Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:5]=[N:6][C:7]([N:13]=[C:14]=[O:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCCCC>[CH:1]([N:5]=[N:6][C:7]([NH:13][C:14]([NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N=NC(C)(CC(C)C)N=C=O
Reactant: NC1CCCCC1
Solvent: CCCCC
Product: CCC(C)N=NC(C)(CC(C)C)NC(=O)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
To 5.3 grams (0.025 moles) of stirred 2-sec.-butylazo-2-isocyanato- 4-methylpentane (from Example XVII) in a 50 ml erlenmeyer flask was added 2.6 grams (0.026 moles) of cyclohexylamine. A solid quickly formed so 25 ml of pentane was added and the slurry stirred for approximately 1/2 hour, the solid filtered, reslurried in 25 ml of fresh pentane and refiltered. The solid was air dried and weighed. The white powder weighed 4.4 grams (57% crude yield) and had a melting range of 118° to 123° C. The infrared spectrum of the product was in agreement with the structure of N-[ 1-(sec.-butylazo)- 1,3-dimethylbutyl]-N'-cyclohexylurea (sharp NH at 3250 cm-1 and strong carbonyl band at 1625 cm-1).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]([CH3:29])[NH:8][CH:13]([CH3:14])[CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4cc(F)cc(F)c4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (s, 1H) 8.12 (d, 1H)) 7.98 (d, 1H) 7.47 (m, 2H) 7.12 (d, 1H) 6.90 (d, 2H) 6.75 (d, 1H) 3.75 (t, 2H) 3.60 (m, 4H) 3.47 (t, 2H) 2.98 (t, 2H) 2.90 (t, 2H) 1.04 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=S)[C:8]([NH:23][CH3:24])=[CH:7][C:6]=1[F:25])[CH3:2].CC(C)N=C=NC(C)C>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([F:25])=[CH:7][C:8]2[N:23]([CH3:24])[C:12]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])=[N:11][C:9]=2[CH:10]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F

Procedure:
Prepared analogously to example 127e from 5-[3-(2,6-dichloro-phenyl)-thioureido]-2-fluoro-4-methylamino-benzoic acid ethyl ester and DIC in acetonitrile.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1>C(#N)C.CCOC(C)=O.O>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][C:15]=1[Br:1]
Reactant: COC(=O)c1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Add 1.79 g (10.05 mmol) of N-bromosuccinimide to a solution of 1.4 g (9.14 mmol) of methyl 5-aminopyrazine-2-carboxylate in 10 mL of acetonitrile. Stir the reaction mixture for 2 h at 20° C. then distribute in 100 mL of EtOAc/water 1:1 mixture. Wash the organic phase with 2×50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 1.66 g of methyl 5-amino-6-bromopyrazine-2-carboxylate in the form of yellow wax.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OCC1CCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OCC1CCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.7 %

Procedure:
Tetrahydrofurfuryl alcohol (19.4 g) was dissolved in anhydrous ether (500 ml) and, after adding pyridine (15 g) under ice cooling, chloromethyl chloroformate (25 g) was added dropwise. After the reaction mixture was stirred at room temperature for 17 hours, the deposited pyridine hydrochloride was removed by filtration and the filtrate was washed with ether (50 ml×2). The washings and the filtrate were combined, washed with water (300 ml×2) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (33.9 g) as a colorless oily product.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:43]([O:47][CH:48]([O:50][NH2:51])[CH3:49])[CH:44]([CH3:46])[CH3:45]>C1COCC1.C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[NH:51][O:50][CH:48]([O:47][CH2:43][CH:44]([CH3:46])[CH3:45])[CH3:49]
Reactant: CC(C)COC(C)ON
Reactant: COC(=O)CCCCCCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCC(=O)NOC(C)OCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 907 %

Procedure:
Monomethyl suberate (25.0 g, 13.3 mmol, 1.0 eq) was dissolved in THF (300 mL) and DCM (300 mL). EDC.HCl (25.46 g, 13.3 mmol, 1.0 eq) was added to the stirred solution, followed by HOBt (17.95 g, 13.3 mmol, 1.0 eq) and triethylamine (48.5 mL, 34.5 mmol, 2.6 eq). O-(1-Isobutoxy-ethyl)-hydroxylamine (21.9 mL, 15.9 mmol, 1.2 eq) was added to the viscous solution and the reaction allowed to stir overnight at room temperature. The reaction mixture was concentrated under vacuum, DCM (350 mL) was added and washed with water (250 mL) and brine (200 mL). The organic layer was isolated, dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a white solid (36.6 g, 91% yield) LCMS purity 88%, m/z 302 (M++H)+. This was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=[O:22])=CC=1.[C:25]1([CH3:31])C=CC=CC=1>>[Br:1][C:2]1[C:7]([CH:8]2[O:22][CH2:25][CH2:31][O:9]2)=[C:6]([F:10])[C:5]([CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCCc1ccc(Br)c(C=O)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCc1ccc(Br)c(C2OCCO2)c1F
Yield: 99 %

Procedure:
A Dean-Stark condenser was attached, and a mixture of compound (51) (52.4 g, 213.8 mmol) prepared in Example 1, EG (39.8 g, 641.4 mmol) and PTSA (0.52 g, 1 wt %) was refluxed in a toluene (300 mL) solvent for 3 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and dried over magnesium sulfate. Toluene was distilled off by an evaporator, and thus 2-(6-bromo-2-fluoro-3-propylphenyl)-1,3-dioxolane (78) (61.2 g, yield 99.0%) was obtained.
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].I[CH2:11][CH2:12][CH2:13][CH3:14].Cl[C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][N:21]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:11]([S:6][C:5]1[S:1][C:2]([S:7][C:16]2[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][N:21]=2)=[N:3][N:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCI
Reactant: N#Cc1nccnc1Cl
Reactant: Sc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 4 by using 1,3,4-thiadiazole-2,5-dithiol (300 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), 1-iodobutane (0.263 ml, 2.30 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (8 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23])=[S:12].[CH3:24][NH:25][C:26](=S)[SH-:27]C>>[CH3:23][C:22]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:17][S:16][CH2:15][CH2:14][NH:13][C:11](=[S:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH3:24])=[S:27]
Reactant: Cc1[nH]cnc1CSCCNC(=S)NCCCCCCCCN
Reactant: CNC(=S)[SH-]C
Product: CNC(=S)NCCCCCCCCNC(=S)NCCSCc1nc[nH]c1C

Procedure:
Reaction of N-(8-aminooctyl)-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]thiourea (see Example 22) with N,S-dimethyldithiocarbamate yields 1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)thioureido]-8-[N'-methylthioureido]octane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of n-butylithium (50.97 cm3, 0.1274 mol, 2.5M in hexane) was added dropwise to a cooled (−78° C.) stirred solution of 4-bromo4′-octyloxybiphenyl (40.00 g, 0.1108 mol) in THF (400 cm3). After 1 h, trimethyl borate (23.05 g, 0.2216 mol) was added dropwise to the reaction mixture maintaining a temperature of −78° C. The reaction mixture was allowed to warm to room temperature overnight. 20% hydrochloric acid (350 cm3) was added and the resultant mixture stirred for 1 h. The product was extracted into diethyl ether (3×300 cm3). The combined organic layers were washed with water (300 cm3), dried (MgSO4), filtered and the filtrate evaporated down under partially reduced pressure. The crude product was stirred with hexane for 30 minutes and filtered off to yield a white powder (26.20 g, 73%, m.pt. 134-136° C.).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: Nc1ccccc1NC1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(R)-Acenaphthen-1-yl-amine•hydrochloride (25 g) was dissolved in water (200 ml) and the mixture was alkalified with potassium carbonate and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained (R)-acenaphthen-1-yl-amine (21 g, 124 mmol) was dissolved in ethanol (200 ml). Potassium carbonate (2.5 g, 18 mmol) and 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g) dissolved in water (100 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)-1-(acenaphthen-1-yl)-piperidin-4-one (22 g) as a red-yellow oil. (4) A solution of (R)-1-(acenaphthen-1-yl)-piperidin-4-one (12.6 g, 50 mmol) and 1,2-phenylenediamine (10.8 g, 100 mmol) in THF (100 ml) was cooled to (0° C.), sodium triacetoxy borohydride (30 g) and acetic acid (12 ml) were added thereto, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into water, and potassium carbonate was added for neutralization. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)—N-[1-(acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g) as yellow crystals. (5) (R)—N-[1-(Acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g, 26 mmol) was dissolved in THF (100 ml), and carbonyldiimidazole (5 g, 30 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8.8 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1O.FC(F)(F)C1C=C([N+]([O-])=O)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[C:16]([F:15])([F:27])[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (1.45 g), 2-trifluoromethyl-4-nitrophenol (1.38 g) [which was prepared from 3-trifluoromethylnitrobenzene according to the method described in J. Org. Chem., 63 4199 (1998)] and triphenylphosphine (2.27 g) in dichloromethane (65 ml) was added dropwise diethyl azodicarboxylate (1.4 ml) in an ice bath and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant to give the desired compound (2.28 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O)(=O)[CH3:12].C1(C)C(C)=CC=CC=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([CH3:12])=[C:14]3[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: CC(=O)C1CCCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
A solution of 19.7 parts of 4-chloro-2-fluorophenylhydrazine and 14.0 parts of 2-acetylcyclohexanone in 50 parts of xylene and 1 part of glacial acetic acid were refluxed for 24 hours with a Dean Stark trap to collect the water formed. The xylene was distilled from the mixture. The residual oil was dissolved in arm hexane solution. On cooling, 6.2 parts of crude product was obtained. Recrystallization of this product yielded white crystals of 2-(4-chloro-2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole, melting point 84.5°-87.5° C; ir bands (1570 cm-1, 905 cm-1, 822 cm-1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[C:25]([NH2:34])[CH:26]=2)[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:34][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:19][CH3:20])[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]3=2)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCn1c2c(c3cc(N)ccc31)CCCC2
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.7 %

Procedure:
To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (172 mg, 0.70 mmol), 9-ethyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (150 mg, 0.70 mmol) and DIEA (0.367 mL, 2.10 mmol) in DMF (8 mL) was added HATU (399 mg, 1.05 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (179 mg, 0.404 mmol, 57.8%) as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH:12]C(OC(C)(C)C)=O)[CH2:8][O:7]1)(=[O:3])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH2:12])[CH2:8][O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1C=C[C@H](NC(=O)OC(C)(C)C)CO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCC1C=C[C@H](N)CO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of {(5S)-5-[(tert-butoxycarbonyl)amino]-5,6-dihydro-2H-pyran-2-yl}methyl acetate (205 mg, 0.756 mmol) in methylene chloride (5.2 mL) was added 4.0 M hydrogen chloride in dioxane (1.5 mL, 6.0 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to give the desired product as white solid. LCMS calculated for C8H14NO3 (M+H)+: m/z=172.1. Found: 172.1.
Reaction SMILES: CC(C)([O:4][C:5]1[N:10]=[C:9]([O:11]C(C)(C)C)[C:8]([C:16]2(O)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=[CH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:7][N:6]=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:27]1[C:18]2[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]([C:8]3[C:9](=[O:11])[NH:10][C:5](=[O:4])[NH:6][CH:7]=3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 5-(2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol and triethylsilane (64 ml) in dry dichloromethane (400 ml) at 0° C. was added trifluoroacetic acid (150 ml) dropwise over ten minutes. The cooling bath was removed and the solution was stirred at room temperature overnight. Toluene (300 ml) was added and solution was evaporated under vacuum. The residue was azeotroped with toluene (3 times). The oil was treated with diethyl ether and the precipitated product collected as a white powder (44 g).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][CH2:9][CH2:10]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:8][CH2:9][CH2:10][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7]
Reactant: OCCBr
Reactant: O=C1CSC(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CSC(=O)N1CCBr
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-thiazolidine-2,4-dione (10 g, 85.38 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), 2-bromoethan-1-ol (10.6 g, 84.82 mmol, 1.00 equiv), triphenylphosphane (27 g, 102.94 mmol, 1.20 equiv). This was followed by the addition of a solution of DIAD (21 g, 103.96 mmol, 1.20 equiv) in tetrahydrofuran (30 mL) dropwise with stirring at 0-10° C. in 30 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/50) to give 9 g (47%) of 3-(2-bromoethyl)-1,3-thiazolidine-2,4-dione as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH3:7].[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)CNC(=O)C(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CNC(=O)C(C)c1ccc(-c2ccsc2)cc1
Yield: 26.8 %

Procedure:
To a solution of N-2-methylpropyl-2-(4-bromophenyl)2-methylacetamide 1.1 g (3.9 mmol, part B above), 0.7 g (5.8 mmol) of thiophene-3-boronic acid and 0.8 g (5.8 mmol) of potassium carbonate in 12 mL of 3:1 dioxane/water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 16 hours, cooled and diluted with 10 mL of water. The mixture was extracted three times with 10 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (65 g of silica gel, 35% ethyl acetate/hexanes) of the residue afforded 0.3 g (31%) of the final title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH3:11])[N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 2,4-dichloro-6-methylpyrimidine (4.0 g) in 90 mL THF was cooled to −78 C and treated dropwise with LDA (2 M, 14.7 mL). After 35 min, iodomethane (1.55 mL) was added and the reaction was stirred for 3 more hours at −78 C. The reaction was allowed to slowly warm to room temperature, then quenched with 0.5 mL of water. The mixture was dissolved in water and extracted with ethyl acetate. Chromatography (30% ethyl acetate in hexanes) provided 1.64 g of 2,4-Dichloro-6-ethylpyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.C(O)C.Cl[CH:16]([CH3:20])[C:17](=O)[CH3:18]>CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:16]([CH3:20])=[C:17]([CH3:18])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc(C)c(C)s2)cc1
Yield: 87.3 %

Procedure:
To a stirred mixture of 65.1 g (4-methoxy)thiobenzamide and 156 ml ethanol was added dropwise 50.1 g 3-chloro-2-butanone, and the reaction mixture was heated at reflux for 3 hours. An additional 6.1 g 2-chloro-3-butanone was added and heating was continued for an additional hour. The reaction mixture was cooled, 300 ml ether added, and the solid which precipitated was collected and dried to give 74.5 g 2-(4-methoxyphenyl)-4,5-dimethylthiazole in the form of its hydrochloride monohydrate, m.p. 166°-170° C.