Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[C:34]([O:38][C:39](=[O:53])[CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](O)=[O:48])([CH3:37])([CH3:36])[CH3:35].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:47]([C:46]2[CH:45]=[C:44]([CH:52]=[CH:51][CH:50]=2)[CH2:43][S:42][CH2:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:53])=[O:48])[CH:10]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-morpholinophenyl)isonicotinamide (200 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (160 mg, 0.84 mmol, 2.00 equiv), and 4-dimethylaminopyridine (60 mg, 0.49 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. After a conventional aqueous/organic workup, the resulting mixture was concentrated under vacuum to yield 100 mg of crude product as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([NH:12][C:13]1[CH:22]=[CH:21][C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][CH:14]=1)(=O)C.[N:23]1C=CC=CC=1>>[NH2:12][C:13]1[CH:22]=[CH:21][C:16]([S:17]([NH:23][C:5]2[CH:4]=[C:3]([CH2:2][NH2:1])[CH:8]=[CH:7][N:6]=2)(=[O:19])=[O:18])=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: NCc1ccncc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: NCc1ccnc(NS(=O)(=O)c2ccc(N)cc2)c1
Temperature: 0 °C
Yield: 43.9 %

Procedure:
To a 250 ml round bottom flask was added 50 ml of dry pyridine, 4-(aminomethyl) pyridine (10.4 9, 50.0 mmol) and a magnetic stir bar. The mixture was stirred and cooled to 0° C. under nitrogen followed by the addition of N-acetylsulfanilyl chloride (12.8 g, 55.0 mmol) The resultant mixture was stirred at 0° C. under nitrogen for 5 min, and the reaction was allowed to warm to rt and stirred for 16 h. The reaction mixture was concentrated to a thick residue and poured onto about 500 g of ice and water. The residue in the flask was rinsed into the ice and water with 25 ml of MeOH to precipitate the N-acetyl sulfanilamide. The resultant precipitate was filtered, washed with excess water and dried under vacuum at 50° C. The solid was suspended in 75 ml of 1 N hydrochloric acid and heated to 100° C. until all starting material had been consumed. The reaction mixture was cooled and neutralized with ammonium hydroxide. The precipatate was filtered and dried under vacuum at 50° C. to yield 5.78 g, 43.9 % of 4-amino-N-(4-aminomethylpyridinyl)-benzenesulfonamide: 1H NMR (DMSO-d6): δ 8.42 (d, 2H), 7.76 (t, 1H), 7.39 (d, 2H), 7.22 (d, 2H), 6.56 (d, 2H), 5.91 (s, 2H), 3.89 (d, 2H); APCI−MS m/z 264 (MH)+. The title compound was prepared in 33% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(4-aminomethylpyridinyl)benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.15 (d, 1H), 10.9 (s, 1H), 9.24 (s, 1H), 8.44 (d, 2H), 8.24 (m, 1H), 8.05 (d, 1H), 7.81 (d, 1H), 7.76 (m, 2H), 7.56 (d, 2H), 7.24 (d, 2H), 7.1 (d, 1H), 4.01 (d, 2H); APCI−MS m/z 464 (MH)+
Reaction SMILES: C([O-])(=O)C.[Ni+2:5].C([O-])(=O)C.[C:10]([OH:29])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:10]([O-:29])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Ni+2:5].[C:10]([O-:29])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Ni+2]
Agent: CC(=O)[O-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Nickel (II) oleate is prepared by mixing 2.48 g of nickel acetate and 5.64 g of oleic acid with stirring for about one hour. The mixture is heated to about 150° C. to evaporate the acetic acid and form a transparent liquid of nickel (II) oleate. Nickel (II) oleate can also be prepared by mixing 2.57 g of nickel acetylacetonate and 5.64 g of oleic acid with stirring. The mixture is then heated to evaporate the acetylacetonate and form a transparent liquid of nickel (II) oleate.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].[C:34](=[O:37])([O-])[O-:35].[K+].[K+].[CH3:40][C:41]1([CH3:49])[CH2:46][C:45](=[O:47])[NH:44]C(=O)[CH2:42]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][NH:44][C:45]([CH2:46][C:41]([CH3:49])([CH3:42])[CH2:40][C:34]([OH:35])=[O:37])=[O:47])[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: CC1(C)CC(=O)NC(=O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=O)CC(C)(C)CC(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and 4,4-dimethylpiperidine-2,6-dione (54 mg), and the mixture was stirred at 80° C. overnight and then at 100° C. for one day. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (3.5 mg, yield 5%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9]>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)(Cl)(Cl)Cl>[CH2:6]([NH:10][C:11]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=C=O
Reactant: c1c[nH]cn1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCNC(=O)c1ncc[nH]1
Yield: 18 %

Procedure:
A solution of 0.10 mol of imidazole and 0.10 mol of n-butyl isocyanate in 40 ml of nitrobenzene was heated under reflux for 8 hours. After cooling the reaction mixture, it was diluted with carbon tetrachloride and the solid was filtered off and washed with carbon tetrachloride until the carbon tetrachloride runnings were colourless. After drying, imidazole-2-carboxylic acid n-butylamide was obtained in 18% yield. Melting point: 188°-190° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=O.[Cl-].C([O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][CH2:11][C:10]2[O:9][C:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:7][C:6]=2[CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:30][CH:29]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Reactant: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-1,3-oxazole-5-carbaldehyde (3.00 g), 4-benzyloxybenzyltriphenylphosphonium chloride (6.58 g), potassium carbonate (1.84 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). A mixture of the obtained colorless oil, 5% palladium on carbon (5.00 g) and tetrahydrofuran (200 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hrs. After removing palladium on carbon by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to give 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (3.24 g, yield 79%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 102-103° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]([CH3:46])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][CH2:36][C:35]([NH:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:46])=[O:45])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CN(C)CCCNC(=O)CCc1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Triethylamine (0.62 ml) and octadecyl isocyanate (1.38 ml) were added to a solution containing N-[3-(dimethylamino)propyl]-3-(2-hydroxyphenyl)propanamide (1.00 g) in methylene chloride (10 ml). After being stirred for 3.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol=30: 1 to 10: 1), thereby yielding the entitled compound (1.93 g) as white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C@H:8]([CH2:24][OH:25])[C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl.C(N(CC)CC)C>[C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[C@@H:8]([CH:24]=[O:25])[C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@@H](CO)C1CCCCCCCCC(=O)OC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@H](C=O)C1CCCCCCCCC(=O)OC(C)C

Procedure:
A solution (10 ml) of the compound (13-4)(3.18 g) in dichloromethane was subjected to Swan oxydation using oxalyl chloride(2M, CH2Cl2 solution, 8.78 ml), a solution (20 ml) of DMSO (2.49 ml) in dichloromethane and triethylamine (5.87 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=7/3) to give the titled compound (13-5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-[(4-tert-Butylcyclohexylimino)methyl]benzoic acid methyl ester (21.0 g, 69.2 mmol) was suspended in methanol (300 mL), and acetic acid (50 mL) was added. To the resulting clear solution was added sodium cyanoborohydride (3.5 g, 55.5 mmol), and the mixture was stirred at ambient temperature for 30 min. The reaction volume was then reduced to one third by rotary evaporation, and ethyl acetate (500 mL) was added. The organic phase was washed with sodium carbonate solution (5%, 500 mL), and dried with sodium sulphate. The solvent was removed by rotary evaporation to leave the title material as a white crystalline solid sufficiently pure for further reactions. Yield: 21.1 g (100%).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12].[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[K+]>ClCCl>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12]
Reactant: FC(F)Oc1ccccc1OC(F)F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC(F)F)c(OC(F)F)c1

Procedure:
A solution of 15 g of 1,2-bis(difluoromethoxy)-benzene and 15 ml of 100% strength nitric acid in 150 ml of dichloromethane is stirred at room temperature for 7 hours. The mixture is neutralized with potassium bicarbonate solution and the organic layer is separated off and chromatographed on silica gel by means of cyclohexane/ethyl acetate (4:1). 1,2-Bis-(Difluoromethoxy)-4-nitro-benzene is obtained. This is hydrogenated and acetylated analogously to Example 21a to give N-[3,4-bis(difluoromethoxy)-phenyl]acetamide (m.p. 81°-83° C.). Analogously to Example 21, furthermore, N-[4,5-bis(difluoromethoxy)-2-nitrophenyl]acetamide (m.p. 65°-67° C.), N-[4,5-bis(difluoromethoxy)-2-nitro]aniline (m.p. 107°-109° C.), 4,5-bis(difluoromethoxy)-1,2-phenylenediamine dihydrochloride and the title compound of m.p. 285°-287° C. (decomposition; from isopropanol) are obtained.
Reaction SMILES: [CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)[CH:2]=[CH2:3].C(O)CO.NN.[OH-].[K+]>>[CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccccc2)CCCCC1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: C=CCC1(c2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 2-allyl-2-phenylcyclohexanone (1.97 g, 9.19 mmol) in ethylene glycol (8 mL, 143 mmol) were added hydrazine (0.8 mL, 25.5 mmol) and potassium hydroxide (1.547 g, 27.6 mmol), and the mixture was stirred at 100° C. for 1 hr and refluxed in a 180° C. oil bath for 2.5 hrs. TLC showed that the hydrazone formation nearly complete. Then the excess hydrazine and water were distilled out in a 200° C. oil bath, and it was continued to heat at the same temperature for 4 hrs. After cooling to room temp it was added to ether and washed with water and brine. The combined aqueous layers were back-extracted with ether (2×) and combined. Dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with hexane followed by 5:95 EtOAc-hexane to give product (825 mg). 1H NMR (400 MHz, CCl3D) δ ppm 7.31 (4H, d, J=4.39 Hz), 7.17 (1H, dq, J=4.39, 4.25 Hz), 5.32-5.45 (1H, m), 4.89 (1H, s), 4.83-4.87 (1H, m), 2.26 (2H, d, J=7.47 Hz), 2.07 (2H, dd, J=13.84, 6.59 Hz), 1.33-1.63 (8H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C)cc(Cl)cc2c(O)c1C
Product: Cc1nc2c(C)cc(Cl)cc2c(Cl)c1C
Temperature: 25 °C

Procedure:
Prepared according to procedure S using 6-chloro-2,3,8-trimethylquinolin-4-ol (3.25 g, 1.65 mmol) in POCl3 (20 mL) and heating at reflux for 3 h. After this time the reaction mixture was cooled to rt and poured into ice water. The resulting solid was filtered and washed with water. The product was then dried under vacuum and 4,6-dichloro-2,3,8-trimethylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=241 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (4-fluorophenyl)acetate (0.5 g) was dissolved in DMF (81 mL). The mixture was cooled in an ice bath and NaH (131 mg, 60% w/w in mineral oil) was added. The mixture was stirred for 1 h at RT and again cooled in an ice bath before the addition of MeI (633 mg). The mixture was warmed to RT and, the reaction was quenched with ½ (sat.) aqueous ammonium chloride. Work up consisted of extraction of the aqueous layer with ether (2×). The combined organic fractions were washed with water and brine, then dried (MgSO4). The solvent was evaporated under reduced pressure and methyl 2-(4-fluorophenyl)propanoate was purified on silica gel (ethyl acetate/hexanes). Methyl 2-(4-fluorophenyl)propanoate (420 mg) was dissolved in 12 mL THF and 6 mL MeOH. 6 mL of KOH (2M) was added and the mixture was stirred for 2 h at RT. Water was added and the organic solvents were removed. The base was quenched with icy hydrochloric acid (1N), DCM was added and the phases separated with a phase separator. The solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][CH:9]([F:12])[CH2:10][OH:11].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>CCCCCC.CCOCC>[F:8][CH:9]([F:12])[CH2:10][O:11][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
The preparation was conducted according to the description in the document (J. Med. Chem., (1994), 37, 3977-3985). Sodium hydride (3.36 g, 55%, 77.0 mmol) was added to a DMF (100 mL) solution of 2,2-difluoroethanol (5.75 g, 70.0 mmol) under ice-cooling over 5 minutes under a nitrogen gas flow. The resulting mixture was stirred at the same temperature for 10 minutes, and then to the reaction solution was dropwise added a DMF (40 mL) solution of 4-fluorobenzaldehyde (9.56 g, 77.0 mmol) over 5 minutes. The mixture was stirred at room temperature for 4 hours, and the reaction solution was poured into ice water (500 mL). The resulting mixture was extracted with ether:n-hexane (300 mL, 1:1, V/V) three times. The extracted organic layer was washed with water (300 mL) three times and with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a crude product. A solution mixture of ether:n-hexane (20 mL, 1:10, V/V) was added to this crude product, and the supernatant was removed. This procedure was repeated four times in total to wash the crystalline product to give 10.1 g of the title compound (colorless crystal, yield: 77%).
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:42])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:38]=[CH:37][C:36]([B:39]([OH:41])[OH:40])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1.N#N.B(Br)(Br)Br>C(Cl)Cl>[B:39]([C:36]1[CH:37]=[CH:38][C:33]([C:20]2[C:21]([CH3:32])([CH3:31])[C@H:22]3[C@:17]([CH3:42])([CH2:18][CH:19]=2)[C@@H:16]2[C@:25]([CH3:30])([C@@:26]4([CH3:29])[C@H:13]([CH2:14][CH2:15]2)[C@H:12]2[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]2([C:9]([OH:10])=[O:8])[CH2:28][CH2:27]4)[CH2:24][CH2:23]3)=[CH:34][CH:35]=1)([OH:41])[OH:40]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(B(O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(B(O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A −78° C. solution of (4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((benzyloxy)carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)phenyl)boronic acid (0.200 g, 0.308 mmol) in DCM (3 mL) was purged with N2(g). Boron tribromide (1M solution in DCM) (1.079 mL, 1.079 mmol) was added dropwise. The resulting yellow reaction mixture was stirred at −78° C. for 1 h. The cold bath was removed and H2O (5 mL) was added to quench the reaction. The resulting white paste was filtered and washed with H2O. The crude material was dissolved in THF and DCM loaded onto a silica gel column and eluted with 1:1 hexanes:EtOAc to give 93 mg crude material which was further purified by reverse phase HPLC to give (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-boronophenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (45.2 mg, 24.15%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.09 (br. s., 1H), 7.97 (br. s., 2H), 7.68 (d, J=7.9 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), 5.18 (d, J=4.6 Hz, 1H), 4.70 (s, 1H), 4.57 (s, 1H), 3.02-2.90 (m, 1H), 2.33-2.23 (m, 1H), 2.12 (d, J=6.4 Hz, 1H), 2.05 (dd, J=17.2, 6.3 Hz, 1H), 1.80 (d, J=7.3 Hz, 2H), 1.69-1.66 (m, 1H), 1.65 (s, 3H), 1.56 (t, J=11.3 Hz, 1H), 1.50 (br. s., 1H), 1.45-1.36 (m, 8H), 1.33-1.28 (m, 1H), 1.23 (br. s., 1H), 1.21-1.12 (m, 3H), 1.02-0.98 (m, 1H), 0.97 (s, 3H), 0.93 (s, 6H), 0.87 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=O.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[C:12]1([S:1]([C:3]2[CH:4]=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of sulfanilic acid (10 g, 0.52 mmol), benzene (4.7 g, 0.56 mmol) and trifluoroacetic anhydride (42 g) in trifluoroacetic acid (42 g) was heated to reflux for 3 days. The solvent was removed in vacuo and the residue taken up in 10% aqueous sodium hydroxide and heated to 100° C. for 15 minutes. The resulting white precipitate was filtered off, washed with water and dried to give [4-(phenylsulfonyl)phenyl]amine. 1H NMR (400 MHz, d6-DMSO) δ 7.83-7.81 (2H, m), 7.61-7.51 (5H, m), 6.62-6.58 (2H, m), 6.15 (2H, s).