Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:21][C:22]1[C:23](=[O:38])[O:24][CH:25]([CH2:35][CH2:36]O)[C:26]=1[O:27]CC1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][CH:25]2[O:24][C:23](=[O:38])[C:22]([OH:21])=[C:26]2[OH:27])=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Solvent: CCOCC
Product: O=C1OC(CCOc2ccc(-c3ccccc3)cc2)C(O)=C1O
Yield: 32 %

Procedure:
Mitsunoble coupling of 0.20 g (1.2 mmol) of 4-hydroxy-1,1′-biphenyl with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 100 mg (32% yield) of 5-[2-((1,1′-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone as a white powder after trituration with ether and hexanes: 1H NMR (acetone-d6) δ 7.71-7.02 (m, 9H), 4.97 (dd, J=4.9, 8.7 Hz, 1H), 4.25 (dd, J=2.6, 4.7 Hz, 2H), 2.58-2.41 (m, 1H), 2.10-1.92 (m, 1H). Anal Calcd for C18H16O5+1H2O: C, 67.49; H. 5.66. Found: C, 67.34; H, 5.42.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C([O:14][C:15](=O)[CH:16]([CH3:19])[CH:17]=O)C>C(O)C>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][C:15](=[O:14])[C:16]([CH3:19])=[CH:17][N:8]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C=O
Agent: [Na]
Solvent: CCO
Product: Cc1cnc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
Sodium metal (276 mg, 12 mmol) was added portion wise to ethanol (15 ml) under a nitrogen atmosphere and the mixture allowed to stir at room temperature for 30 minutes until the reaction became homogeneous. 4-Chloro-benzamidine (hydroiodide salt) (1.41 g, 5 mmol) was then added in one portion and the reaction stirred at room temperature for a further 60 minutes. 2-Methyl-3-oxo-propionic acid ethyl ester (716 mg, 5.5 mmol) was finally added drop wise. The reaction was left to stir at room temperature overnight before quenching the reaction slowly with 2M Hydrochloric acid until reaction pH measured pH 1. The resulting precipitate was filtered and air dried, to give 2-(4-Chloro-phenyl)-5-methyl-3H-pyrimidin-4-one as a white solid (570 mg, 2.58 mmol, 52% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:12]=C[CH2:10][C:9]2[C:8](=[O:13])[C:7]([O:14][CH3:15])=[CH:6][C:5](=[O:16])[C:4]1=2)[CH3:2].[Cl:17]Cl.CCO.[K+].[Br-].[CH:24]([Cl:27])(Cl)Cl>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Cl:17][CH:12]1[CH:24]([Cl:27])[CH2:10][C:9]2[C:8](=[O:13])[C:7]([O:14][CH3:15])=[CH:6][C:5](=[O:16])[C:4]=2[CH:3]1[CH2:1][CH3:2]
Reactant: CCC1C=CCC2=C1C(=O)C=C(OC)C2=O
Reactant: ClCl
Reactant: ClC(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC1C2=C(CC(Cl)C1Cl)C(=O)C(OC)=CC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5,8-dihydro-5-ethyl-2-methoxynaphthalene-1,4-dione (2.00 g, 9.16 mmol) in CHCl3 (100 mL, passed through silica gel prior to use), a solution of Cl2 in CCl4 (8.3 mL, ~1.1M) was added dropwise over a 5 min period. After addition, the reaction was allowed to stir an additional 30 min at 25° C. Analysis (NMR) indicated partial consumption of the starting material. An additional portion of the Cl2 solution (4 mL) was added. The reaction was allowed to stir at 25° C. for 1 hr. The analysis now indicated the absence of starting material. The solvent was removed in vacuo to give an orange syrup. The addition of 95% EtOH (10 mL) and steam bath warming prompted solidification. The solvent was removed in vacuo to given an orange solid. Crystallization from 95% EtOH (dissolved in boiling solvent (10 mL), hot filtered, allowed to cool to rt) yielded a yellow granular solid (1.37 g, 52%, pure by TLC (5% EtOAc/95% CHCl3), approximately a 2:1 mixture of diastereomers by NMR); mp 115°-118° C.; 1H NMR (CDCl3) δ1.03 (overlapping t, 3H), 1.90 (m, 2H), 2.93 (m, 1H), 3.27 (m, 2H), 3.82 (s, 3H), 4.40 (m, 2H), 5.90 and 5.92 (overlapping s, 1H); IR (KBr) 2970, 2938, 1675, 1652, 1633, 1609, 1226, 855 cm-1.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Li]CCCC.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1.C(OCC)(=O)C>[C:12]([NH:6][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C/C=C/C(N)=O
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C

Procedure:
Experimental Procedure: To a suspension of (E)-but-2-enamide (1.0 equiv) in 3.5 mL THF was added n-BuLi in hexanes (2.5 M,1.2 equiv) slowly at −78° C. The reaction mixture was warmed up to room temperature and stirred for 8 h before a solution of methacryloyl chloride (2.0 equiv) in 2 mL of THF was added drop wise at −78° C. The reaction mixture was allowed to warm up to rt overnight. The crude reaction mixture was diluted with ethyl acetate, and quenched with cold NH4Cl(aq, sat), and the organic layer separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. After filtration and evaporation under reduced pressure, the residue was purified by column chromatography to yield the pure compound.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCC1)OC2
Temperature: 130 °C
Yield: 76.3 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.5 g, 1.63 mmol), pyrrolidine (2.0 ml, 24.0 mmol) and EtOH (4.0 ml) was heated in a micro wave oven at 130° C. for 30 min. The mixture was evaporated to dryness. The residue was chromathographed on a silica column using EtOAc/MeOH (10:1) as eluent, affording the title compound (0.37 g, 76%). The title compound (0.26 g) was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 199° C. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J 18 Hz, J 21.6 Hz), δ 7.40 (1H, d, J 1.6 Hz), δ 7.31 (1H, d, J 8 Hz), 5.29 (1H, t, J 4.4 Hz), δ 5.03 (2H, dd, J 56 Hz, 16 Hz), δ 3.1 (3H, s), 2.92 (2H, m), δ 2.70 (4H, m), δ 1.83 (4H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:7]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CC(=O)OCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2noc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1,1-Dimethylethyl 4-{5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate (13.57 g, 41.6 mmol) was dissolved in methanol (100 mL) followed by addition of aqueous sodium hydroxide (4M, 10.4 mL) and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned with ethyl acetate and 0.1M aqueous hydrochloric acid. The organic layer was then washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration afforded 1,1-dimethylethyl 4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (10.51 g, 89% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 4.75 (s, 2H), 3.53-3.50 (m, 4H), 3.44-3.42 (m, 4H), 3.20 (br s, 1H), 1.48 (s, 9H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Product: Cc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (example B.18) (227 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 43%). MS (ISP) 507.3[(M+H)+]; mp 265-267° C.
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]2[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH:9]2[O:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-]>>[CH3:20][O:19][CH:9]1[CH:8]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(N(c2ccccc2)c2ccccc2)C(OC)C1
Agent: [H-]
Product: COC1CNCCC1N(c1ccccc1)c1ccccc1

Procedure:
treating the ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with an alkali metal hydroxide or hydride to yield 3-methoxy-N,N-diphenylpiperidin-4-amine
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:51]1([C:57]2[C:61]([C:62]([F:65])([F:64])[F:63])=[C:60]([C:66]3[S:67]C4C5C(=CC(C=C)=CC=5)CCC=4[N:70]=3)[O:59][N:58]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[C:8]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2[S:67][C:66]([C:60]4[O:59][N:58]=[C:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[C:61]=4[C:62]([F:65])([F:64])[F:63])=[N:70][C:28]=2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 91A employing 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)isoxazole (Preparation 82E) as a starting material. The reaction was heated at 70° C. for 7 hr. The compound had an LC/MS M+1=692.4.
Reaction SMILES: [ClH:1].Cl.[O:3]([CH2:5][CH:6](O)[CH2:7][NH:8][CH3:9])[NH2:4].S(F)(F)(F)[F:12]>F>[ClH:1].[ClH:1].[O:3]([CH2:5][CH:6]([F:12])[CH2:7][NH:8][CH3:9])[NH2:4]
Reactant: FS(F)(F)F
Reactant: CNCC(O)CON
Agent: Cl
Agent: F
Product: CNCC(F)CON
Reaction time: 24 h

Procedure:
4.8 g (25 mmol) of N-(3-aminoxy-2-hydroxypropyl)-methylamine dihydrochloride are dissolved at -78° in 80 g of liquid hydrogen fluoride in a Teflon autoclave. 5.6 g of sulfur tetrafluoride are introduced and the vessel is closed and left to stand for 24 hours at room temperature. After degassing, the residue is dissolved in 2N hydrochloric acid. This solution is filtered and the filtrate is neutralised, in portions, with solid sodium hydrogen carbonate; a solution of 13 g of di-tert-butyl dicarbonate in 50 ml of tetrahydrofuran is added and the mixture is left to stand for 1 hour. The reaction mixture is diluted with 200 ml of ether and the organic phase is separated off, washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation. The oil that remains behind is chromatographed with a mixture of hexane:ethyl acetate 3:1 over 500 g of silica gel, yielding the starting compound in the form of a yellow oil, Rf value 0.18.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:5][CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCC=C(C(=O)CCCCC=O)C1
Solvent: Cc1ccccc1
Product: CC1(C)CCC=C(C(=O)CCCCCO)C1
Temperature: 100 °C

Procedure:
6-(5,5-dimethylcyclohex-1-en-1-yl)-6-oxohexanal (6.67 g, 0.03 mol.), toluene (20 g, 300 wt. %) and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium (bispivalate) (2.3 mg, 0.003 mmol, 0.01 mol.%) were loaded altogether in a 125 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 97.5% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 1-(5,5-dimethylcyclohex-1-en-1-yl)-6-hydroxyhexan-1-one was obtained in 93% yield.
Reaction SMILES: [N:1]1([CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C[C@]12[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC[C@@H]1[C@H]1[C@H](C(C)=C)CC[C@]1(CNCCN1CCN(S(C)(=O)=O)CC1)CC2.[NH:99]1[CH2:104][CH2:103][CH:102]([CH2:105][OH:106])[CH2:101][CH2:100]1>>[OH:106][CH2:105][CH:102]1[CH2:103][CH2:104][N:99]([CH2:3][CH2:2][NH:1][CH2:4][C@:5]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:40])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:25])([CH3:26])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:38][CH:39]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:100][CH2:101]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: OCC1CCNCC1
Agent: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCC(CO)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-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)benzoate following the procedure described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethylamino)methyl)-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)benzoic acid, using piperidin-4-ylmethanol as reagent in step 1. The product was isolated as a white solid (5 mg, 16.7%). LCMS: m/e 685.5 (MH+), 2.33 min (method 9). 1H NMR (400 MHz, METHANOL-d4) δ 7.90 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.28 (d, J=4.5 Hz, 1H), 4.74 (br. s., 1H), 4.63 (br. s., 1H), 3.74-3.38 (m, 8H), 3.07 (br. s., 2H), 2.98-2.85 (m, 2H), 2.48 (br. s., 1H), 2.21-1.93 (m, 4H), 1.90-1.64 (m, 11H), 1.63-1.40 (m, 10H), 1.39-1.24 (m, 4H), 1.23-1.09 (m, 4H), 1.04 (m, 6H), 0.94 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]=[O:13]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A solution of 2,3-dimethyl-6-nitrobenzenemethanol (34.88 g, 0.192 mole) in dichloromethane (150 mL) was added to a stirred mixture of pyridinium chlorochromate (62.2 g, 0.288 mole) in dichloromethane (250 ml). The mixture was stirred vigorously for 4 hours, diluted with diethyl ether (500 mL) and the organic layer decanted. The residue was washed with diethyl ether (500 mL) and the combined organic solution filtered through a plug of silica gel (6"×11/2"). Evaporation of the solvent afforded 2,3-dimethyl-6-nitrobenzaldehyde (32.08 g, 93%). An analytical sample was prepared by crystallizing from diisopropyl ether and had m.p. 66°-68° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (2.0 mL, 16.14 mmol) and dichloromethane (14.25 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 mL, 48.42 mmol) and dichloromethane (57.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The solid was slurried in hexanes (150 mL) and was filtered to give 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.61 g, 61%) as a tan solid. ESI-MS m/z calc. 264.07. found 265.3 (M+1)+; Retention time: 1.22 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.12-8.05 (m, 1H), 7.58 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.52-7.41 (m, 2H), 7.25-7.19 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1cccc(N)c1C#N
Product: COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N

Procedure:
Prepared as in Example 53a from 2-amino-6-methoxybenzonitrile and benzoyl isocyanate as light orange solid (118 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.54 (t, J=8 hz, 2H), 7.64 (t, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.6 Hz, 2H), 11.35 (s, 1H), 11.51 (s, 1H). MS 295 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[S:11])[CH:7]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:13][C:7]1([CH3:12])[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[S:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc2c1NC(=S)C2C
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1NC(=S)C2(C)Cl

Procedure:
A solution of 7-methyl-3-methylthiooxindole (1 g, 0.0052 mol) and N-chlorosuccinimide (0.7 g, 0.0052 mol) in chloroform (100 ml) was stirred at room temperature for 1 hour. The solution was evaporated, yielding crude 3-chloro-7-methyl-3-methylthiooxindole, and the residue was dissolved in a minimum amount of tetrahydrofuran (ca. 10 ml) and added to a vigorously stirred slurry of red mercuric oxide (1.13 g, 0.0052 mol) and boron trifluoride ethereate (0,75, 0.0054 mol) in 50 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, 150 ml of ether was added, the reaction mixture was filtered through a pad of Celite, and the organic phase of the filtrate was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The red residue was recrystallized from methanol to give 0.6 g (71%) 7-methylisatin, mp 267°-269°.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:31].[I-].[Na+]>CN(C=O)C>[Cl:31][C:21]1[CH:22]=[C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]1[CH3:14]
Reactant: CCS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.68 g, 13.1 mmol) in dry DMF (95 ml) is added sodium hydride (577 mg of a 60% dispersion in mineral oil, 14.41 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-ethanesulfonyl-benzene (6.6 g, 22.2 mmol) and sodium iodide (3.3 g, 22.2 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (600 ml) and extracted with 1:1 ethyl acetate/diethyl ether (4×300 ml). The organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:2) to yield the titled product. (MH+ 421)
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:24]>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:23][CH3:24])[CH2:37][CH2:36]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Product: CCOc1ccccc1N1CCN(C(=O)Nc2cc(CC)c(C)nc2OCC)CC1
Yield: 79 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([O:14]C)=[C:10]([CH:13]=1)[CH:11]=[O:12]>C(Cl)Cl>[Cl:5][C:6]1[C:7]([C:16]([F:17])([F:18])[F:19])=[CH:8][C:9]([OH:14])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: COc1cc(C(F)(F)F)c(Cl)cc1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(C(F)(F)F)cc1O
Temperature: 50 °C

Procedure:
A 1M DCM solution of BBr3 (24.0 mL, 24.0 mmol) was added to neat 5-chloro-2-methoxy-4-(trifluoromethyl)benzaldehyde (3.4 g, 14.4 mmol) and the resulting mixture was heated to 50° C. After 1 h the resulting mixture was diluted with DCM and ice and the layers were separated. The aqueous phase was added was extracted with DCM and the combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.