Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:16])[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H][H]>C(O)C.[Pd]>[CH2:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C1C=CCCCCCCCCCCC=C1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCCCCCCCCCCC1
Yield: 94 %

Procedure:
A solution of 1.00 g (4.55 mMole) of cyclopentadeca-2,14-dien-1-one in 20 ml of ethanol was hydrogenated in the presence of 50 mg of palladium on charcoal. Hydrogen uptake (230 ml) was complete after 1 h at 20°. The mixture was filtered, evaporated and distilled to give 0.96 g (94%) of EXALTONE® having b.p. 115°/0.1 Torr; m.p. 65°-66°.
Reaction SMILES: [CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC3C=CC=CC=3)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O1CCCC1>[Pd].CO>[CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 76.6 %

Procedure:
1.03 g (2.8 mmol) of VII-15, 0.1 g of 5% Pd-C, 15 ml of tetrahydrofuran and 5 ml cf methanol were mixed and the mixture was subjected to catalytic hydrogenation under normal pressure. When the hydrogen absorption reached 66 ml, the reaction was stopped and the catalyst was filtered away. The filtrate was concentrated and purified by column chromatography to obtain 0.76 g (98% yield) of (+)-4'-(1-octyloxyethyl)4-biphenylcarboxylic acid. [α]D25 =+67.5° (c=1, CHCl3), m.p.=139°-140° C.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:18]Br)[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:8]([OH:9])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: ONCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: ON(Cc1ccccc1)Cc1ccc(CN(O)Cc2ccccc2)cc1

Procedure:
The procdure of Example 1 is repeated using 5.59 g of benzylhydroxylamine, 5.99 g of p-xylylene dibromide and 6.0 g of anhydrous sodium carbonate. The reaction product is recrystallized from acetonitrile to give the product as a white solid; m.p. 160°-163° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:32])[C:11](=[O:31])[CH2:12][N:13]([C:18]1[CH:23]=[C:22]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH2:14][C:15](O)=[O:16].Br.[Br:34][CH2:35][CH2:36][NH2:37].C(N(CC)C(C)C)(C)C>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[N:10]([CH3:32])[C:11](=[O:31])[CH2:12][N:13]([C:18]1[CH:23]=[C:22]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH2:14][C:15]([NH:37][CH2:36][CH2:35][Br:34])=[O:16]
Reactant: Cc1nc(-c2ccc(C)c(N(CC(=O)O)CC(=O)N(C)N3Cc4ccccc4C3)c2)no1
Reactant: NCCBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccc(C)c(N(CC(=O)NCCBr)CC(=O)N(C)N3Cc4ccccc4C3)c2)no1
Yield: 70 %

Procedure:
Using the compound (1.24 g, 2.85 mmol) of Example 15, step A, 2-bromoethylamine hydrobromide (786 mg, 3.84 mmol), and N,N-diisopropylethylamine (0.70 ml, 4.1 mmol), and according to the method of Example 1, step B, the title compound (1.08 g, yield 70%) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.C([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])C>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([NH:51][CH2:50][CH2:49][C:48]([OH:47])=[O:52])=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17]
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)NCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and β-alanine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 6.87-7.35 (m, 11 H), 6.68 (m, 1 H), 6.48 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.90 (t, 2 H), 3.64 (s, 1 H), 3.22 (dd, 2 H), 2.90 (s, 3 H), 2.35 (m, 2 H), 2.33 (s, 3 H), 2.19 (t, , 2 H), 1.87 (m, 2 H); MS (ESI) m/z 682 (M+H+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCCC1.ClCCl>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (60% dispersion in oil; 2.2 g) in dry tetrahydrofuran (25 mL) at 15°-20° C. is treated portionwise with a solution of 4-amino-3,5-dichloropyridine (4.5 g; that is prepared as described in Reference Example 5) in dry tetrahydrofuran (40 mL), with cooling. The mixture is stirred for a further 30 minutes, and then it is cooled to 10° C. and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4 g) in dry tetrahydrofuran (40 mL), dropwise, during 45 minutes at 10° C. The mixture is stirred at 10° C. for 30 minutes and is then treated with dilute hydrochloric acid (50 mL; 1N), followed by dichloromethane (75 mL). The layers are separated and the aqueous layer is washed with a further quantity of dichloromethane (25 mL). The combined organic layers are washed with water (50 mL), with saturated aqueous sodium bicarbonate solution (100 mL), and with water (50 mL), dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from isopropanol, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (7.0 g).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]#[N:19])=[O:8])=[CH:3][CH:2]=1.[OH2:21]>>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]([NH2:19])=[O:21])=[O:8])=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(C(=O)c2cccc3c2CCC3C#N)cc1
Product: Cc1ccc(C(=O)c2cccc3c2CCC3C(N)=O)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 2.3 g. of 4-(p-toluoyl)indan-1-carbonitrile is added 75 g. of polyphosphoric acid and the mixture is worked into a homogeneous solution by heating on a water bath at 90° C. for 30 minutes and, then, on an oil bath at 120°-130° C. for 30 minutes. Following the addition of water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate and water in the order mentioned and, then, dried. It is, then, treated with activated carbon and concentrated under reduced pressure. The resultant crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. The described procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystals melting at 188°-191° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OC(=O)C)C>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
0.180 g (1.0 mmol) of trans-stilbene, a measured amount of the supported palladium catalyst prepared in Example 3 (the amount corresponding to 2 mol % of palladium based on the amount of trans-stilbene) and 4 mL of ethylacetate were mixed and stirred at room temperature for 60 min under 1 atm of H2. The resulting mixture was filtered and the solvent was removed. The resulting residue was subject to silica gel column chromatography (eluent: hexane/ethylacetate(10/1)) to obtain 0.182 g of the title compound, 1,2-diphenylethane (yield: 100%).
Reaction SMILES: C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[BH4-].[Na+].[C:17]([O:20][C:21]1[CH:38]=[CH:37][C:36]2[C@@H:35]3[C@H:26]([C@H:27]4[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C@@H:30]3[O:39][C@@H:29]3[CH2:28]4)[CH2:25][CH2:24][C:23]=2[CH:22]=1)(=[O:19])[CH3:18].OO.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(O)C>[C:17]([O:20][C:21]1[CH:38]=[CH:37][C:36]2[C@@H:35]3[C@H:26]([C@H:27]4[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C@H:30]([OH:39])[CH:29]=[CH:28]4)[CH2:25][CH2:24][C:23]=2[CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3O[C@@H]3C[C@@H]12
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C=C[C@@H]12
Temperature: 0 °C

Procedure:
1.7 g. of diphenyldiselenide is dissolved in 90 ml. of absolute ethanol and mixed at room temperature with 480 mg. of sodium borohydride. After decolorization of the yellow solution, 2.2 g. of 3-acetoxy-16α,17α-epoxy-1,3,5(10)-estratriene [V. Prelog et al., Helv. 28, 250 (1945)] is added thereto and the mixture heated for 20 hours under reflux. After cooling to 0° C., 5 ml. of 30% H2O2 is added dropwise, and the solution is gradually warmed to 50° C. The product is worked up in accordance with Example 3, and then an after-acetylation is carried out in 5 ml. of pyridine with 2.5 ml. of acetic anhydride. The reaction solution is introduced into ice water. The thusprecipitated product is vacuum-filtered, washed with water, dissolved in methylene chloride, and dried over sodium sulfate. By chromatography of the crude product on silica gel with acetone/hexane, 930 mg. of 3-acetoxy-1,3,5(10),15-estratetraen- 17α-ol is obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:25]3[C:33]4[CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH2:29][C:28]=4[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=3)[N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4].N1C=CN=C1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O>CN(C)C=O.C(OCC)(=O)C>[Si:49]([O:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:25]3[C:33]4[CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH2:29][C:28]=4[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:26]=3)[N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4])([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(CO)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)amide (265 mg, 0.42 mmol) in N,N-dimethylformamide (2.7 ml) were added imidazole (35 mg, 0.51 mmol) and tert-butyldiphenylsilyl chloride (132 μl, 0.51 mmol) under ice-cooling, and the mixture was stirred at room temperature for 8 hr. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (341 mg, yield 93%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O>[N+:18]([C:14]1[C:10]2[C:11](=[O:13])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:1](=[O:8])[C:9]=2[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 2-benzoyl-6-nitrobenzoic acid (2.0 grams; 0.0074 mole) in 10 mls. of concentrated sulfuric acid (99.5% by weight) was stirred at 100° C. for 3 hours, then cooled to room temperature and poured into a mixture of ice and water. The resulting mixture was filtered to recover the precipitated solids. The filter cake was then washed successively with a dilute aqueous solution of sodium carbonate and water, and dried to obtain 1-nitroanthraquinone (1.59 grams; 85% yield). The product was identified by comparison of its vapor phase chromatographic spectrum with that of an authentic sample.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)(C)COP(=O)(O)O.[ClH:31].C(OC(=O)[NH:38][C:39]([C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([O:69][C@H:70]3[CH2:75][CH2:74][C@H:73]([C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:72][CH2:71]3)[C:61]=2[C:65]([F:68])([F:67])[F:66])[N:56]=1)([CH3:54])[CH2:40][O:41][P:42]([O:49]C(C)(C)C)([O:44]C(C)(C)C)=[O:43])(C)(C)C>>[NH2:38][C:39]([C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([O:69][C@H:70]3[CH2:71][CH2:72][C@H:73]([C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:74][CH2:75]3)[C:61]=2[C:65]([F:68])([F:66])[F:67])[N:56]=1)([CH3:54])[CH2:40][O:41][P:42](=[O:43])([OH:44])[OH:49].[ClH:31]
Reactant: CC(C)(C)OC(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CC(N)(COP(=O)(O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: Cl
Product: CC(N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
Phosphoric acid mono-{2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propyl} ester Enantiomer 1 was synthesized as per Phosphoric acid mono-{2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propyl}ester Enantiomer 1 (Example 30) in 88% yield as bis-HCl salt using [1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-(di-tert-butoxy-phosphoryloxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester Enantiomer 1 as starting material. (Note that HPLC purification was not necessary and compound was isolated as bis-HCl salt). MS: m/z=505.20 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm: 8.67 (d, J=8.5 Hz, 1H), 8.31 (d, J=9.5 Hz, 1H), 7.85 (d, J=9.3 Hz, 1H), 7.79 (d, J=9.3 Hz, 1H), 4.50-4.62 (m, 1H), 4.34-4.42 (m, 1H), 4.26-4.34 (m, 1H), 2.17-2.29 (m, 2H), 1.88-1.98 (m, 2H), 1.80 (s, 3H), 1.45-1.59 (m, 2H), 1.20-1.34 (m, 2H), 1.07-1.19 (m, 1H), 0.93 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]#[N:25])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][C@H:17]4[CH3:23])[C:5]=3[C:4]=2[CH:3]=1.OO.C(=O)([O-])[O-:29].[K+].[K+]>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]([NH2:25])=[O:29])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][C@H:17]4[CH3:23])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C(N)=O)c2[nH]c3ccc(F)cc3c12
Temperature: 70 °C

Procedure:
To a stirred solution of 8-fluoro-1-{[(1R,2R,4R)-4-hydroxy-2-methylcyclohexyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (4.8 g, 14.2 mmol) in DMSO (100 mL) were added hydrogen peroxide (30%, 14.5 mL, 142 mmol) and potassium carbonate (10.6 g, 77 mmol). The reaction mixture was heated to 70° C. overnight, cooled to room temperature, treated with brine, and extracted with EtOAc (×3). The combined organics were dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H); 7.94 (dd, 1H); 7.57 (dd, 1H); 7.13 (dt, 1H); 3.98 (m, 1H); 3.67 (m, 1H); 1.22-2.12 (series of m, 7H); 1.01 (d, 3H). LRMS (APCI) calc'd for (C19H21FN4O2) [M+H]+, 357.2. found 357.1.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][NH2:1])=[CH:14][CH:15]=1)[CH2:6][CH2:7][CH3:8]
Reactant: O=N[O-]
Reactant: CCCCc1ccc(N)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Sodium nitrite (11.74 g, 0.17 mol) in water (50 mL) was added over 30 min to an ice-cooled and stirred suspension of 4-n-butylaniline (24.30 g, 0.16 mol) in 6 N hydrochloric acid (190 mL). After an additional 15 min, a suspension of tin chloride dehydrate (108.3 g, 0.4 mol) in 6 N hydrochloric acid (190 mL) was added slowly, and the resulting suspension was stirred at 0° C. for 3 h. The solid was filtered and dissolved in a mixture of 40% potassium hydroxide solution (200 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with 10% hydrochloric acid (120 mL), a solid started to develop in the organic layer. After cooled it to 0° C., the solid was filtered. The organic layer was separated, dried over Na2SO4, and the solvent was evaporated. The resulting solid was recrystallized from ethanol to afford a white solid (17.35 g, 54%). 1H NMR (300 MHz, DMSO-d6): δ 10.18 (s, 3H), 7.10 (d, 2H, J=8.4 Hz), 6.92 (d, 2H, J=8.7 Hz), 2.51 (t, 2H, J=7.5 Hz), 1.50 (pentet, 2H, J=7.5 Hz), 1.27 (sextet, 2H, J=7.8 Hz), 0.88 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25](OCC)=[O:26])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C[O-].[Na+].Cl.C([NH2:36])=O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([NH2:36])=[O:26])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(C(=O)O)cc2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)nn2-c2ccc(C(=O)O)cc2)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (3.9 g) and sodium methoxide (3 g) in formamide (40 ml) was stirred at 45° C. for 3 hours. The mixture was poured into a mixture of ice-water and hydrochloric acid. The precipitates were collected, washed with water, and dried to give crystals of 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]-pyrazole-3-carboxamide (3.2 g).
Reaction SMILES: OO.O.[OH-].[Li+].C([C@@H]1COC(=O)N1C(=O)[CH:20]([CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[C:28]([O:35][CH2:36][CH2:37][O:38][CH3:39])[CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].[C:47](=O)([O-:49])[OH:48].[Na+]>O1CCCC1.O>[CH3:39][O:38][CH2:37][CH2:36][O:35][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[CH:26]=[C:25]([CH2:24][CH:20]([CH:21]([CH3:23])[CH3:22])[C:47]([OH:49])=[O:48])[CH:34]=[CH:33]2
Reactant: COCCOc1cccc2ccc(CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C(C)C)cc12
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(C(=O)O)C(C)C)cc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
122 ml of hydrogen peroxide (30%) are added dropwise and then 0.17 g of lithium hydroxide monohydrate is added to the solution of 0.95 g of 4(R)-benzyl-3-{2-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-3-methylbutyryl}oxazolidin-2-one in 12 ml of tetrahydrofuran and 4 ml of water at 0° C. After 6 hours at room temperature, the reaction mixture is cooled to 0° C. and admixed with a solution of 1.54 g of sodium sulphite in 9 ml of water (negative peroxide test). The reaction mixture is adjusted to pH 9.8 with saturated aqueous sodium hydrogen-carbonate solution and clarified by filtration, and the tetrahydrofuran is concentrated by evaporation. The residue is washed with dichloromethane (3×)—the combined organic phases are washed with phosphate buffer/25% conc. ammonia solution (pH 9.8). The combined aqueous phases are adjusted to pH 3.0 with 4N HCl and extracted with dichloromethane (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1)[CH3:3].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]([O:21][C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C@H:2]([OH:1])[CH3:3])[S:14][C:13]=2[CH:15]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3[C@@H](C)O)sc3cc(OC)ccc23)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3[C@@H](C)O)sc3cc(O)ccc23)cc1
Yield: 18.7 %

Procedure:
To a solution of afford (R,E)-methyl 3-(4-((2-(2-(1-hydroxyethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27.5 mg, 0.060 mmol) N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.00922 mL, 0.090 mmol) and K2CO3 (8.25 mg, 0.060 mmol). The resulting mixture was subjected to microwave irradiation at 190° C. for 1 h after which time the reaction was diluted with EtOAc and washed with brine. The layers were separated and the aqueous layer was further extracted with EtOAc, the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (R,E)-methyl 3-(4-((6-hydroxy-2-(2-(1-hydroxyethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (5 mg, 0.011, 19% yield). LC/MS (m/z, MH+): 445.0.