Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:23][CH:24]=1.O>CN(C)C=O>[C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][CH:7]4[S:11][C:10](=[O:12])[NH:9][C:8]4=[O:13])=[CH:4][CH:3]=3)[N:21]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)S1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (9.4 g) in N,N-dimethylformamide (80 ml) was added 60% sodium hydride in oil (3.4 g), and the mixture was stirred for 30 minutes. Then, a solution of 4-chloromethyl-2-phenyloxazole (9.6 g) in N,N-dimethylformamide (20 ml) was added dropwise thereto at room temperature. After being stirred at 70° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 5-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (9.1 g, 47.4%). Recrystallization from ethanol yielded colorless needles. m.p. 188°-189° C. Elemental analysis for C20H16N2O4S; Calcd.: C, 63.15; H, 4.24; N, 7.36. Found: C, 63.19; H, 4.16; N, 7.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=3[CH:27]=[N:26][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc(Cl)c4c(c3)CCC(=O)N4C)cncc21
Yield: 35 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-8) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound (47.2 mg, 35%) as a white solid. MS: 434.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[Br:16]Br.[OH-].[Na+]>C(O)(=O)C>[Br:16][C:4]1[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:13]([O:14][CH3:15])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2c(c(Br)c1OC)CCNCC2
Temperature: 70 °C

Procedure:
To a solution of 12.8 g. (0.052 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 1) in 50 ml. of glacial acetic acid at 55° C. was added 3.0 ml. of bromine (8.8 g., 0.055 mole) dropwise over 1 hour with stirring. After addition was completed, the temperature was raised to 70° C. for 2 hours. The reaction mixture was poured into ice/water and made basic with 40% sodium hydroxide solution. The basic solution was extracted with ethyl acetate and the extract dried over sodium sulfate. Removal of the solvent gave 6-bromo-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12]>C1(C)C=CC=CC=1>[F:10][C:4]1[CH:3]=[C:2]([CH:11]=[CH2:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (4.92 g, 0.0246 mol), vinyltributyltin (0.78 g, 0.246 mol), and tetrakistriphenylphosphine (0.67 g, 0.58 mmol) in 250 mL of toluene was refluxed under nitrogen overnight. The solvent was evaporated and the residue was flash chromatographed on silica gel with heptane:CH2Cl2 (1:1) to pure CH2Cl2. A colourless oil was obtained that crystallised. Yield: 3.0 g (82%).
Reaction SMILES: C([N:8]1[C@@H:17]2[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CCO>[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:12]2[C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H]2CCCC[C@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN[C@H]2CCCC[C@H]21
Yield: 95.7 %

Procedure:
Pearlman's catalyst (0.24 g) was added to an EtOH (25 ml) solution of (4aS,8aR) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.4 g, 7.26 mmol). This suspension was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered through celite, and the residue was washed with EtOH. Then, the filtrate was concentrated under reduced pressure to obtain (4aS,8aR)-tert-butyl decahydroquinoxaline-1-carboxylate (1.67 g, yield: 96%) in a colorless oil form.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[N:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][N:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1cnc(C)cn1
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.054 g, 0.25 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.112 g, 0.002 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.033 g, 0.75 mmol) was added and stirred for further 1 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 60% yield). 8-Ethyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.000149 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.019 g, 0.000149 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.035 g, 50% yield).
Reaction SMILES: CI.[CH3:3][C:4](=[N:9][OH:10])[C:5](=[O:8])[CH2:6][CH3:7].[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][N:9]=[C:4]([C:5](=[O:8])[CH2:6][CH3:7])[CH3:3]
Reactant: CCC(=O)C(C)=NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)C(C)=NOC
Reaction time: 12 h

Procedure:
49.7 g (0.35 mol) of methyl iodide are added dropwise at room temperature to a solution of 40.2 g (0.55 mol) of pentane-2,3-dione 2-oxime and 52.0 g (0.38 mol) of potassium carbonate in 400 ml of acetone, and stirring is continued for 12 hours at this temperature.
Reaction SMILES: [CH:1]12[C:13](=O)[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13.[CH3:19][NH2:20].[BH4-].[Na+]>CO.C(O)C>[CH3:19][NH:20][CH:1]1[CH:8]2[C:2]3[C:3]([CH2:18][CH:17]=[CH:16][CH:15]=3)=[C:4]3[CH:13]1[CH:5]3[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12
Reactant: CN
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNC1C2C3=CC=CCC3=C3C(c4ccccc42)C31

Procedure:
An amount of 11.6 g (0.05 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one [V. Ioan, M. Popovici et al.: Tetrahedron Letters 38, 3383 (1965)] is dissolved in 200 ml of methanol, and 50 ml of a 33% solution of methylamine in ethanol added; the whole is heated, with stirring, to 35°, and subsequently stirred for a further hour at ca. 20°, whereby a thick precipitate is formed. There is then introduced into the reaction mixture with stirring, 3.8 g (0.1 mole) of sodium borohydride, with the temperature being maintained at 20° by cooling. The reaction mixture is subsequently stirred for one hour at 20° and then briefly refluxed. After cooling, the reaction mixture is completely concentrated in a waterjet vacuum. The residue is distributed between water and ether, and the ethereal phase extracted with 2N hydrochloric acid. The combined acidified extracts are rendered alkaline with concentrated ammonia and extracted with ether; the combined ether extracts are washed with water, dried over sodium sulphate and concentrated in a waterjet vacuum to obtain N-methyl-1,1a,6,10-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cycloheptene-11-amine; M.P. 142°-143°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[C:5]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]3=[N:3][C:2]=4[NH2:1])=[CH:19][CH:18]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: BrC1CCCC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC4CCCC4)cc3)cc12

Procedure:
2-(4-(Cyclopentyloxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using bromocyclopentane. 1H NMR (Acetone-d6): δ 8.75 (d, 2H), 8.30 (d, 1H), 7.45 (s, 1H), 7.20 (d, 1H), 7.14 (d, 2H), 6.79 (d, 2H), 4.73-4.81 (m, 1H), 3.22 (t, 2H), 3.05 (t, 2H), 2.47 (s, 3H), 1.85-1.96 (m, 2H), 1.70-1.79 (m, 4H), 1.56-1.64 (m, 2H). LRMS [M+H]=398.2
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH3:19][C:16]1[N:15]=[C:14]([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[O:18][N:17]=1
Reactant: COc1cc(-c2nc(C)no2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: Cc1noc(-c2cc(O)c(O)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.5 g of 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole are dissolved in 70 ml of methylene chloride. After cooling to -60° there is added dropwise thereto within 20 minutes while stirring a solution of 23.62 g of boron tribromide in 50 ml of methylene chloride, whereupon the mixture is held at the reflux temperature for 48 hours. After cooling to -60°, the mixture is treated with 60 ml of ethanol and subsequently stirred at room temperature for 30 minutes. The yellow solution is evaporated to dryness, whereupon the residue is treated three times with 100 ml of toluene/ethanol (1:1) each time and the solvent is distilled each time. After crystallization from ethanol, there is obtained 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitropyrocatechol in the form of yellow crystals of m.p. 201°-202°.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:3]2[C:2]=1[N:1]=[C:21]([CH2:20][Cl:19])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:4]2=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Yield: 74.1 %

Procedure:
Prepared according to Procedure B with 1h (500 mg, 1.78 mmol) and chloroacetyl chloride (0.49 mL, 6.13 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by recrystallization from isopropanol to afford 448 mg of a yellow solid (74%). 1H NMR (CDCl3) δ: 8.23 (dd, J=1.4, 8.0 Hz, 1H); 7.90 (dd, J=1.4, 7.8 Hz, 1H); 7.61-7.66 (m, 1H); 7.51-7.55 (m, 3H); 7.47 (t, J=8.0 Hz, 1H); 4.48 (d, J=12 Hz, 1H), 4.12 (d, J=12 Hz, 1H). MS (ES): m/z 339.0 (M+).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([I:3])[CH:5]=2)[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3-iodobenzyl alcohol (1.85 g; 7.9 mmol) in anhydrous DMF (5 mL) over 30 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.0 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 2 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting solid is filtered, washed with water, and dried under vacuum at 30° C. overnight to give 1.86 grams of 2-fluoro-6-(3-iodobenzyloxy)-benzonitrile.
Reaction SMILES: [CH:1]([C:3]1([OH:13])[CH2:8][CH2:7][CH:6]([C:9](C)(C)C)[CH2:5][CH2:4]1)=[CH2:2].[C:14]1(C)C=CC=C[CH:15]=1>>[CH:1]([C:3]([OH:13])([CH2:8][CH2:7][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH3:9])=[CH2:2]
Reactant: Cc1ccccc1
Reactant: C=CC1(O)CCC(C(C)(C)C)CC1
Product: C=CC(O)(CCCC)CCCC

Procedure:
A solution of 2.0 grams of 1-vinyl-4-tert-butylcyclohexanol in 30 ml of toluene containing 40 mg of MTO was refluxed 4 hrs. TLC analysis indicated the presence of some residual starting material, so an additional 10 mg of MTO was added and reflux continued until the starting material was consumed. Workup as in the case of 5-vinyl-5-nonanol above gave 1.25 g (69%) of product as a colorless liquid, bp 90 deg C./15 mm Hg. NMR spectrum was consistent with that expected for the product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:15](I)([CH3:17])[CH3:16].O>CN(C=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1ccc(I)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 4-iodoaniline (4.38 g, 20.0 mmol), Cs2CO3 (16.3 g, 50.0 mmol), isopropyliodide (3.0 mL, 30.0 mmol) in DMF (20 mL) was stirred in a sealed tube at 70° C. for 24 h. The mixture was cooled to room temperature and poured into water (200 mL). The organic layer was separated and washed with water and brine and purified on silica gel (CH2Cl2/hexanes, 1:1) to provide (4-iodophenyl)-isopropylamine (3.26 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1>C(OCC)C.C1COCC1>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CC(O)(Cc2cc3ccccc3[nH]2)C(F)(F)F)CCOc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a chilled (−78° C.) solution of 95.0 mg (0.72 mmol) of 2-methylindole in 10 mL of diethyl ether was added 710 μL (1.77 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 5 minutes, 1.16 mL (1.16 mmol) of a 1 M solution of potassium tert-butoxide in THF was added and the mixture was warmed until a yellow precipitate formed. After 20 minutes, the reaction was cooled to −78° C. and 200 mg (0.72 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 2 mL of diethyl ether was added. The reaction stirred at −78° C. for 30 minutes and was then warmed to room temperature, quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a PLC plate with hexanes-EtOAc (8:2) to afford a mixture of two diastereomers. The diastereomers were separated on a PLC plate (hexanes-CH2Cl2 (1:1)) to give two diastereomer. One was purified again by PLC plate (hexanes-CH2Cl2 (1:1)) to afford 20 mg of the first diastereomer (M+1=408) and the second was triturated with hexanes and the solid collected by filtration to afford 15 mg of the other diastereomer (M+1=408) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:12][NH:13][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ncc(C(F)(F)F)cc1Cl)c1ccco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine (1 mmol) in tetrahydrofuran (5 ml) was added triethylamine (1 mmol) at room temperature and the mixture was stirred at room temperature for 1.5 hour. The mixture was added to a solution of 2-furoyl chloride (1 mmol) in tetrahydrofuran (5 ml) at room temperature and left to stir at room temperature overnight. The mixture was evaporated to dryness and the residue washed with water. The solid was filtered, washed with diethyl ether/light petroleum (b.p. 60-80° C.) and dried to give the title product, 1H N.M.R. (CDCl3) δ (ppm) 4.9 (2H, d), 6.55 (1H, m), 7.2 (1H, m), 7.5 (1H, s), 7.8 (1H, br.s), 8.0 (1H, s) and 8,8 (1H, s).
Reaction SMILES: Cl.[C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)(=[NH:4])[CH3:3].[C:34]([O:37][CH:38]([O:40][C:41](C1C=C([N+]([O-])=O)C=CC=1O)=[O:42])[CH3:39])(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:34]([O:37][CH:38]([O:40][C:41]([CH2:3][C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[NH:4])=[O:42])[CH3:39])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)OC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
A solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 0-(1-acetoxyethoxycarbonyl)-4-nitrophenol (63 mg) and diisopropylethylamine (72 mg) in DMF (4 ml) was stirred at 50t for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water, sodium hydrogen carbonate aqueous solution and brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give a colorless solid of the title compound (89 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([CH2:20]OS(C)(=O)=O)[C:16]2=[O:26])=[CH:11][CH:10]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([CH2:20][N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:32][CH2:33]3)[C:16]2=[O:26])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Reactant: COCCN1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 86.3 %

Procedure:
Triethylamine (8.0 g) was added to a solution of 18.5 g of 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 17.6 g of 1-(2-methoxyethyl)piperazine in 50 mL of acetonitrile, and the mixture was heated under reflux for 4 hours. After concentrating, water was added to the reaction mixture to precipitate crystals, which were then collected by filtration and dried in vacuo to give 18.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:62][S:59]([CH:56]6[CH2:58][CH2:57]6)(=[O:61])=[O:60])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 29 (85 mg, 0.14 mmol) and CDI (47 mg, 0.29 mmol) in dry THF (7 mL) is heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). The reaction mixture is cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) is added. Then, DBU (50 μL, 0.33 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. Solvent is evaporated, and the residue partitioned between AcOEt and acidic water (pH=3). The crude material is purified by column chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1). The residue is crystallized in Et2O, filtered to give the target compound contaminated with the cyclopropyl-sulfonamide. This material is triturated in 3 ml of water, filtered, washed with water and dried overnight in the high vacuum pump to give the target compound 30 as a white powder: m/z=708 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14][S:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=3)(=[O:25])=[O:24])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(COCCC2CC2)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCCC2CC2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-(trifluormethyl)-benzenesulfonyl chloride (0.11 g) as a light yellow gum (0.106 g). MS (ESI−): 399.2 ([M−H]−).