Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:19])[CH2:17][OH:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[CH2:17][O:18][C:20]([CH3:25])([CH3:21])[O:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1oc2cccc(C(O)CO)c2c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2cccc(C3COC(C)(C)O3)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 973.2 %

Procedure:
To a solution of 0.150 g (0.568 mmol) of 4-(1,2-dihydroxyethyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester dissolved in 5 mL of acetone was added 0.010 g of p-toluenesulfonic acid and the reaction was stirred at room temperature overnight. Saturated sodium bicarbonate was added and the acetone was removed in vacuo. The residue was extracted with ether, the organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:5) to provide 0.172 g of 4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][C:20](=[O:28])[C@H:21]([C:24](=[O:27])[O:25][CH3:26])[NH:22][CH3:23]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:16])[N:22]([CH:21]([C:20]([NH:19][CH3:18])=[O:28])[C:24]([O:25][CH3:26])=[O:27])[CH3:23])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Agent: Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(I)cc2)cc1
Yield: 57.9 %

Procedure:
Using 4′-iodobiphenyl-4-carboxylic acid (1.8 g) obtained by the same method as the synthesis method described in the literature (Zhurnal Organicheskoi Khimii, 1981, Vol. 17(12), pp. 2598-2601) and N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 1.1 g), the same procedure as in Example 4-(4) was performed to obtain 4-iodo-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (light yellow solid) (1.5 g, 58%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21](OCC)(=O)CCCCCCCCCCC.COCCNCCN>>[CH2:1]([O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:21]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: CCCCCCCCCCCC1=NCCN1CCOC
Agent: COCCNCCN
Product: CCCCCCCCCCCC1=NCCN1CCOCC

Procedure:
1-(2-methoxyethyl)-2-undecyl-2-imidazoline was similarly prepared from 30.8 g of ethyl dodecanoate and 16 g of N-(2-methoxyethyl)ethylenediamine. Distillation of the crude product at 150° C./0.1 mm gave 9.3 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=[C:13]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:21])[F:22])[N:14]=[C:13]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1
Reactant: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone with concentrated sulphuric acid during 2 minutes at 0° C. there is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, 1H14 NMR (CDCl3, 400 MHz): 7.30 ppm (d,1H), 6.87 ppm (d,1H), 4.00 ppm (s,3H);
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[CH2:7][CH2:6]1)=[O:4].ClC1C=CC(N2CCNCC2)=C(F)C=1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:54][C@H:51]3[CH2:52][CH2:53][C@H:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([N+:38]([O-:40])=[O:39])=[C:42]([C:55]([F:56])([F:57])[F:58])[CH:43]=4)[CH2:49][CH2:50]3)[CH2:6][CH2:7]2)=[C:12]([F:18])[CH:13]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2F)CC1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: Fc1cc(Cl)ccc1N1CCNCC1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(Cl)cc2F)CC1

Procedure:
1-[4-(4-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine (also known as 2-chloro-1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-ethanone) was prepared from 1-(4-chloro-2-fluoro-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-chloro-2-fluoro-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(4-chloro-2-fluoro-phenyl)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (13% yield). The structure was confirmed using Protocol II-A. Calculated mass=559; observed mass=559; HPLC retention time=4.57 min.
Reaction SMILES: C(Cl)(Cl)Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[N:56]=[C:55]([C:58]1[N:62]3[CH:63]=[C:64]([C@@H:67]([N:72]4[CH2:76][CH2:75][C@H:74]([NH:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:73]4)[C:68]([F:71])([F:70])[F:69])[CH:65]=[CH:66][C:61]3=[N:60][N:59]=1)[CH:54]=[CH:53]2.[CH2:85]([SH:87])[CH3:86].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:85]([S:87][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[N:56]=[C:55]([C:58]1[N:62]3[CH:63]=[C:64]([C@@H:67]([N:72]4[CH2:76][CH2:75][C@H:74]([NH:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:73]4)[C:68]([F:71])([F:70])[F:69])[CH:65]=[CH:66][C:61]3=[N:60][N:59]=1)[CH:54]=[CH:53]2)[CH3:86]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cccc(Br)c5n4)n3c2)C(F)(F)F)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCSc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Yield: 62 %

Procedure:
CHCl3 (8.75 mg, 0.00845 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.78 mg, 0.0169 mmol), tert-butyl (S)-1-((R)-1-(3-(8-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.169 mmol), ethanethiol (31.5 mg, 0.507 mmol) and N-ethyl-N-isopropylpropan-2-amine (131 mg, 1.01 mmol) in dioxane were heated to 150° C. under microwave irradiation for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(8-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (60 mg, 62.0% yield)
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].[NH2:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CO
Solvent: CN(C)C=O
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a solution of Z-(D)-Nva-OH(380 mg), H-Leu-Arg(NO2)-Pro-Gly-NH2 (690 mg.) and HONB (300 mg.) in 5 ml. of dimethylformamide is added 340 mg. of DCC at 0°C with stirring. The mixture is stirred for 2 hours at 0°C and for additional 10 hours at room temperature. The reaction mixture is filtered to remove the formed dicyclohexyl-urea, and the filtrate is evaporated to dryness. The resulting residue is dissolved in 100 ml. of chloroform and the solution is washed with 4 % aqueous sodium bicarbonate solution and water. The washed solution is dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is then triturated with a mixture of ethylacetate (25 ml.) and ether (25 ml.) to give a white powder, which is collected by filtration and reprecipitated from ethanol-ether: yield, 1.12 g., [α]D23 -50.5°(c=1.1 in Methanol), Rf1 =0.32.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:22][NH2:23]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH3:22])=[CH:16][N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCSc1cccc(CN(C)C)n1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSc1cccc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[2-(6-Dimethylaminomethyl-2-pyridylthio)ethylamino]-1-methylthio-2-nitroethene (0.45 g, 0.0014 mol) is added to ethanol (8 ml) saturated with monomethylamine gas at ice bath temperature and is allowed to stir at ambient temperature for 18 hours. Evaporation of the solvent yielded a glassy product.
Reaction SMILES: C[Al](C)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=3)=[N:25][O:26][C:27]=2[CH3:28])=[N:17][CH:16]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:5][N:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:13])=[CH:16][N:17]=3)=[C:27]([CH3:28])[O:26][N:25]=2)=[N:30][CH:31]=1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)nc1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 0.58 mL, 1.1 mmol) was added dropwise (exothermic) to a solution of N-aminomorpholine (111 μL, 1.2 mmol) in dioxane (2.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.29 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 90° C. overnight and then cooled to room temperature and then poured into Seignette salt solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1) afforded the title compound (47 mg, 40%) which was obtained as a white solid. MS: m/e=414.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[C:5]=1[F:22].[AlH4-].[Li+].[OH-].[Na+].Cl>O1CCCC1>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[C:5]=1[F:22])(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(CO)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To 3-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-benzoic acid methyl ester (74, 0.955 g, 2.8 mmol) in 22 mL of tetrahydrofuran, lithium tetrahydroaluminate (6 mL, 1M in tetrahydrofuran, 6 mmol) is added at −40° C. under nitrogen. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is poured into 1M aqueous sodium hydroxide, then neutralized with 1M aqueous hydrochloric acid. The solids are filtered through a bed of celite, and the celite bed is washed with ethyl acetate and tetrahydrofuran. The filtrate layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (75, 0.875 g). MS (ESI) [M−H+]−=316.
Reaction SMILES: O[CH2:2][CH2:3][Si:4]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]O.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.O>[CH2:27]([N:34]1[CH2:6][CH2:5][Si:4]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C[Si](CCO)(CCO)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[Si]1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8.5 g of 2-[(2-hydroxy-ethyl)-methyl-phenyl-silanyl]-ethyl alcohol is put in 80 ml of anhydrous dichloromethane under nitrogen. 14.2 ml of triethylamine is added, and then, at 0° C., 6.9 ml of mesyl chloride is added dropwise using a dropping funnel. The mixture is stirred for 2 h at 0° C. and gradually turns orange with appearance of a precipitate. Once conversion is complete, 14.2 ml of triethylamine is added and then 4.7 ml of benzylamine at 0° C. The reaction mixture is brought back to room temperature and then refluxed for 6 h. After hydrolysis with H2O at room temperature, the reaction mixture is extracted with ethyl acetate three times. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The raw product obtained is chromatographed on silica gel, eluting with a gradient of ethyl acetate and heptane containing 3% of triethylamine varying from 0/10 to 3/7. 3.6 g of 1-benzyl-4-methyl-4-phenyl-[1,4]azasilinane is obtained in the form of a clear yellow oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.Cl>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:10]([CH3:12])([CH3:11])[C:9]#[N:13])=[CH:17][CH:18]=1
Reactant: CC(C)C#N
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (11.0 mL, 21.9 mmol, 2 Min tetrahydrofuran, Aldrich) in tetrahydrofuran (100 mL) was added isobutyronitrile (2.0 mL, 21.9 mmol) at 0-5° C. After 30 minutes of stirring, a solution of 1-(bromomethyl)-4-chlorobenzene (3.0 g, 14.6 mmol) in tetrahydrofuran (10 mL) was added at the same temperature. After stirring at room temperature for 2 hours, the reaction mixture was treated with 10% hydrochloric acid (50 mL), and concentrated under reduced pressure to remove tetrahydrofuran. The concentrate was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed successively with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by column chromatography using an Analogix® Intelliflash 280™ (SiO2, 0-30% of ethyl acetate in hexanes) to obtain the titled compound. MS (DCI+) m/z 211 (M+NH4)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:22][CH2:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:23]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2].CC(C)=O.C([O-])(=O)C.[Na+].BrN1C(=O)CCC1=O>[Cl-].[Na+].O.CCCCCC.N1C=CC=CC=1.C(O)(=O)C.O>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:23][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@@H:20]1[C:7](=[CH:6][C:5](=[O:4])[CH2:22][CH2:21]1)[CH:8]=[CH:9]3
Reactant: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(C)=O)CC[C@@H]34)[C@H]2CC1
Agent: CC(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 3 h

Procedure:
The compound 3,17β-diacetoxyestr-3,5-diene, 60.0 g (0.158 mole) prepared as in Example 1, is placed in an acetone buffered solution containing 3,180 ml of acetone, 816 ml of water, 81.6 ml of acetic acid, 18 ml of pyridine, and 81.6 g of sodium acetate. The solution is cooled to 0°-5° C. using a salt-methanol-ice bath and 32.1 g (0.18 mole) of N-bromosuccinimide is added at one time. The reaction mixture is totally shielded from light and stirring continued for a period of 3 hours at 0°-5° C. The solution is poured onto 12 liters of cold brine and the product extracted with 1 liter of ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under vacuum at temperatures below 20° C. The amber oil residue is dissolved in 75 ml of dimethylformamide and rapidly added to a vigorously refluxing suspension of 750 ml of dimethylformamide, 60 g of lithium bromide and 60 g of lithium carbonate under nitrogen. Residual ether is permitted to evaporate and the reaction mixture is refluxed for a period of one hour. On cooling, the suspension is filtered and the filtrate is poured into an ice-water mixture. The product is extracted into ether and the combined ether extracts are washed with water, 2 liters of a 5% sodium hydroxide solution and washed again with water. The solution is dried over anhydrous magnesium sulfate and concentrated under vacuum to yield a yellow solid which is layered with hexane and filtered to yield 34.6 g of the desired 17β-hydroxy-estra-4,6-dien-3-one acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[CH:24]=[O:25])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1cc2cccnc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1[nH]c2ncccc2c1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
Phosphorous oxychloride (4.01 mL, 43 mmol) was added drop-wise to N,N-dimethylformamide (9.96 mL, 129 mmol) at 0° C. and the mixture was stirred for 20 min. A solution of 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 28.7 mmol) dissolved in N,N-dimethylformamide (30 mL) was added and the resulting mixture was slowly warmed up to room temperature. The mixture was stirred at room temperature for 2 h then at 40° C. for 3 h, and cooled in an ice bath, and 0.5 mL water was added. The reaction mixture was slowly warmed to 40° C. and stirred for 20 h. The mixture was poured onto approximately 100 mL ice, neutralized with an aqueous sodium hydroxide (5%) and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified via silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.4 g, 11.9 mmol, 41% yield) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:3]=1.[OH-].[Na+:21].C>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:16]([O-:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])ccc12

Procedure:
Approximately 76 g. of 1-amino-3,6-naphthalenedisulfonic acid is added to a solution of 22 g of sodium hydroxide in 100 ml of water. This solution is treated with charcoal filtered through diatomaceous earth and washed with sufficient water to bring the combined filtrate and washings to 200 ml. The filtrate is diluted to 1000 ml with ethanol and after standing the resulting solid is filtered and washed with absolute ethanol and twice with ether. The product is dried overnight giving 1-amino-3,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]2[CH2:25][C@@H:11]1[C:12](=[O:33])[N:13]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[C:1]([O:9][C@@H:10]1[C@@H:11]([CH2:12][OH:33])[CH2:25][C@@H:14]([NH:13][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@H](OC(=O)c1ccccc1)[C@@H]2OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl (1R,4S,5R,6S)-5,6-bis(benzoyloxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.09 g, 4.62 mmol) in MeOH (60.0 mL) was added sodium borohydride (700. mg, 18.5 mmol) at 0° C. and the reaction was allowed to warm to rt. After 1.5 h, the mixture was quenched with 1.00 N HCl solution (20.0 mL), and concentrated in vacuo. The aqueous layer was extracted with DCM (3×50 mL) and the combined organic layers were washed with H2O (100. mL), dried over MgSO4 and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 20 to 60% EtOAc in hexanes to afford the title compound (1.50 g, 80%).