Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9]Br)[CH3:2].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][C:14]=2[O:13]1.[OH-].[K+]>COCCOC>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9][O:21][C:16]1[CH:17]=[CH:18][C:19]2[O:20][CH2:12][O:13][C:14]=2[CH:15]=1)[CH3:2]
Reactant: CCOCCCC(C)=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOCCCC(C)=CCOc1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
2.21 g (0.01 mol) of 6-ethoxy-1-bromo-3-methyl-2-hexene are added at 5° and while stirring to 1.38 g (0.01 mol) of 3,4-methylendioxyphenol and 0.56 g (0.01 mol) of potassium hydroxide in 50 cc of 1,2-dimethoxyethane. After stirring at 5° for 2 hours the mixture is stirred at 20°-25° during the course of 60 hours, is subsequently filtered and the filtrate is evaporated at reduced pressure. The residue is taken up in ether, is washed with water, dried with sodium sulphate, and the ether is distilled off. After chromatography of the residue on silica gel with hexane/ethyl acetate 9 : 1, 5-(6-ethoxy-3-methyl-2-hexenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5192.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:14]([O:16][CH3:17])=O.CI>CN(C)C=O.O.CO.O1CCCC1.CCCCCC>[CH3:14][O:16][CH:17]=[C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: COC=C(C(=O)OC)c1ccccc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine hexane washed sodium hydride (24 g, 60% in oil, 580 mmol) and tetrahydrofuran (400mL). Cool to about 5° C. Simultaneously, add dropwise methyl phenylacetate (40 g, 270 mmol) and the methyl formate (35 g, 580 mmol). Add methanol (0.5 mL). Warm to ambient temperature. After 18 hours, pass nitrogen gas over the reaction mixture to remove the solvent to give a residue. Dissolve the residue in dimethylformamide (400 mL) and cool to about 5° C. Slowly add methyl iodide (76 g, 540 mmol). After the addition is complete, warm to ambient temperature. After 3 hours, pour the reaction mixture into water and extract 2 times with diethyl ether. Extract the combined organic layers 5 times with water and once with aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4 and evaporate in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]1(=[O:21])[O:15][CH2:14][CH:13]2[CH2:16][CH2:17][CH:18]3[CH2:20][CH:19]3[CH:12]12>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH:13]2[CH2:16][CH2:17][CH:18]3[CH:19]([CH2:20]3)[CH:12]2[C:11]([OH:21])=[O:15])=[CH:6][CH:5]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1OCC2CCC3CC3C12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1C(CSc2ccc(F)cc2)CCC2CC21
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (165 mg, 4.05 mmol) in dry dimethylformamide (10 mL) under an atmosphere of dry nitrogen was added 4-fluorothiophenol (430 μL, 4.05 mmol) dropwise and the reaction was stirred for 15 min. A solution of (3αR/S,5αS/R,6αR/S,6βR/S)-octahydro-1H-cyclopropa[3,4]benzo[1,2-c]furan-1-one (202 mg, 1.35 mmol) in dry dimethylformamide (2 mL) was added to the reaction mixture and was heated to 110° C. for 4.5 h. The reaction mixture was cooled to room temperature and quenched with aqueous 10% HCl, the product extracted with ethyl acetate, and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 2/8+0.5% AcOH) to afford the desired product (1R/S,2R/S,3R/S,6S/R)-3-{[(4-fluorophenyl)-sulfanyl]methyl}bicyclo[4.1.0]heptane-2-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[S:22][C:12]3=[N:13][C:14](O)=[C:15]([N+:18]([O-:20])=[O:19])[C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:14]1[N:13]=[C:12]2[S:22][C:9]([CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:10][N:11]2[C:16](=[O:17])[C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: O=c1c([N+](=O)[O-])c(O)nc2sc(CCC3CCCCC3)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: O=c1c([N+](=O)[O-])c(Cl)nc2sc(CCC3CCCCC3)nn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 30 ml of phosphorous oxychloride was suspended 10.2 g of 2-(2-cyclohexylethyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 4 ml of tripropylamine was added dropwise to the suspension at room temperature while stirring. The stirring was continued at 80° to 85° C. for an additional 3 hours. After cooling, the reaction mixture was poured into ice-water, and the precipitate formed was collected by filtration and washed with water to obtain 10.4 g of 7-chloro-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a crystalline powder.
Reaction SMILES: C[O-].[Na+].[CH3:4][CH:5]([SH:7])[CH3:6].[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)([O-:10])=[O:9]>CO>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][S:7][CH:5]([CH3:6])[CH3:4])[CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)SCc1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxide (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with 2-propanethiol (6.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (300 mL), washed with water (2×100 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (12.3 g) was thus obtained and used without further purification.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])C1C=CC=CC=1>>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][C:5]([O:27][CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(OC)cc1
Yield: 59 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting p-anisoyl chloride for benzoyl chloride, the title compound was obtained as a light yellow solid in 59% yield: 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.87 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.30(t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.39 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.19, 24.29, 24.75, 28.91, 28.96, 34.21, 38.06, 55.37, 60.10, 113.58, 130.02, 130.21, 163.23, 173.71, 198.93.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1

Procedure:
2-Methyl-4-thiazolecarboxylic acid ethyl ester (1 g) (Liebigs Ann. Chem. 1981, 623), N-bromosuccinimide (1.04 g) and a catalytic amount of benzoyl peroxide in chloroform (25 ml) was heated at reflux for 20 hours. After cooling, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 40% ethyl acetate in isohexane to give the product as an oil. Yield 0.5 g.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:21]=C)[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+].C(OCC)(=O)C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:21]=[O:26])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OCCNC(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(C=O)c1OCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
tert-Butyl [2-(6-acetyl-4-chloro-3-methyl-2-vinylphenoxy)ethyl]carbamate (4.1 g, 12 mmol) was dissolved in tetrahydrofuran (300 mL) and 0.157 M osmium tetraoxide in water (10 mL) was added followed by a solution of sodium metaperiodate (7.4 g, 35 mmol) in water (20 mL). The reaction was stirred at 60° C. for 2 hours. Additional 0.157 M osmium tetraoxide in water (10 mL) and a solution of sodium metaperiodate (7.4 g, 35 mmol) in water (20 mL) were added and the mixture was heated at 60° C. for 2 more hours. The mixture was poured into ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-12%) gave the desired compound (3.0 g, 73%) (note: elutes as 2 separate peaks in both normal and reversed phase chromatography). LCMS calculated for C17H22ClNO5Na (M+Na)+: m/z=378.1; found: 378.0.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
0.13 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2-trifluoromethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.18 g of the title compound. ES MS (+) m/z 411.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[S:15][C:16]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[S:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)OCc2ccccc2)csc1-c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 64.5 %

Procedure:
10% Pd/C (13.7 mg, 13 μmol, 20 mol % Pd) was added to methyl 4-(benzyloxycarbonylamino)-2-(4-chlorophenyl)-5-bromothiophene-3-carboxylate (6) (31.0 mg, 64 μmol) in ethanol:ethyl acetate:dichloromethane (2:1:1, 2.0 mL). The mixture was degassed and placed under H2 (1 atm) and stirred for 4 h. The mixture was filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 7 (16.6 mg, 64%) as a solid: LRESIMS m/z 401.9 [M+H]+, calcd. for C20H17Cl1N1O4S1 402.6.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[S:39][CH:43]=[CH:42][CH:41]=1)(=[O:20])=[O:21])(=[O:30])=[O:29]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccs3)c2c1
Yield: 36.5 %

Procedure:
2-Methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)-benzenesulfonamide can be obtained as described in Example 47 from 1.5 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 339 mg of 2-thiopheneboronic acid, 50 ml of dimethylformamide, 4.8 ml of a saturated aqueous sodium hydrogencarbonate solution and 64 mg of tetrakis(triphenylphosphine)palladium[0]. 350 mg of 2-methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of an ochre solid melting at 246° C. (analysis C18H15N3O4S3 % calculated C, 49.87; H, 3.49; N, 9.69; O, 14.76; S, 22.19. % found C, 49.82; H, 3.67; N, 9.08; S, 20.42).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH:16]=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.[CH:18]([Mg]Br)([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH:16]([OH:17])[CH:18]([CH3:20])[CH3:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Br
Reactant: COc1ccc(C=O)cc1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C)cc1-c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 4′-fluoro-6-methoxy[1,1′-biphenyl]-3-carbaldehyde (5.00 g) in THF (80 ml) was added dropwise a solution (0.63; 44.8 ml) of isopropylmagnesium bromide in THF at 0° C., and the mixture was stirred for 1 h 45 min. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane:ethyl acetate=6:1→2:1) to give the title compound (3.82 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:26]([CH:22]4[CH2:25][CH2:24][CH2:23]4)=[O:27])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)C1CCC1
Product: Cc1ccc(NC(=O)C2CCC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)cyclobutanecarboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and cyclobutanecarboxylic acid using method D. NMR; δH [2H6]—DMSO 9.71,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.52-7.49,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.21-3.14,(3H, m), 2.24-2.15,(5H, m), 2.07,(2H, m), 1.91, (1H, m), 1.78,(1H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.30 min, MH+363.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:15]
Reactant: Cn1nnnc1CCCCC(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
(5-(1-Methyl-1,2,3,4-tetrazol-5-yl)valeric acid (1.8 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at rood temperature, and the mixture is stirred for 2 hours. Dimethylformamide is distilled off under reduced pressure, and the residue is purified by column chromatography (Wakogel C-200). After eluting with benzene-chloroform (1:1), the eluate is distilled under reduced pressure to give N,N-diethyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeramide (0.7 g), colorless liquid, b.p. 190°-200° C. (bath temperature)/0.07 mmHg, nD25 =1.4907.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]=[O:9].[C:14]([Mg]Br)#[CH:15]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]([OH:9])[C:14]#[CH:15]
Reactant: C#C[Mg]Br
Reactant: O=CCc1sc2ccccc2c1Cl
Solvent: C1CCOC1
Product: C#CC(O)Cc1sc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A solution of 2-(3-chlorobenzo[b]thiophen-2-yl)acetaldehyde (1.100 g, 5.60 mmol) in 10 mL THF was added dropwise (cannula) to an ice-cold solution of the ethynylmagnesium bromide (25 mL, 12.5 mmol, 0.5 M/THF). The reaction was stirred for 1 h at 0° C. and for 1 h at room temperature and then was quenched by addition of 100 mL saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (3×) and the combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (475 mg, 65%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CN(C)C=O.CC([N:16]([C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[CH:31])[CH:28]=2)[N:23]([C:32](=[O:34])[CH3:33])[C@@H:22]([CH3:35])[CH2:21]1)[C:17](=[O:19])[O-:18])(C)C>[Cu]I.CO>[C:32]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[N:3]=[N:2][N:1]([CH2:4][CH2:5][OH:6])[CH:31]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:16][C:17](=[O:19])[O:18][C:27]([CH3:30])([CH3:28])[CH3:26])[CH2:21][C@@H:22]1[CH3:35])(=[O:34])[CH3:33]
Reactant: [N-]=[N+]=NCCO
Reactant: C#Cc1ccc2c(c1)[C@H](N(C(=O)[O-])C(C)(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A flask was charged with 2-azidoethanol (318 mg, 3.65 mmol) and copper(I) iodide (17.40 mg, 0.091 mmol) then filled with N,N-dimethylformamide (DMF) (13 mL) and methanol (1.5 mL). This mixture was treated with 1,1-dimethylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 48) (600 mg, 1.827 mmol) and the resulting mixture was stirred at 100° C. for 2 h under microwave irradiation then cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, and then dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:0 to 5% MeOH in DCM) gave 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (659 mg, 1.523 mmol, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([NH:15][C:14]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:13]=2[CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NC(=O)c1cnc(Cl)nc1Cl
Temperature: 50 °C

Procedure:
To a mixture of 20.3 g (96 mmol) of 2,4-dichloropyrimidine-5-carbonyl chloride 29 and Amberlyst A21 (2.1 g) in 400 mL of EtOAc was added dropwise 11.7 mL of 2,6-dimethylaniline (95 mmol) at room temperature. The resulting mixture was heated to 50° C. for 12 h, and then was filtered. The filtrate was washed sequentially with water (200 mL), 1N HCl (50 mL), 1N NaOH (50 mL), and brine (100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was washed with a small amount of DCM to give the title compound as a white solid. Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.36 g, 42% yield), mp=68–72° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=−21.0° (c=1, EtOH).