Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Br:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>C(#N)C>[CH3:4][CH2:3][CH2:2][CH2:1][N+:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH3:9].[Br-:5]
Reactant: CCCCN(CCCC)CCCC
Reactant: CCCCBr
Solvent: CC#N
Product: CCCC[N+](CCCC)(CCCC)CCCC
Product: [Br-]
Yield: 87 %

Procedure:
A solution of 60.3 g. n-butylbromide and 74.1 g. tributylamine in 100 ml chromatoquality acetonitrile was refluxed for 20 hours under argon. The reaction mixture was cooled and evaporated at 20°-30°C to near dryness. The resulting crystalline mass was washed with 300 ml cyclohexene, dissolved in 100 ml water, and further washed with cyclohexene, and then with 100 ml hexane. TBAB yield = 87 percent.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[N+:10]([C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])([O-:12])=[O:11]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1)[C:17](=[O:18])[CH:16]([O:15][C:14]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][C:13]=1[N+:10]([O-:12])=[O:11])[CH3:20])[CH3:2]
Reactant: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CCNCc1ccco1
Solvent: ClCCl
Product: CCN(Cc1ccco1)C(=O)C(C)Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: -15 °C

Procedure:
N-Ethyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-ethyl-N-furfuryl-2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionamide.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][S:8][CH:9]=1)[CH2:2][CH3:3].C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>C1COCC1.CCCCCC>[CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:16])([CH3:15])[CH3:17])(=[O:12])=[O:11])=[C:7]([C:23]([OH:25])=[O:24])[S:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C=O
Reactant: CCCSc1cscc1S(=O)(=O)NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCSc1csc(C(=O)O)c1S(=O)(=O)NC(C)(C)C
Temperature: 20 °C

Procedure:
A solution of 12.15 g 4-propylthio-3-N-(1,1-dimethylethyl)-3-thiophenesulfonamide in 150 mL THF was cooled to -30° C. and treated dropwise with 31.6 mL 2.69M n-butyllithium in hexane. The solution was warmed to 20° C. for 1.5 hours and then cooled to -80° C. 8.8 g Solid carbon dioxide was added in one portion, the mixture was warmed to 20° C. and poured over ice and hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to a solid. The product was purified by recrystallization from butyl chloride to give 10.4 g of light yellow solid; m.p. 123°-126° C.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:62]=[C:63]([NH2:66])[S:64][CH:65]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:66][C:63]1[S:64][CH:65]=[C:61]([C:58]2[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=2)[N:62]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-Pro-OH (1.46 g, 5.85 mmol) and HATU (2.2 g, 5.85 mmol) were combined in 30 mL of dry DMF. To this solution was added DIEA(1.5 mL, 8.8 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 4-(4-nitro-phenyl)-thiazol-2-ylamine (1.0 g, 4.5 mmol). Reaction mixture was stirred at room temperature overnight. The crude material was purified using HPLC to yield 2-[4-(4-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester. MS: 453.1 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:17]([O:21][C:22](=[O:38])[CH2:23]OC1C=NC(C2C=CC=CC=2F)=CC=1)([CH3:20])([CH3:19])[CH3:18].C(OC(=O)CBr)(C)(C)C>CN(C=O)C>[C:17]([O:21][C:22](=[O:38])[CH2:23][O:16][C:13]1[CH:14]=[N:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nc1
Reactant: Oc1ccc(-c2ccc(F)cc2)nc1
Agent: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
119 mg (2.72 mmol) of sodium hydride (55% in mineral oil) were added to 430 mg (2.27 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ol (prepared analogously as described in Example 76(a) to (d)) in 10 ml of DMF, and the mixture was stirred at room temperature for 60 min. Then 532 mg (2.72 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 3 h. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried, and evaporated. Yield: 433 mg.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6]C[C:4]1=O)=C.[C:9](NCCCN(C)C)(=[O:13])[C:10]([CH3:12])=C.C(N1CCCC1=[O:28])=C.CN(CCCC=C(C)C(N)=O)C.CC(C(NCCC[N+](C)(C)C)=O)=C.C=CN1C(=O)CCC1.[Cl-]>>[C:9]([O:13][CH2:6][CH2:7][N:3]([CH3:1])[CH3:4])(=[O:28])[CH:10]=[CH2:12]
Reactant: C=CN1CCCC1=O
Reactant: C=C(C)C(=O)NCCCN(C)C
Agent: C=C(C)C(=O)NCCC[N+](C)(C)C
Agent: CC(=CCCCN(C)C)C(N)=O
Agent: [Cl-]
Product: C=CC(=O)OCCN(C)C

Procedure:
vinylpyrrolidone/methacrylamidopropyldimethylamine copolymers sold, for example, under the name STYLEZE CC 10 by ISP, quaternized vinylpyrrolidone/dimethylaminopropylmethacrylamide copolymers such as the product sold under the name GAFQUAT HS 100 by the company ISP, and crosslinked polymers of methacryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salts such as the polymers obtained by homopolymerization of dimethylaminoethyl acrylate quaternized with methyl chloride, or by copolymerization of acrylamide with dimethylaminoethyl acrylate quaternized with methyl chloride, the homo- or copolymerization being followed by crosslinking with a compound containing olefinic unsaturation, such as methylenebisacrylamide. In at least one embodiment, a crosslinked acrylamide/methacryloyloxyethyltrimethylammonium chloride copolymer (20/80 by weight) in the form of a dispersion containing 50% by weight of the copolymer in mineral oil can be used. This dispersion is sold under the name SALCARE® SC 92 by the company Ciba. In some embodiments, a crosslinked methacryloyloxyethyltrimethylammonium chloride homopolymer containing about 50% by weight of the homopolymer in mineral oil or in a liquid ester can be used. These dispersions are sold under the names SALCARE® SC 95 and SALCARE® SC 96 by the company Ciba.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice-water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1 H), 7.02 (d, J=2.1 Hz, 1 H), 6.87 (dd, J=2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H).
Reaction SMILES: [NH2:1][OH:2].[CH:3]1([O:8][C:9]2[C:10]([O:27][CH3:28])=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][CH2:21][C:22](OCC)=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)C>[CH:3]1([O:8][C:9]2[C:10]([O:27][CH3:28])=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][CH2:21][C:22]([NH:1][OH:2])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)CNc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Reactant: NO
Solvent: CCO
Product: COc1ccc2c(NCC(=O)NO)cc(=O)oc2c1OC1CCCC1
Reaction time: 6 h

Procedure:
Hydroxylamine (0.5 mL, 50% water, 8.2 mmol) was added to a solution of ethyl 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetate (40 mg, 0.11 mmol, Example 8) and ethanol (0.5 mL) and stirred vigorously. After 6 h, the precipitate was filtered, washed with 65% ethanol (2 mL), and dried to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)-N-hydroxyacetamide: 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.97 (s, 1H), 7.93 (t, 1H), 7.71 (d, 1H), 7.07 (d, 1H), 4.90 (s, 1H), 4.80 (m, 1H), 3.86 (s, 3H), 3.77 (d, 2H), 1.90-1.46 (m, 8H); MS (ESI): 348.9.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:26]=[CH:25][N:24]=1>O>[CH3:22][C:23]1[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:27][CH:26]=[C:25]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:24]=1
Reactant: Cc1nccnc1-c1ccccc1
Reactant: [Li]c1ccccc1
Solvent: CCCCOCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
In a nitrogen atmosphere, 10 mL of a dibutyl ether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd., 2.1 mol/L) and 120 mL of diethylether were mixed. While the mixed solution was being cooled with ice, 2.87 g of 2-methyl-3-phenylpyrazine was added thereto and stirred at a room temperature for 24 hours. Water was added into this mixture, and an organic layer was extracted with ethyl acetate. The organic layer obtained was dried with magnesium sulfate. The solution after drying was added with activated manganese dioxide excessively and filtration was conducted. A solvent of the obtained filtrate was distilled off, so that a residue was obtained. This residue was purified by silica gel column chromatography which uses dichloromethane as a developing solvent; thereby obtaining an objective pyrazine derivative Hmppr-P (orange oily substance, yield of 12%). A synthetic scheme of Step 1 is shown in the following (a-5).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20]([OH:22])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:26](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20](=[O:22])[NH2:26])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc2c(C(=O)O)cn(CC(=O)OC(C)(C)C)c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(C(N)=O)cn(CC(=O)OC(C)(C)C)c2c1
Reaction time: 16 h

Procedure:
To a mixture of 1-tert-butoxycarbonylmethyl-6-methoxy-1H-indole-3-carboxylic acid (500 mg, 1.28 mmol) in DMF (6 mL) were added successively NH4Cl (137 mg, 2.55 mmol), HBTU (1.21 g, 3.19 mmol) and DIPEA (0.90 mL, 5.11 mmol), and stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 16 h, water was added and the aqueous layer was extracted repeatedly with EtOAc. The combined organics were washed with saturated aqueous NaHCO3 solution and brine, dried (phase separator) and concentrated in vacuo. Purification by preparative HPLC (Macherey Nagel, VP250/40, C18 nucleosil 100-10, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) and lyophilization of the purified fractions afforded the title compound as a beige solid. MS: 305 [M+H]+, 609 [2M+H]+; tR (HPLC conditions c): 4.26 min.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[OH:61])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33].Br[CH2:63][CH2:64][F:65]>>[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[O:61][CH2:63][CH2:64][F:65])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a pale yellow semi-solid. IR (liq.) 2969, 2935, 1609, 1563, 1482, 1391, 1294, 1243, 1206, 1182, 1172, 1159, 1124, 1110, 1047 cm−1; OAMS supporting ions at: ESI+ 450.0; MS (CI) m/z 450 (MH+); HRMS (FAB) calcd for C27H32FN3O2+H1 450.2556, found 450.2544. Anal. Calcd for C27H32FN3O2: C, 72.14; H, 7.17; N, 9.35. Found: C, 72.24; H, 7.20; N, 9.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH3:10].Cl[CH:12](Cl)[O:13]C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[CH:4][C:5]([CH:12]=[O:13])=[C:6]([F:8])[CH:7]=1
Reactant: CCc1ccc(F)cc1Cl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(C=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TiCl4 (0.90 mL) was added to 2-chloro-1-ethyl-4-fluorobenzene (645 mg, 4.1 mmol) at 0° C. and stirred to 10 min. Dichloro(methoxy)methane (0.725 mL) was added and the mixture was stirred overnight at ambient temperature. The mixture was diluted with CH2Cl2 (50 mL) and poured onto crushed ice (40 g). After stirring 30 min the layers were separated. The organic layer was washed with H2O (2×), brine (2×), dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 440 mg of intermediate 390.2 as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (t, J=7.58 Hz, 3H) 2.69 (q, J=7.58 Hz, 2H) 7.05-7.29 (m, 1H) 7.67 (m, 1H) 10.23 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:26][CH2:27][NH2:28]>CCCCC.CN(C=O)C>[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:26][CH2:27][NH2:28])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil; 0.934 g, 23.36 mmol) is washed three times with pentane. DMF (5 mL) is added, followed by 9-benzyl-9H-Carbazol-4-ol (1.52 g, 5.56 mmol) dissolved in DMF (10 mL) added over 10 min. The mixture is stirred an additional 5 min and then cooled in an ice-water bath. A solution of 2-chloroethylamine hydrochloride (1.29 g, 11.12 mmol) dissolved in DMF (5 mL) is added dropwise over about 5 min. The cooling bath is removed and the mixture is allowed to stir at room temperature over the weekend. Aq. sodium bicarbonate is added and the mixture partitioned between EtOAc, brine, and aq. sodium bicarbonate. The organic layers are dried over MgSO4 and taken to dryness. The residue is chromatographed on silica gel (120 mL) using CH3OH—CH2Cl2 (4/96) to give 1.26 g (72%) of the title compound as a white solid. An aliquot is crystallized from CH2Cl2-EtOAc-hexane; IR (drift) 1597, 1587, 1458, 1441, 1342, 1329, 1269, 1156, 1145, 1110, 1045, 860, 785, 749, 726 cm−1; 1H NMR (CDCl3) δ3.30, 4.29, 5.51, 6.70, 7.00, 7.12, 7.2-7.4, 8.34. Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 78.70; H, 6.41; N, 8.70.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a 1 L round bottom flask, charged with 20 g (102.5 mmol) of 6-bromohexanoic acid and 500 mL of methanol was bubbled hydrogen chloride gas for 2-3 minutes. The mixture was stirred at room temperature for 4 h and then concentrated to afford 21.0 g of the product (1) as a yellow oil (99%): 1H-NMR (200 MHz, d6-DMSO); 3.57 (s, 3H), 3.51 (t, 2H), 2.30 (t, 2H); 1.78 (pentet, 2H), and 1.62-1.27 (M, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.CC(C)([O-])C.[K+].[C:30](#[N:33])[CH:31]=[CH2:32]>C1C=CC=CC=1>[C:30]([CH2:31][CH2:32][O:21][CH2:14][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][CH2:8][C:7]4[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=[C:3]([O:2][CH3:1])[C:20]=43)[C@@H:11]1[CH2:12][CH2:13][CH2:16]2)#[N:33]
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(COCCC#N)CCC[C@H]3[C@@H]1CC2
Reaction time: 5 h

Procedure:
A solution of 1,3-dimethoxy-17β-hydroxyestra-1,3,5(10)-triene (1.5 g, 4.7 mM), potassium t-butoxide (0.053 g, 0.47 mM) and acrylonitrile (0.5 g, 9.4 mM) in 25 ml of anhydrous benzene is refluxed with vigorous stirring for 5 hrs. An additional 0.5 g of acrylonitrile and 0.025 g of potassium t-butoxide are added; the solution is refluxed for 2 hrs and allowed to stir at room temperature for 18 hrs. The resulting suspension is filtered and the filtrate evaporated in vacuo to give an oily residue which is chromatographed on 100 g of neutral silica gel. Elution with chloroform gives an oil which after trituration with hexane gives 17β-(2-cyanoethoxy-1,3-dimethoxyestra-1,3,5(10)-triene, yield 1.06 g (60.6%); m.p. 142°-144° (toluene-hexane).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][CH3:37])=[O:4].CO.[Li+].[OH-]>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C@H:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH3:37])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)=[CH:24][CH:23]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (872 mg) was dissolved in 24 mL THF and 20 mL MeOH and 591 mg LiOH was added. The flask was flushed with nitrogen and placed under a nitrogen balloon and stirred at 0° C. 12 mL water was then added in portions while stirring, then the reaction stirred at rt 15 h. 119 mg LiOH and 6 mL water were added to the reaction and stirring continued for 2 h. 4 mL water was added and stirring continued for 30 min, then 2 mL water was added. After 1.5 h the pH was adjusted to 7 with 2% w/v aqueous citric acid and the reaction extracted with EtOAc. The organic solution was washed with brine and dried over Na2SO4 and evaporated, to give 820 mg desired compound after drying. LCMS: m/z 605 (M+1).
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>N1C=CC=CC=1>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:28]([NH2:31])(=[O:30])=[O:29])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: NS(N)(=O)=O
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: NS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (1.5 g, 3.0 mmol) and sulfamide (1.7 g, 18 mmol) in pyridine (60 mL) was heated in a microwave at 130° C. for 10 min. The reaction mixture was concentrated to give the crude intermediate N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}sulfamide. A solution of the crude intermediate in methanol (90 mL) was treated with 2 N NaOH (12 mL, 24 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with 6 M HCl until the solution was acidic and extracted with ethyl acetate (250 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. This material was purified by preparative LCMS to give the desired product (1.1 g, 82%) as a gummy solid. LCMS for C13H17F3N7O4S (M+H)+: m/z=424.0. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1H), 9.12 (s, 1H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.21-7.18 (m, 1H), 7.07 (s, 1H), 6.95 (d, J=10.0 Hz, 1H), 6.52 (br s, 3H), 6.17 (t, J=6.0 Hz, 1H), 3.28-3.22 (m, 2H), 2.93-2.89 (m, 2H), 1.77-1.73 (m, 2H).