-Methoxyphenol (1.5 g) was added to a suspension of sodium hydride (0.6 g 50% oil dispersion, washed with petroleum) in dry dimethyl sulphoxide (30 ml) and the mixture stirred for 15 minutes. A solution of the combined products (1.5 g) from several preparations carried out as described in paragraph (d), in dimethylsulphoxide (20 ml) was added to the reaction mixture and heated to 60° C. for four hours. A further amount of sodium hydride (0.3 g of 50% oil dispersion, washed with petroleum), and potassium carbonate (1.38 g) was added. Heating was continued for another 4 hours. The mixture was poured into ice and water, and extracted with ether (400 ml). The ether extracts were washed with water, dilute sodium hydroxide, and water, dried, and evaporated to give the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)s3)c(F)c2)C(=O)O1
Temperature: 90 °C
Yield: 57.5 %

Procedure:
N-{[(5S)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (273 mg, 0.72 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (250 mg, 0.72 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (180 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[C:15](=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[F:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N1CCc2c(F)cccc21
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)N1CCc2c1ccc([N+](=O)[O-])c2F
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Fuming nitric acid (0.22 mL) was added dropwise to a solution of 1-(4-fluoro-indolin-1-yl)ethanone (1 g, 5.58 mmol) in concentrated sulfuric acid (10 mL) at −15° C. to 0° C. The reaction mixture was stirred at 0° C. for 2 h and then the resulting mixture was basified with sodium bicarbonate solution (100 mL). The reaction mixture was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with chloroform (5×30 mL). The combined organic layers were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to give the crude product. Purification by column chromatography over neutral alumina using 10-12% ethyl acetate in hexane as eluent afforded 1-(4-fluoro-5-nitro-indolin-1-yl)ethanone (0.56 g, 45%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:23]#[N:24])=[CH:13]2)[CH:6]=1)C.O1CCCC1.C(O)C.[OH-].[Li+]>O>[C:23]([C:14]1[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][N:12]([C:7]2[CH:6]=[C:5]([C:10]([OH:11])=[CH:9][N:8]=2)[C:4]([OH:25])=[O:3])[CH:13]=1)#[N:24]
Reactant: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cn(-c2cc(C(=O)O)c(O)cn2)cc1-c1ccccc1
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a solution of 2-(3-cyano-4-phenylpyrrole-1-yl)-5-hydroxyisonicotinic acid ethyl ester (0.050 g) in a mixed solvent of tetrahydrofuran (3.6 mL) and ethanol (1.2 mL) was added 1 mol/L aqueous lithium hydroxide solution (1.2 mL) at room temperature, and this mixture was stirred at same temperature for 5 hours. This mixture was poured into water, this mixture was washed with diethyl ether. To this aqueous layer was added 1 mol/L hydrochloric acid (1.2 mL), and the precipitated solid was collected by filtration, and washed with water and n-hexane. This solid was dried under reduced pressure at 50° C. to give the title compound (0.030 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][N:40]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:22]=[C:17]([C:7]4[CH:6]=[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)[N:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=5)[CH:8]=4)[CH:18]=[N:19][CH:20]=3)=[CH:30][CH:29]=2)[CH2:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(6′-cyclopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-benzaldehyde (Example 2.64)(1 eq, 0.204 mmol, 80 mg) in DCM (3 ml) is treated with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.2 eq, 0.448 mmol, 83.2 mg) followed by AcOH (1.2 eq, 0.245 mmol, 0.14 ml) and sodium triacetoxyborohydride (3.1 eq, 0.632 mmol, 134 mg). The reaction mixture is stirred at room temperature overnight and then extracted with DCM. The organic portion is washed with water, dried (MgSO4) and concentrated in vacuo to afford the title compound which is used in the next step without further purification; [M+H]+ 563.
Reaction SMILES: [CH:1]([NH:4][S:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27](S(C)(=O)=O)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:23](=[O:45])[C:24]2[CH:29]=[N:28][C:27]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][CH:14]=3)=[N:26][C:25]=2[N:34]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39]3)[CH:35]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CC(C)NS(=O)(=O)CCc1ccc(N)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCS(=O)(=O)NC(C)C)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (58 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (50 mg, 36%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.34 (s, 1H), 8.53 (s, 1H), 7.88 (br, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.27 (m, 3H), 7.18 (d, J=7.9 Hz, 1H), 6.94 (br, 2H), 5.88 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.61 (m, 1H), 3.22 (m, 2H), 3.10-2.96 (m, 6H), 2.23 (m, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.25 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:9]([OH:11])=O)[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([N:14](CC)CC)[CH3:13].ClC(OCCCC)=O.C(N)C>O1CCCC1>[CH2:12]([NH:14][C:9](=[O:11])[C@H:4]([CH2:3][S:2][CH3:1])[NH:5][C:6](=[O:8])[CH3:7])[CH3:13]
Reactant: CSC[C@H](NC(C)=O)C(=O)O
Reactant: CCN(CC)CC
Agent: CCCCOC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CSC)NC(C)=O
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
S-Methyl-N-acetyl-L-cysteine (3.54 g, 20 mmole) was dissolved in 25 ml of tetrahydrofuran and 2.8 ml (20 mmole) of triethylamine was added thereto. Upon cooling to -15° C., 2.7 ml (20 mmole) of butyl chloroformate was added dropwise and the mixture was stirred for 20 minutes at that temperature. After cooling to -40° C., 3.0 ml (46.6 mmole) of aqueous 70% ethylamine solution was added in one portion and stirred for 3 hours under ice cooling. The reaction mixture was extracted with 100 ml of ethyl acetate three times and the extracts were washed successively with 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The resulting crystals were collected and washed with ethyl ether to give 2.20 g (53.8% yield) of S-methyl-N-acetyl-L-cysteine ethylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:22](=[O:24])[CH3:23])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 16.2 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.45 g, 1.5 mmol) in tetrahydrofuran (10 mL), was added acetyl chloride (0.63 mL, 8.8 mmol) and heated at 80° C. for one hour. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide (80 mg, 16% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.15 min (98.6%); mp, 320-322° C.; 1HNMR (DMSO-d6) 2.16 (s, 3H, CH3), 2.18-2.24 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH2, CH3), 5.32 (dd, J=6, 11 Hz, 1H, CH), 7.28-8.54 (m, 3H, Ar), 11.08 (s, 1H, NH), 11.70 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.65, 23.35, 25.29, 30.57, 56.71, 107.39, 115.09, 120.38, 135.63, 139.84, 147.84, 154.71, 163.01, 168.67, 169.29, 172.60. LCMS MH=329; Anal Calcd For C16H16N4O4+2.2H2O: C, 52.23; H, 5.59; N, 15.23. Found: C, 52.20; H, 5.57; N, 15.21.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F-].[K+].[CH:19]1([CH2:22][S:23][C:24]2[S:25][C:26]([SH:29])=[N:27][N:28]=2)[CH2:21][CH2:20]1>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:29][C:26]1[S:25][C:24]([S:23][CH2:22][CH:19]3[CH2:20][CH2:21]3)=[N:28][N:27]=1)=[N:3]2
Reactant: Sc1nnc(SCC2CC2)s1
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(SCC2CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (65 mg, 0.23 mmol) in DMF (4 ml) was added potassium fluoride 40% wt on alumina (103 mg, 0.71 mmol) followed by addition of 2-cyclopropylmethylsulfanyl-5-mercapto-1,3,4-thiadiazole (53 mg, 0.26 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:20 affording the title compound.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.[OH-].[Na+].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>O.[Sn](Cl)(Cl)(Cl)Cl>[CH3:2][C:1]([CH3:4])([O:5][CH2:6][CH:8]([OH:10])[CH2:9][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:3]
Reactant: C1CCNC1
Reactant: ClCC1CO1
Reactant: CC(C)(C)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OCC(O)CN1CCCC1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A mixture of 100.0 g (1.35 m) of tert.butyl alcohol and 51.4 g (1.35 m) of epichlorohydrin in 240 ml of xylenes was stirred and heated to 50° C. Tin (IV) chloride (3.5 g; 1.6 ml; 0.031 m) was added all at once and the reaction mixture immediately exothermed to about 100° C. The reaction mixture was stirred at about 50° C. for 1.5 hrs then cooled to 5° C. while a mixture of 97 g of 50% sodium hydroxide solution and 195 g of ice was added followed by 115.1 g (1.62 m) of pyrrolidine. The reaction mixture was stirred and heated to reflux for 1 hr. The reaction mixture was cooled to RT, diluted with 1 liter of water and extracted with ether. The ether soluble portion was dried and concentrated in vacuo to give 92.4 g of oil which was distilled at 97.5°-97° C./0.075 mm to yield 63.85 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][CH2:46][CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]=1>C1COCC1>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:45][CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:49]=2)=[O:27])=[CH:18]1
Reactant: NCCc1ccc2ccccc2n1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccc2ccccc2n1
Temperature: -22 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a stirred solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (1.59 g, 4.0 mmole) in dry THF (50 mL) at -22° C. was added N-methylmorpholine (0.644 g, 6.3 mmole) and isobutyl chloroformate (0.632 g, 4.6 mmole). The mixture was stirred at -22° C. for 1 hour and then a solution of 2-(2-aminoethyl)quinoline (0.690 g, 4.0 mmole) in dry THF (15 mL) was added. After stirring at this temperature 4 hours the reaction mixture was allowed to stir at room temperature 15 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 5% citric acid (2×50 mL), water (2×50 mL), 5% NaHCO3 (3×50 mL), water (2×50 mL), and brine (2×50 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed on silica gel, eluting with EtOAc-n-hexane. The oil obtained was triturated with cold Et2O, yielding the product as an amorphous white solid, (0.38 g, 17%); 1H NMR (CDCl3) δ1.41-1.88 (17H, m), 3.00-3.04 (2H, m), 3.40 (2H, q, J 9.59 Hz), 3.68-3.70 (2H, m), 4.70 (1H, s), 5.43 (1H, br s), 6.90 (1H, d, J 2.23), 6.96-7.22 (4H, m), 7.45-7.55 (2H, m), 7.63-7.70 (2H, m), 7.78 (1H, d, J 8.06), 7.89 (2H, d, J 8.10), 8.03 (1H, d, J 8.46).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]([S:9](/[N:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])([CH3:8])[CH3:7].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH3:8][C:6]([S:9]([NH:11][CH:12]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:1]=[CH2:2])=[O:10])([CH3:5])[CH3:7]
Reactant: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Reactant: C=C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)c1ccc(S(=O)(=O)CCC)cc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
Vinylmagnesium bromide (3.3 mL of a 1.0 M solution in THF, 3.3 mmol) was added dropwise to a solution of 2-methyl-N-{(1E)-[4-(propylsulphonyl)phenyl]methylene}-propane-2-sulphinamide (1.0 g, 3.17 mmol, prepared as described in Example 50a in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. The reaction mixture was quenched by addition of saturated NH4Cl(aq) and the product extracted into ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated. The product was purified by gradient chromatography on silica eluting with 30 to 80% ethyl acetate in hexane giving the title compound as a yellow solid (485 mg, 45% yield). m/z (ES+) 366 (M+Na), 344 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([C:11]([N:14]([CH3:16])[CH3:15])(Cl)[Cl:12])[CH3:10]>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][N:9]([C+:11]([N:14]([CH3:16])[CH3:15])[Cl:12])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)C(Cl)(Cl)N(C)C
Product: CN(C)[C+](Cl)N(C)C
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2.1 g (18.4 mmol) of trifluoroacetic acid are added with stirring to 3.0 g (17.5 mmol) of bis(dimethylamino)dichloromethane. The reaction is stirred for one hour at room temperature, and all volatile products are subsequently removed under reduced pressure at 7 Pa and 60° C., giving 4.19 g of bis(dimethylamino)chlorocarbenium trifluoroacetate as a very viscous oil, corresponding to a yield of 96.1%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(Cl)CCl.CCOC(C)=O>[OH:1][C:2]1[C:3]([C:8](=[S:20])[NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=S)c1ncccc1O
Yield: 69.1 %

Procedure:
A stirred solution of 3-hydroxypicolinamide (1.35 g, 9.75 mmol) and Lawesson's reagent (2.37 g, 5.85 mmol) in dry ClCH2CH2Cl (12 mL) was heated to reflux under nitrogen for 5 hr. At ambient temperature, the mixture was diluted with EtOAc (50 mL), washed with half-saturated aq. NaCl (30 o5 mL) containing NaHCO3 (840 mg) and with brine (20 mL). After drying over MgSO4 and filtration, the filtrate was concentrated in vacuo to give a brown solid, which was subject to flash chromatography on silica gel CH2Cl2 as eluent) to provide 3c (623 mg, 42%) as a greenish yellow solid after crystallization from EtOAc/hexane. mp 152.0°-153.0° C.; IR (KBr) 3372, 3259, 2464, 1626, 1458, 1317 cm-1 ; 1H NMR (DMSO-d6) δ 7.33 (1H, dd, J=8.6 and 1.0 Hz, Ar), 7.46 (1H, dd, J=8.6 and 4.3 Hz, Ar), 8.07-8.10 (1H, m, Ar), 8.15(1H, s, NH), 8.49 (1H, s, NH), 12.76 (1H, s, OH); FABMS m/z 154 (M+); Anal. Calcd for C6H6N2OS: C, 46.74; H, 3.92; N, 18.17. Found: C, 46.83; H, 3.89; N, 17.90.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]1[O:5][CH2:4]1.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>>[CH2:13]([NH:14][CH2:4][CH:3]([OH:5])[CH:2]([CH3:6])[CH3:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:4][CH:3]([OH:5])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)C1CO1
Reactant: NCCCCCCN
Product: CC(C)C(O)CNCCCCCCNCC(O)C(C)C

Procedure:
Condensation of 3-methyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3-methylbutylamine] (I: R = (CH3)2CH, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([CH3:36])[CH:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]2)=[C:29]([CH3:36])[CH:28]=1)=[O:26]
Reactant: CC(C)C[C@H](N)CO
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methyl butylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.