Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48](=[NH:50])[NH2:49])[CH:44]=2)[CH:39]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:17][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48](=[NH:49])[NH2:50])[CH:44]=2)[CH:39]=1)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 4.3 g of n-pentadecanoic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ethyl ether, then with acetone, dissolved in a methanol-dimethylformamide mixture, freed from the insolubles by filtration, and concentrated under reduced pressure. The crystals formed upon addition of ethyl ether were recrystallized from methanol to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl pentadecanoate methanesulfonate.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22][C:23](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:22]([N:8]1[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4][CH:3]([CH2:1][CH3:2])[C:9]1=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC1Oc2cccc3nc4c(c(c23)N(CC)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.98 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (2.26 g). The mixture was stirred for 20 mins, bromoethane (5.0 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with sodium bicarbonate solution (250 ml), and extracted twice with ethyl acetate (250 ml). The extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was triturated first with pentane and then diethyl ether to give 4.40 g (80.3%) of 1,3-diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 50%), MS (ISP) m/z=390.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-hydroxyacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: N#CCBr
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.2 %

Procedure:
4-Methyl-3-nitrophenol (5.0 g) (TCl America, Portland, Oreg.) and 4.70 g of bromoacetonitrile were dissolved in 30 ml of 2-butanone; then 13.5 g of potassium carbonate was added and the mixture was stirred and heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate, washed with water, dried, and evaporated to give 6.1 g of (4-methyl-3-nitrophenoxy)-acetonitrile as a brown oil. ##STR74##
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:36](O)=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][CH:27]=[N:26]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2ncccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5ncccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: CS(C(C)C(OCC)=O)(=O)=O.BrCCC=C.[CH3:17][C:18]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:24][CH2:25][C:26]#[CH:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:17][C:18]([S:28]([CH3:31])(=[O:29])=[O:30])([CH2:24][CH2:25][CH:26]=[CH2:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C#CCCC(C)(C(=O)OCC)S(C)(=O)=O
Agent: C=CCCBr
Agent: CCOC(=O)C(C)S(C)(=O)=O
Product: C=CCCC(C)(C(=O)OCC)S(C)(=O)=O
Yield: 46 %

Procedure:
The title compound (8.0 g, 46%) was prepared from ethyl 2-(methylsulfonyl)propanoate (13.3 g, 74.1 mmol) and 4-bromobut-1-ene (10.0 g, 74.1 mmol) by following the procedure described for the synthesis of ethyl 2-methyl-2-(methylsulfonyl)hex-5-ynoate (Preparation 1, Step B). MS (GCMS) m/z 235 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.33 (t, J=7.17 Hz, 3H) 1.63 (s, 3H) 1.91-2.08 (m, 2H) 2.13-2.29 (m, 1H) 2.32 (d, J=7.51 Hz, 1H) 3.05 (s, 3H) 4.29 (q, J=7.06 Hz, 2H) 4.95-5.16 (m, 2H) 5.67-5.93 (m, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1CCCC1=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C

Procedure:
Compound 20 (10.00 g, 35.7 mmol) and cuprous cyanide (13.00 , 71.4 mmol) were suspended in 1-methyl-2-pyrollidinone (250 ml) and heated under reflux for 24 h. The reaction mixture was cooled to room temperature and filtered through ‘hyflo’ to remove the excess cuprous cyanide. Water (200 ml) was added to the solution which was subsequently washed with ether (2×400 ml). The combined ether extracts were then washed with water (2×500 ml) and brine (500 ml) and then dried (MgSO4). The drying agent was filtered off and the solvent removed in vacuo to yield an off-white solid which was purified by column chromatography (dichloromethane) on silica to yield colourless crystals. Yield 5.79 g (71%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)ncnc21
Reaction time: 2 h
Yield: 53.8 %

Procedure:
6-Chloropurine (5.0 g, 32 mmol) in DMF (75 mL) was treated with potassium carbonate (9.0 g, 65 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (7.0 g, 42 mmol) and stirred for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried (MgSO4), concentrated in vacuo and purified by column chromatography (SiO2, 20% EtOAc in isohexane) to give the title compound (4.9 g, 54%) as an off-white solid. δH (CDCl3) 8.82 (1H, s), 8.32 (1H, s), 5.71 (2H, s), 3.71-3.61 (2H, m), 1.03-0.93 (2H, m), 0.00 (9H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH3:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.CO>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:7])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)c1ccco1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccco1
Reaction time: 48 h
Yield: 60.8 %

Procedure:
To an equimolar solution of 1-furan-2-yl-ethanone (250 mg, 2.27 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (454 mg, 2.27 mmol) in dichloromethane (14 mL) 1M titanium(IV) chloride in dichloromethane (1.13 mL, 1.13 mmol) and triethylamine (0.31 mL, 2.27 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere for 2 days. Then sodium cyanoborohydride (430 mg, 6.8 mmol) in methanol (7 mL) was added dropwise with stirring and the solution was allowed to stir overnight at room temperature. 35% sodium hydroxide was added and the product was extracted with ethyl acetate. The solvent was removed under reduce pressure and the crude was purified by flash chromatography (dichloromethane/methanol:95/5) to give the final compound as a red oil (406 mg, 61%).
Reaction SMILES: Cl.[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)S(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25].O>C(Cl)Cl>[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:24]([O-:26])=[O:25])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCCc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Pentylbenzothiazole hydrochloride (20.5 g, 0.084 mol) is added, at 0° C., to trifluoromethanesulfonic acid (44.6 ml 0.504 mol) and 100% nitric acid (10.6 ml, 0.215 mol) in methylene chloride (270 ml), and the mixture is stirred at 0° C. for 1.5 hours and at room temperature for one hour. Water (150 ml) is added dropwise and the phases are separated. The organic phase is washed with 0.5M NaHCO3 and with water. The resulting solution is dried, filtered and concentrated. The solid obtained is recrystallized from petroleum ether. Yield: 10.6 g (50%); Rf (8/2 petroleum ether/ethyl acetate): 0.71; 1H-NMR (d6-DMSO) 9.05 (d, 1H); 8.25 (dd, 1H); 8.15 (d, 1H); 3.13 (t, 2H); 1.28-1.36 (m, 4H); 0.85 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[N:21]([O-])=[O:22].[Na+]>Cl>[CH2:6]([C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][S:13][N:21]=[O:22])=[O:9]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Temperature: 0 °C
Yield: 80 %

Procedure:
Briefly, to a stirred ice-cold solution of glutathione (GSH) (154 mg, 0.5 mmol) in 5 ml of 0.2 N HCl was added a portion of NaNO2 (35 mg, 0.5 mmol). This reaction gives GSNO in a high yield of more than 80%. The final red solution was protected from light with aluminum foil and stable in the dark, which allow it to be used directly after synthesis without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])N(C)OC)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Reactant: Fc1ccc(Br)cc1
Product: Nc1nc2ccc(C(=O)c3ccc(F)cc3)cn2c1-c1ccccc1

Procedure:
The 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (584 mg, 1.97 mmol) and 1-bromo-4-fluorobenzene were converted to product in a manner substantially analogous to Example 141 to yield 205 mg. (52%). NMR (200 MHz, CDCl3) d 4.31 (bs, 2H, NH), 7.15 (m, 2H, F—ArH ), 7.25-7.56 (m, 7H, ArH+H7+H8), 7.78 (m, 2H, F—ArH), 8.69 (s, H5).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)CCC([O-])=O.C([O-])(O)=O.[Na+].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O.O>[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47]([NH:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cccc(C)c1OCC(=O)Cl
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
[2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane×0.5 succinate (111.9 g, 0.25 mol) was charged to a 2L, 3-necked round-bottomed flask with mechanical stirring. NaHCO3 (106 g, 1.26 mol), 600 ml H2O and 600 ml EtOAc were added and stirred vigorously until all solids were dissolved (15 minutes). Stirring was slowed and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via addition funnel. After 30 min of stirring, starting materials were consumed (HPLC analysis) and the layers were separated. The aqueous layer was extracted with EtOAc, the organic layers were combined and washed with 200 ml of 1 M NaOH, 200 ml of 10% HCl, 200 ml of brine, dried over MgSO4, filtered and concentrated to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[OH:10])=[O:4]
Reactant: COC(=O)C1CCCC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H]1O
Reaction time: 6 h
Yield: 94.9 %

Procedure:
2-Methoxycarbonyl-cyclopentanone (4.26 g) was dissolved in methanol (5 mL) and 0.1 mL 1N HCl was added. The mixture was deoxygenated, 1 (36 mg) was added and the mixture was exposed to hydrogen at 40 psi and 40° in a Parr shaker apparatus. After 6 h the reaction was complete, providing a single product (4.10 g) in >95% ee: 1H NMR (CDCl3, 250 MHz) 4.40 (q, J=7.5 Hz, 1H), 3.71 (s, 3H), 2.65 (q, J=7.2 Hz, 1H), 2.1-1.5 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:34])([F:33])[C:21]([NH:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([O:31][CH3:32])=[O:30])=[O:22].[Br:35]CCBr.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:35][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:33])[F:34])[CH:28]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Temperature: -78 °C

Procedure:
To a solution of diisopropylamine (20 mL) in tetrahydrofuran (200 mL) was added 1.6M n-butyllithium/hexane solution (82.4 mL) while stirring under ice-cooling, and the mixture was stirred at 0° C. for 15 min. After stirring, the reaction system was cooled to −78° C., and a solution of methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (10 g) in tetrahydrofuran (50 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and 1,2-dibromoethane (20.6 mL) was added. After stirring at the same temperature for 30 min, the reaction system was allowed to warm to room temperature, and further stirred for 30 min. The reaction system was poured into saturated aqueous sodium hydrogen carbonate (600 mL), and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.3 g) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.CCN(CC)CC>CO>[CH:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCc1ccccc1I
Reactant: C1=CCCCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OCc1ccccc1C1CCCCC1
Yield: 42 %

Procedure:
According to example 61, 10.0 g of 2-iodobenzyl alcohol was treated with 25 mL of cyclohexene (Aldrich) using 0.96 g of Pd(O Ac)2, 2.60 g of tri-ortho-tolyphosphine, and 6.6 mL of Et3N at 100° C. for 48 h. The resulting olefin mixture was hydrogenated for 6.5 h using 0.36 g of 5% Pt(C) in MeOH to afford 3.37 g (42%) of 2-cyclohexyl benzyl alcohol as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[Cl:8].NN>CO>[NH2:20][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 296 (4.71 g, 10.5 mmol) in MeOH was added hydrazine (0.336 g, 10.5 mmol) and the reaction was stirred at RT overnight. The thick white suspension was taken up in hot MeOH, sonicated, filtered and washed with MeOH. The filtrate was concentrated to afford 2.98 g (89%) of tert-butyl 3-amino-3-(3,4-dichlorophenyl)propylcarbamate (298) as a pale yellow foam: LRMS (APCI pos) m/e=319.0 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH2:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=CCCCCCCOc1ccc(-c2ccc(C(=O)OCC(C)CC)cc2)cc1
Yield: 76.9 %

Procedure:
5.1 g of 8-bromo-1-octene, 8.2 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, and 4.0 g of potassium carbonate were refluxed in acetone for 20 hours. After the conclusion of the reaction, the reaction product was diluted with dichloromethane, and the inorganic matters were removed by filtration. The solvent was distilled out under reduced pressure, and the residue was purified by column chromatography to obtain 8.1 g of the objective 2-methylbutyl 4'-(7-octenyloxy)biphenyl-4-carboxylate. (Yield: 77%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27]([NH:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:28])[CH3:23]
Reactant: Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)CC(=O)Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-(2-chloro-phenylethynyl)-6-trifluoromethyl-phenylamine and chlorocarbonyl-acetic acid ethyl ester. Off white solid (1.2 g, 45%) LC-MS (ESI): 444 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:17]1[S:21](=O)[CH2:20][CH2:19][CH2:18]1.C(OC(C)C)(C)C.[F:30][C:31]([F:55])([S:51]([O-:54])(=[O:53])=[O:52])[CH:32]([O:37][C:38]([C:40]12[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([C:43]3=[O:50])[CH2:41]1)[CH2:47]2)=[O:39])[C:33]([F:36])([F:35])[F:34].C([NH+](CC)CC)C>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[F:55][C:31]([F:30])([S:51]([O-:54])(=[O:52])=[O:53])[CH:32]([O:37][C:38]([C:40]12[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([C:43]3=[O:50])[CH2:41]1)[CH2:47]2)=[O:39])[C:33]([F:34])([F:36])[F:35].[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S+:21]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][CH:6]=1
Reactant: O=S1CCCC1
Reactant: FC(F)(F)COc1cccc2ccccc12
Agent: CC[NH+](CC)CC
Agent: CS(=O)(=O)O
Agent: O=C1C2CC3CC1CC(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])(C3)C2
Solvent: CC(C)OC(C)C
Solvent: O
Product: FC(F)(F)COc1ccc([S+]2CCCC2)c2ccccc12
Reaction time: 8 h

Procedure:
In 6 g of Eaton's reagent (Aldrich, diphosphorus pentoxide/methanesulfonic acid solution) was dispersed 2.4 g (0.0107 mol) of 1-(2,2,2-trifluoroethoxy)naphthalene in Synthesis Example 1-3. With stirring, 2.2 g (0.0214 mol) of tetramethylene sulfoxide was added dropwise to the dispersion. The solution was matured overnight at room temperature and combined with 30 g of water and 30 g of diisopropyl ether, from which a water layer was separated. The water layer was again washed with 30 g of diisopropyl ether. This aqueous solution was combined with an aqueous solution of triethylammonium 1,1,3,3,3-pentafluoro-2-(4-oxoadamantane-1-carbonyloxy)-1-propanesulfonate (corresponding to 0.0086 mol) synthesized in accordance with the teaching of JP-A 2008-106045, after which extraction was effected twice with 50 g of dichloromethane. The organic layer was washed with water, distilled in vacuum to remove the solvent, and dried, obtaining the target compound. Amorphous solids, 5.2 g, yield 84%.