Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[BH4-].[Na+]>CO>[OH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) solution of 4-(diethyoxymethyl)benzaldehyde (5.2 g, 24 mmol) in MeOH (50 mL) was added NaBH4 (0.93 g, 24 mmol), and the reaction mixture was stirred for 3 hours. The MeOH was removed and the residue was taken up in DCM and diluted with water. The aqueous layer was extracted with DCM (3×50 mL). The combine organic layers were dried, filtered and concentrated. The crude oil was dissolved in MeOH (50 mL) and cooled to 0° C. To this was added 2N HCl (10.0 mL) in ether. The reaction mixture was left at room temperature for 24 hours. The MeOH was removed and the crude product was purified by flash column chromatography, eluting with EtOAc/Hexane (3:7) to yield 2.92 g of 4-(hydroxymethyl)benzaldehyde (11) as a colorless oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:40])[C@@H:5]([NH2:39])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH2:36][CH3:37])([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([CH3:35])[CH:22]=3)[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:38])=[CH:8][CH:7]=1>CC(C)=O>[NH2:39][C@@H:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH2:19][CH3:20])([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([OH:34])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:23]([CH3:35])[CH:22]=3)[CH2:36][CH3:37])=[CH:14][C:13]=2[CH3:38])=[CH:10][CH:11]=1)[C:4]([OH:40])=[O:3]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)OC)cc2)c(C)c1
Agent: Cl
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)O)cc2)c(C)c1
Temperature: 140 °C
Yield: 6.5 %

Procedure:
A 4 N hydrochloric acid aqueous solution (0.80 mL) was added to a solution of the mixture containing (S)-amino-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (220 mg) in acetone (0.60 mL), and the mixture was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was purified by high performance liquid chromatography (GL Sciences Inertsil ODS-3, 20 mm I.D.×150 mm, methanol:water=20:80 to 100:0, 20 mL/min) and concentrated under reduced pressure to give the target compound as a white solid (14.0 mg, 36% in two steps).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])=[CH:37][CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NCc1ccc(Br)cc1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCc1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (93.8 mg, 0.21 mmol), cyclopropanecarboxylic acid 4-bromo-benzylamide (50.6 mg, 0.20 mmol), and Pd[P(Ph)3]4 (13.7 mg, 5.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 15.0 mg. MS: 498.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.61-0.79 (m, 4H), 1.56-1.69 (m, 3H), 2.11-2.35 (m, 1H), 3.38-3.59 (m, 2H), 4.25-4.43 (m, 3H), 4.89-5.15 (m, 2H), 7.00-7.65 (m, 12H), 7.85-7.95 (m, 1H), 8.51-8.63 (m, 1H), 10.07-10.16 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[C:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=1>>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20]1[N:21]=[CH:22][C:23]([NH:26][C:11]([C:8]2[O:9][C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]=2[CH3:14])=[O:13])=[CH:24][CH:25]=1
Reactant: Cc1c(C(=O)O)oc2c(F)cccc12
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2oc3c(F)cccc3c2C)cn1

Procedure:
With a procedure similar to the example above, 7-fluoro-3-methyl-benzofuran-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 7-fluoro-3-methyl-benzofuran-2-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H20FN3O3 (m/e) 357, obsd 358 (M+H).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H](CO)O)O)O.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14].[OH-].[Na+]>>[CH2:21]([OH:22])[C@H:19]1[O:20][C@:13]([OH:14])([CH2:12][OH:11])[C@@H:15]([OH:16])[C@@H:17]1[OH:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 58 °C

Procedure:
The above experiment was repeated, except that the xylose isomerase was bound on an alumina carrier. The same dextrose feed liquor, pre-adjusted to a pH of 8.3 - 8.4 with 4 N NaOH, was pumped through the column, which was maintained at a temperature of 58°C, at a rate to provide 45% by weight levulose, dry basis, in the effluent. The residence time was less than one hour. The following is an analysis of the pH of the feed syrup and effluent syrup after a prolonged continuous conversion campaign:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:21]=2)[N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:21]=2)[NH:16][CH:15]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2C(=O)c4ccccc4C2CCO)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4C(=O)c5ccccc5C4CCO)c3n2)cc1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
3-(2-hydroxyethyl)-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (58 mg, 0.08068 mmol) dissolved in DCM (2 mL) under N2 and Et3SiH (64.44 μL, 0.4034 mmol) then TFA (300 μL) added. Reaction mixture stirred overnight, then concentrated and residue azeotroped with DCM (×3). Purified by hplc to give the title compound as a pale yellow solid (19.3 mg, 50%); 1H NMR (400 MHz, DMSO) 1.03 (6H, d), 1.72-1.79 (1H, m), 2.00-2.15 (1H, m), 3.00-3.09 (1H, m), 3.32 (1H, sep), 4.28 (1H, t), 5.82-5.85 (1H, m), 7.42 (1H, t), 7.57 (1H, t), 7.65 (2H, d), 7.80 (2H, d), 8.21 (1H, s), 8.32 (2H, d), 8.93 (1H, s), 12.30 (1H, brs); MS (ES+) 477.0.
Reaction SMILES: [CH:1]1([C:5]23[CH2:12][O:11][C:8]([C:13]4[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=4)([O:9][CH2:10]2)[O:7][CH2:6]3)[CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]1([C:5]23[CH2:6][O:7][C:8]([C:13]4[CH:14]=[CH:15][C:16]([C:19]#[CH:20])=[CH:17][CH:18]=4)([O:11][CH2:12]2)[O:9][CH2:10]3)[CH2:2][CH2:3][CH2:4]1
Reactant: C[Si](C)(C)C#Cc1ccc(C23OCC(C4CCC4)(CO2)CO3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C23OCC(C4CCC4)(CO2)CO3)cc1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-cyclobutyl-1-(4-trimethylsilylethynylphenyl)2,6,7-trioxabicyclo[2.2.2]octane (Compound 2) (1.3 g, 3.8 mmol) in dry THF (30 ml) under nitrogen atmosphere was added tetra-butylammonium fluoride (4 ml of 1M solution in THF). The mixture was stirred for one hour, evaporated to dryness and the residue partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous potassium carbonate and evaporated to leave a residue. Purification on a basic alumina column, eluting with hexane: dichloromethane (9:1 v/v) gave 4-cyclobutyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo [2.2.2]octane as a white solid (800 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([C:29]([F:32])([F:31])[F:30])=[N:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:2]2[CH:9]=[C:8]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:13]4[C:12]([C:29]([F:32])([F:31])[F:30])=[N:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:36][CH2:35]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1N[C@H]1CC[C@H](O)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of a mixture of compound (1e) (0.560 g), trans-4-hydroxycyclohexylamine (0.522 g), sodium tert-butoxide (0.218 g), palladium acetate (0.025 g), and 1,1-bis-(diphenylphosphino)-ferrocene (0.126 g) in 1,4-dioxane (12 mL) was stirred under a nitrogen atmosphere at 140° C. for 2 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1f) (0.450 g, 75%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:44])([CH3:43])[C:17]1[CH:18]=[C:19]([CH:36]=[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1)[C:20](NC1N=CC(/C=C/C(OCC)=O)=CC=1)=[O:21]>>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:37]1[CH:36]=[C:19]([CH:18]=[C:17]([Si:16]([CH3:44])([CH3:43])[CH3:15])[CH:38]=1)[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:21]
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Product: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 62 %

Procedure:
Using BTMB (10.0 g) and ethyl 4-aminocinnamate (8.62 g), Compound 3a (10.3 g, 62%) was obtained as a yellow solid in the same manner as Compound 1b was obtained.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH2:15]([N:22]1[CH2:30][C@H:29]2[C@H:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][CH2:27][C:28]2=[O:31])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].O>O1CCCC1.C(OCC)(=O)C>[CH2:15]([N:22]1[CH2:30][C@H:29]2[C@H:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:27][C@H:28]2[OH:31])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
4.0 cm3 of a 1M solution of lithium tri-sec-butyl borohydride in tetrahydrofuran is added over 5 minutes to a solution, cooled to 0° C., of 1.3 g of (3aR, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in 6.0 cm3 of tetrahydrofuran. After stirring for 3 hours at 0° C., the reaction mixture is again supplemented with 0.5 cm3 of the 1M solution of borohydride. After 1 hour at 0° C. and the addition of 50 cm3 of water and 50 cm3 of ethyl acetate, the organic phase is decanted, washed with 20 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR, 4R, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of white crystals; melting point 154° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC#CCOc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCC#CCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate as a pale yellow solid; MS: 638 (M+H)+.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCC/C=C/[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC/C=C/[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 800 mg of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid, 675.64 mg of p-ethoxyphenol, 1.01 g of dicyclohexylcarbodiimide and 49.79 mg of 4-(dimethylamino)pyridine was suspended in 14.5 ml of methylene chloride and stirred at room temperature for 20 hours. The mixture was subsequently diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 1.080 g (83.8%) of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 40 ml of hexane, there were finally obtained 880 mg of product in the form of transparent crystals; m.p. (C-N) 57.2° C., cl.p. (N-I) 93.1° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:38]4[C:26](=[CH:27][C:28]5[C:29]([CH3:46])([CH3:45])[C:30]6[CH:31]=[C:32]([C:39]7[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=7)[CH:33]=[CH:34][C:35]=6[C:36]=5[CH:37]=4)[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:54])C(=O)C1.O>C(#N)C>[Br:54][C:23]1[CH:24]=[C:25]2[C:20]([N:19]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[C:38]3[C:26]2=[CH:27][C:28]2[C:29]([CH3:46])([CH3:45])[C:30]4[CH:31]=[C:32]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:33]=[CH:34][C:35]=4[C:36]=2[CH:37]=3)=[CH:21][CH:22]=1
Reactant: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1ccccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1cc(Br)ccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
138 g (234.6 mmol) of 6-(4,6-diphenylpyrimidin-2-yl)-12,12-dimethyl-2-phenyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3 CN is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2 Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(Cl)Cl.O>[N:13]1([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccccc21
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of di-tert-butylcarbonate (427.1 g, 1.96 mol) in CH2Cl2 (500 mL) was added dropwise at room temperature to a solution of indoline (212 g 1.78 mol) in CH2Cl2 (1000 mL). A solution of NaOH (85.3 g, 2.13 mol) in water (500 mL) was then added dropwise and the mixture was stirred overnight. The layers were separated and the organic layer was washed with 5% NaOH, brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure and the crude product was crystallized with petroleum ether, giving 324 g (68%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([CH2:13][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3[nH]ncc23)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxyindazole (702 mg, 5.24 mmol) in DMF (10 mL) at ambient temperature under argon was added sodium hydride (231 mg of a 60% dispersion in mineral oil, 5.76 mmol). The mixture was stirred for 10 minutes and then benzyl bromide (0.622 mL, 5.24 mmol) was added via syringe. After stirring for 2 hours at ambient temperature, the mixture was quenched with ammonium chloride solution, the solvents were evaporated and ethyl acetate and water were added. The product was extracted into ethyl acetate and the organic solution was dried (Na2SO4) and evaporated.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][S:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.11 mL, 0.11 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 138-(4); 20 mg, 0.037 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give the target compound as a colorless oil (15 mg, 77%).
Reaction SMILES: [Cl-].[Cl-].[NH3+]C1C=CC(C(N[C:11]2[CH:24]=[CH:23][C:14]([NH:15][C:16]3[CH:21]=[CH:20][N+](C)=CC=3)=[CH:13][CH:12]=2)=O)=CC=1.ClC1C2C(=CC=C([N+:38]([O-:40])=[O:39])C=2)N=CC=1>CO.Cl>[N+:38]([C:16]1[CH:21]=[CH:20][C:13]2[C:14](=[CH:23][CH:24]=[CH:11][CH:12]=2)[N:15]=1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Reactant: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc([NH3+])cc3)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=[N+]([O-])c1ccc2ccccc2n1

Procedure:
To a suspension of amide B7 (2.09 g, 5.32 mmol) in dry MeOH (100 mL) were sequentially added 4-chloro-6-nitroquinoline (F1) [1.11 g, 5.32 mmol] and a few drops of concentrated HCl, and the resultant mixture was refluxed for 12 h. After this time, solvent was removed under reduced pressure, and the residue was re-suspended in 1:1 MeOH:EtOAc. This mixture was heated to remove MeOH, and then cooled, and the resulting precipitate collected by filtration. This solid was recrystallized from MeOH:EtOH to give nitroquinoline Cpd. G (2.48 g, 89%) as an amorphous yellow solid; 1H NMR [CD3)2SO]: δ 3.96 (s, 3H, R2N+−CH3), 7.12 (m, 3H, ArH), 7.35 (d, J=8.81 Hz, 2H, ArH), 7.68 (d, J=8.51 Hz, 2H, ArH), 7.96 (d, J=8.81 Hz, 2H ArH), 8.24 (m, 5H, ArH), 8.72 (m, 2H, ArH), 9.83 (d, J=1.69 Hz, 1H, ArH), 10.56 (s, 1H, ArNHAr), 10.67 (s, 1H, ArNHAr), 11.48 (br s, 1H, ArNHAr). LCMS (APCl+): 492 (20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of [2-(3-chloro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (20 g, 73.5 mmol), phthalimide (11.1 g, 73.5 mmol) and PPh3 (25.1 g, 95.5 mmol) in THF (500 mL) was added DEAD (11.4 mL, 95.5 mmol) dropwise at −5 to 0° C. The reaction mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:10) to afford [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamic acid tert-butyl ester. (Yield 20 g, 69%). LC-MS: [M+H]+ 401.