Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].[Li]C(C)(C)C.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:31][CH:30]=1)[C:22](N(OC)C)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCOC(C)=O>C1COCC1>[C:40]([O:39][C:37]([NH:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22](=[O:23])[C:2]([CH3:4])=[CH2:3])=[CH:30][CH:31]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: C=C(C)Br
Reactant: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
2-Bromopropene (3.5 eq., 14.0 mmol, 1.25 mL) was dissolved in THF (50 mL) and cooled to −78° C. tBuLi (6.5 eq., 26.0 mmol, 16.3 mL; 1.6 M in hexane) was added slowly and the mixture was stirred for 1 hour at −78° C. after which Weinreb amide 11 (1 eq., 4.0 mmol, 1.89 g) was added in THF (5 mL). The mixture was allowed to warm to −20° C. in 6 hours after which TLC analysis indicated complete consumption of the Weinreb amide. A saturated aqueous NH4Cl solution and EtOAc were added and the layers were separated. The organic layer was extracted with brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (20%→50% EtOAc/PE) as a colourless oil (yield: 1.71 g, 3.77 mmol, 94%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.24 (m, 5H), 7.11 (d, J=7.87 Hz, 2H), 6.97 (d, J=8.00 Hz, 2H), 6.03 (s, 1H), 5.85 (s, 1H), 5.77 (d, J=8.18 Hz, 1H), 5.30 (dd, J=14.10, 6.11 Hz, 1H), 5.12-5.08 (m, 1H), 5.04 (dd, J=26.54, 12.35 Hz, 2H), 4.21 (d, J=5.41 Hz, 2H), 3.09 (dd, J=13.79, 5.88 Hz, 1H), 2.89 (dd, J=13.76, 5.97 Hz, 1H), 1.84 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=199.28, 155.66, 155.34, 141.99, 137.40, 136.13, 134.60, 129.27, 128.17, 127.80, 127.71, 126.50, 79.01, 66.45, 55.13, 43.96, 38.76, 28.14, 17.44 ppm. HRMS: calcd. for C26H32N2O5 453.23840 [M+H]+. Found 453.23818.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[CH3:16])[CH:2]1[O:4][CH2:3]1.C(O)=[O:18].OO>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([CH2:13][CH:14]2[O:18][CH2:15]2)=[CH:10][C:11]=1[CH3:12])[CH:2]1[O:4][CH2:3]1
Reactant: O=CO
Reactant: C=CCc1cc(C)c(OCC2CO2)c(C)c1
Agent: OO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC2CO2)cc(C)c1OCC1CO1
Yield: 85.5 %

Procedure:
A 350 ml sulfurating flask equipped with thermometer, stirrer, cooler and drip funnel is charged with 21.8 g (0.10 mole) of 4-allyl-2,6-dimethylphenyl glycidyl ether, 10.9 g (0.24 mole) of formic acid and 135 ml of chloroform. At room temperature, 23.2 g (0.47 mole) of hydrogen peroxide are then added dropise over 4 hours. The reaction miture is held at this temperature overnight. It is subsequently taken up in chloroform and the resultant solution is washed twice with 3% NaOH solution until neutral, made peroxide-free with sodium sulfite, dried over sodium sulfate and filtered. The filtrate is concentrated, affording 20.03 g (80.50% of theory) of 4-(2,3-epoxypropyl)-2,6-dimethylphenyl glycidyl ether in the form of a low viscous resin; epoxide content 7.7 equivalents/kg (90.11% of theory).
Reaction SMILES: [CH2:1]([C:4]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[C:5]=1[O:23][CH3:24])[CH2:2][CH3:3].[CH2:25](Br)[CH2:26][CH2:27][CH3:28].[OH-].[K+]>CO>[CH2:25]([N:11]1[CH2:10][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:7]=[C:6]([O:21][CH3:22])[C:5]([O:23][CH3:24])=[C:4]([CH2:1][CH2:2][CH3:3])[C:14]=2[CH2:13][CH2:12]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: CCCc1c2c(cc(OC)c1OC)C(c1ccccc1)CNCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2CCC)C(c2ccccc2)C1

Procedure:
A mixture of 4.5 g of 6-propyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 mole of n-butyl bromide and 0.02 mole of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-propyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=1[O:26][CH3:27])=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=2[O:26][CH3:27])=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: COc1ccc(C(C)=O)c(OC)c1OC
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2ccc(OC)c(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (0.781 g, 4.8 mmol) and 2,3,4-trimethoxyacetophenone (1.0 g, 4.8 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (7.60 ml, 0.096 mol). The reaction mixture was stirred at room temperature for 24 h. A pale yellow precipitate was isolated and dried under vacuum over night. 1.693 g (86%) of a pale yellow powder was isolated. 1H-NMR (CDCl3) δ 7.60 (d, 1H), 7.5 (m, 1H), 4.4 (d, 1H), 7.3 (d, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 3.9 (t, 2H), 3.9 (s, 3H), 3.9 (s, 3H), 3.9 (s, 3H), 1.75 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 191.0. Mass Spectrum m/e (M+1) 357. Anal. Calcd. for C21H24O5.H2O: C, 67.44; H, 7.01. Found: C, 67.49; H, 6.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCNCC
Product: CCOC(=O)c1c(CN(CC)CC)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
According to the same manner as that described in Example 33, ethyl 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylate was reacted with diethylamine to give ethyl 6-chloro-2-(N,N-diethylaminomethyl)-4-phenylquinoline-3-carboxylate. This compound was recrystallized from ethanol. Colorless prisms, mp. 107°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:2].[O-]CC.[K+]>C1(C)C=CC=CC=1>[OH:14][C:13]1[C:12](=[O:18])[N:7]2[CH:6]([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)CC1CCCCN1C(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(O)C(=O)N2CCCCC12
Temperature: 100 °C
Yield: 64.3 %

Procedure:
Intermediate 22B (3.75 g, 13.8 mmol) was suspended in toluene (100 mL) and treated with potassium ethoxide (5.42 mL, 24% in methanol, 13.8 mmol). The clear mixture was heated at 100° C. for 4 h. After cooling to rt, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% citric acid twice, brine twice, dried over Na2SO4, filtered and concentrated to afford Intermediate 22C (2.0 g, 64%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (3H, td, J=7.2, 1.8 Hz), 1.46-1.87 (5H, m), 2.19 (1H, br. s.), 3.12-3.51 (1H, m), 4.09-4.23 (2H, m), 4.27-4.42 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1.[CH2:28](S)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][CH3:28])=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: CCS
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.05 g (2.7 mmol) of 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (EP 166,591, Example 22) and 800 μL of ethanethiol (10 mmol) in 20 mL of CH2Cl2 at -20° C. was added in portions 2.17 g (16 mmol) of AlCl3. The reaction turned light orange and was stirred at room temperature overnight. In the morning, the reaction was completed (tlc) and it was poured into a solution of 1N HCl and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and filtered. The filtrate was evaporated and to the residual syrup (680 mg) was added 20 mL of Et2O followed by an ethereal solution of diazomethane. Evaporation of the solvent left the crude title compound which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[CH3:11])[CH2:6][CH:5]=1.O.[CH3:16]COCC>>[CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]([CH3:16])=[CH2:11])[CH2:6][CH:5]=1
Reactant: CCOCC
Reactant: CC(=O)C1CC=C(O[Si](C)(C)C)CC1
Solvent: O
Product: C=C(C)C1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
From 23.5 g (0.066 mol) of methyltriphenylphosphonium bromide and 6.9 g (0.061 mol) of potassium tert-butylate, in 80 ml of ether at room temperature, the ylide was formed. To this solution were added dropwise at from 20° to 30° C. 10.0 g (0.047 mol) of 1-trimethylsilyloxy-4-acetyl-1-cyclohexene (Org. Synth. Coll. Vol. VI, 445) dissolved in 20 ml of ether. The mixture was stirred at room temperature for 3 hours. Water was then added, and extraction was carried out with ether. A spatula tip of hydroquinone was added to the combined ether phases, which were then dried and concentrated. The residue was extracted by stirring with heptane and the combined heptane phases were concentrated. 8.0 g (81% of theory) were obtained of a colorless oil which was reacted further without purification.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:11][CH:10]([OH:12])[CH:9]2[NH:13][CH2:14][CH2:15][CH:8]12)=[O:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:73]([C:82]([O:84][CH2:85][C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:83])[C@H:74]([C:79](O)=[O:80])[C:75]([CH3:78])([CH3:77])[CH3:76]>CN1C(=O)CCC1.O>[CH2:85]([O:84][C:82](=[O:83])[NH:73][CH:74]([C:79]([N:13]1[CH2:14][CH2:15][CH:8]2[N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:11][CH:10]([OH:12])[CH:9]12)=[O:80])[C:75]([CH3:76])([CH3:77])[CH3:78])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)NC(=O)N1CC(O)C2NCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution containing crude 54 (˜3.8 g, 17.9 mmol) and DIPEA (4.1 mL, 23.3 mmol) in NMP (50 mL) was cooled to 0° C. In a separate flask, Cbz-Tle-OH dicyclohexylamine salt (8.8 g, 19.7 mmol), HATU (7.5 g, 19.7 mmol), and DIPEA (4.1 mL, 23.3 mmol) were dissolved in NMP (130 mL) at 0° C. A portion of the HATU/Cbz-Tle-OH solution (117 mL, ˜1.0 equiv) was added to the solution containing 54. After 30 min, the reaction mixture was diluted with water and extracted with 1:1 Et2O/EtOAc. The combined organic extracts were washed successively with 10% H3PO4, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.2 g of 55 as a beige-colored foam (88%, 4 steps) which was used without further purification. Mass spectrum, m/z [460.9] (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH3:22])[C:14]=3[N:13]=[C:12]([CH3:23])[C:11]=2[CH2:10][CH2:9]1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH3:22])[C:14]=3[N:13]=[C:12]([CH3:23])[C:11]=2[CH:10]=[CH:9]1
Reactant: COc1cccc2c3c(c(C)nc12)CCN3c1ccccc1C
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c1nc(C)c1ccn(-c3ccccc3C)c12
Yield: 48.5 %

Procedure:
1-(2-Methylphenyl)-4-methyl-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (4.57 g, 15 mmol) in diphenyl ether (50 ml) was heated at reflux with 10% palladium-on-charcoal (1.0 g) for 1 hour then the catalyst removed on celite. Chromatography (silica gel, 1% methanolic ammonia in dichloromethane) and recrystallisation from ethyl acetate/petroleum ether gave 1-(2-methylphenyl)-4-methyl-6methoxypyrrolo[3,2-c]quinoline(2.2 g, 48%), m.p. 143°-145°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH:18]=[CH:17]2)[CH3:11]>C(=S)=S>[Cl:1][CH2:2][C:3]([C:14]1[CH:15]=[C:16]2[C:21](=[C:12]([CH2:10][CH3:11])[CH:13]=1)[NH:20][C:19](=[O:22])[CH:18]=[CH:17]2)=[O:4]
Reactant: CCc1cccc2ccc(=O)[nH]c12
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCc1cc(C(=O)CCl)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 62 ml of chloroacetyl chloride in 600 ml of carbon disulfide were added, with ice-cooling, 173 g of aluminum chloride and 44 g of 8-ethylcarbostyril in this order. The mixture was refluxed for 6 hours. The reaction mixture was subjected to distillation to remove carbon disulfide. The residue was poured into ice water. The mixture was stirred at room temperature overnight. The insoluble portion was collected by filtration, washed with water and dried to obtain 55 g of 6-chloroacetyl-8-ethylcarbostyril as a brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:16][CH2:17][CH2:18]OS(C)(=O)=O)=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:16][CH2:17][CH2:18][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: CCOc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOc1cc2ccc(=O)oc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 76 %

Procedure:
Method B (40 h at 50° C.); starting materials: 6-ethoxy-7-[3-(methanesulfonyloxy)-propoxy]-2H-1-benzopyran-2-one (see example 71) and 1-phenylpiperazine; yield 76%; fusion point 116° to 117° C. (from isopropanol). Fumarate: method E; yield 94%; fusion point 185° to 187° C. (from ethanol and acetone).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([OH:12])[C:4]3([CH3:16])[CH:5]=[CH:6][CH:7]([CH2:15][CH:3]13)[C:8]2([CH3:14])[CH3:13]>C(O)C.O=[Pt]=O>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([OH:12])[C:4]3([CH3:16])[CH2:5][CH2:6][CH:7]([CH2:15][CH:3]13)[C:8]2([CH3:13])[CH3:14]
Reactant: CC1(C)C2C=CC3(C)C(C2)C(=O)CCC13O
Agent: O=[Pt]=O
Solvent: CCO
Product: CC1(C)C2CCC3(C)C(C2)C(=O)CCC13O
Yield: 92.3 %

Procedure:
22 mg of 1,2,3,4,4a,5,6,8a-octahydro-2-oxo-4a-hydroxy-5,5,8a-trimethyl-1,6-methanonaphthalene in 4 ml of ethanol is stirred in the presence of 6 mg of PtO2 for 12 hours under a H2 atmosphere (1 atm, 25° C.). The reaction mixture, filtered through Celite and evaporated, gave, after chromatography and sublimation, 20.5 mg of 1,2,3,4,4a,5,6,7,8,8a-decahydro-2-oxo-4a-hydroxy-5,5,8a-trimethyl-1,6-methanonaphthalene (m.p. 120°-123° C., 92% yield).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(OCC)C>[CH2:1]([C:9]1[C:10]([CH3:15])=[C:11]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1C
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Product: CCCCCCCCc1cccc(S(=O)(=O)Cl)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Octyltoluene (50 g.-0.245 mole) as prepared in Table 1 was added slowly at 5°-10° C. with stirring over one half hour (some exotherm) to 81 g. (0.69 mole) chlorosulfonic acid in a 250 ml. round bottom flask fitted with air stirrer, thermometer, addition funnel, reflux condenser, scrubber and ice bath. The reaction mixture was allowed to stir for three hours at 25°-30° C. and then stand overnight. It was poured onto 900 g. ice, 500 ml. diethyl ether was added and the mixture was stirred until the ice melted. The resulting organic phase was washed with water, 30% aqueous Na2CO3, again with water, dried over Na2SO4 and the solvent was evaporated. Thirty nine g. of octylmethylbenzenesulfonyl chloride was obtained.
Reaction SMILES: [BH4-].[Li+].[NH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1.C(OCC)(=O)C>[NH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: O=C(c1c[nH]c2ccccc12)C1CCCN1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(CC3CCCN3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of lithium borohydride (0.33 g, 15.2 mmol, 3.0 eq) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added dropwise a solution of the 3-(pyrrolidin-2-ylcarbonyl)-1H-indole (10 mmol) in anhydrous tetrahydrofuran (40 mL). The resulting reaction solution was heated at reflux under nitrogen for a time depending on the substrate. The reaction was then cooled, and sodium sulfate decahydrate (approximately 25 g) was added slowly with caution, followed by water (1 mL), and ethyl acetate (50 mL). The resulting reaction mixture was stirred at room temperature under nitrogen for 4 hours. Then the reaction mixture was filtered through Celite®, and the filtrate was evaporated under reduced pressure. The residue was column chromatographed using silica gel (approximately 200 g) eluting with an appropriate solvent system to afford the appropriate 3-(pyrrolidin-2-ylmethyl)-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[S:18](=[O:22])(=[O:21])([OH:20])O>>[C:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[C:12]([S:18]([OH:20])(=[O:22])=[O:21])[C:11]([CH3:14])=[C:10]([S:18]([OH:22])(=[O:21])=[O:20])[CH:9]=2)[CH:6]=[C:7]([S:18]([OH:20])(=[O:22])=[O:21])[C:2]=1[OH:1])([OH:17])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(-c2ccc(O)c(C(=O)O)c2)cc1
Product: Cc1c(S(=O)(=O)O)cc(-c2cc(C(=O)O)c(O)c(S(=O)(=O)O)c2)cc1S(=O)(=O)O
Temperature: 30 °C
Reaction time: 24 h

Procedure:
The same procedure as 5a is used with 11.42 g dry 4-hydroxy-4′-methylbiphenyl-3-carboxylic acid (50 mmole, fw=228.25) and 80.1 g 30% fuming sulfuric acid (300 mmole, fw=80.06) which are stirred at 30° C. for 24 hour and then heated with stirring at 70° C. for another 24 hours. Crystallization was effected using 22.2 g distilled water and 145 mL propionitrile. Yield was 21.2 g (84%) of the trisulfonated product as white crystals of the dihydrate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[Li]CCCC.[CH3:13][O:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH2:16][CH2:15][O:14][CH3:13]
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCc1sccc1Br
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
To a solution of 2,3-dibromothiophene (12.6 g, 50 mmol) in THF abs. (125 mL) was added at −75° C. n-BuLi (1.6M/hexane, 31 mL) over 30 minutes. The reaction mixture was further stirred at −75° C. for 30 minutes, and p-toluenesulfonic acid-2-methoxyethylester (11.8 g, 50 mmol) was added dropwise over 1 h. The mixture stirred for 2 h without cooling, quenched with brine, and extracted with ether. The organics were washed, dried, and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 3-bromo-2-(2-methoxy-ethyl)-thiophene (1.8 g) as a colorless liquid. MS (EI): 221.1 (M)
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1ncc2cccnc2c1O

Procedure:
Methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate (10.0 grams, 48.9 mmol) prepared as described in Example 1 was dissolved/suspended in MeOH (100 mL) and treated with 4-fluorobenzylamine (6.1 g, 48.9 mmol). The reaction was brought to reflux and the MeOH allowed to evaporate until the total volume was approximately 30 mL. The reaction was refluxed for 5 hours more and a white solid precipitated. The reaction was cooled and the solid collected by filtration, washed with a minimum of MeOH and dried on the pump to give the product as a white solid.
Reaction SMILES: C([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=O)C.N1C=CC=CC=1.Cl.[CH3:35][O:36][NH2:37]>CO>[C:24]([O:23][C:21]([NH:4][N:5]1[CH2:10][C:9](/[CH:11]=[N:37]/[O:36][CH3:35])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CON
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (1.15 g, 3.00 mmol) in MeOH (1.8 mL) at room temperature was added pyridine (0.88 mL, 10.9 mmol) followed by O-methylhydroxylamine HCl salt (376 mg, 4.50 mmol). The obtained mixture was stirred for 20 h at room temperature and then concentrated under reduced pressure. The residual was redissolved in EtOAc, washed with water and dried (Na2SO4). After evaporation of the solvent, the crude product was obtained as a viscous oil which was used in the subsequent step without further purification. LCMS (Method I) RT 1.77 min. [M+H]+ 372.