Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH2:15])=[O:4].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1c(N)ccc2c1CCCC2
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 5, 1.5 g) in pyridine (20 mL) was added benzenesulfonyl chloride (0.95 mL). The mixture was stirred for 1 hour then concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated under vacuum to give the title compound as an off-white crystalline solid (2.4 g).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][CH2:15]OC2C=CC=CC=2)[C:11]2[C:10](=[O:23])[N:8]([CH3:9])[C:7](=[O:24])[N:6]([CH3:25])[C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+].[BrH:28]>>[Br:28][CH2:15][CH2:14][CH2:13][N:12]1[C:11]2[C:10](=[O:23])[N:8]([CH3:9])[C:7](=[O:24])[N:6]([CH3:25])[C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1CCCOc1ccccc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1CCCBr
Yield: 82 %

Procedure:
A mixture of 8-ethyl-7-(3-phenoxypropyl)theophylline (23.0 g; 0.067 M) and 48% aqueous hydrogen bromide (150 ml) was heated at reflux for 20 hours. The mixture was cooled and poured into dilute aqueous sodium hydroxide solution. The suspension was extracted with chloroform and the organic phase was washed with water, aqueous 10% sodium hydroxide solution and water and was dried (MgSO4), filtered and the filtrate was evaporated to dryness leaving a colourless solid. This solid was crystallised from ethanol to give the required compound as colourless prisms, (8.2 g) (82%) mp 119°-120°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 69 %

Procedure:
Using the general method of Example 245 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with p-toluenesulfonyl chloride (1.08 g, 5.55 mmol) to provide 1.57 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamide as an off white powder, m.p. 197.0-198.5° C. Analysis: Calculated for C24H29N5O2S: % C, 63.83; % H, 6.47; % N, 15.51; Found: % C, 63.68; % H, 6.40; % N, 15.51.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[I:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28](OCC)=[O:29])[CH:24]=[CH:23]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:28]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[C:18]([I:17])[CH:19]=[N:20][CH:21]=2)[N:26]=1)=[O:29])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCOC(=O)c1ccc2cncc(I)c2n1
Reactant: CCN(CCN)CCOc1cccnc1F
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1ccc2cncc(I)c2n1)CCOc1cccnc1F
Yield: 96.8 %

Procedure:
This compound was prepared, starting from compound 5 (100 mg, 0.44 mmol) and ethyl 8-iodo-[1,6]naphthyridine-2-carboxylate (72) (102 mg, 0.31 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 73 (151 mg, 0.30 mmol) as a yellow oil. Yield 96%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.65; IR (CCl4) ν 1467, 1518, 1685, 2700-3000 cm−: 1H NMR (200 MHz, CDCl3) δ 1.10 (t, 3H, J=7.1 Hz), 2.71 (q, 2H, J=7.1 Hz), 2.83 (t, 2H, J=6.0 Hz), 2.97 (t, 2H, J=5.6 Hz), 3.59 (q, 2H, J=6.0 Hz), 4.12 (t, 2H, J=5.6 Hz), 6.82 (ddd, 1H, 5JH-F=0.5 Hz, J=4.8, 7.9 Hz), 7.12 (ddd, 1H, 4JH-F=10.1 Hz, J=1.6, 7.9 Hz), 7.43 (td, 1H, 4JH-F=1.6 Hz, J=1.6, 4.8 Hz), 8.32 (d, 1H, J=8.4 Hz), 8.40 (d, 1H, J=8.4 Hz), 8.79 (m, 1H), 9.10 (s, 1H), 9.13 (s, 1H); ESI-MS m/z 509.9 [M+H]+.
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:9]=1
Reactant: Sc1cccc(Br)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(SC2CCCC2)c1
Reaction time: 1.5 h

Procedure:
Iodocyclopentane (3.93 ml) was added to a mixture of 3-bromobenzenethiol and potassium carbonate (5.4 g) in acetone (50 ml) and the reaction was stirred under nitrogen for 1.5 h. A further portion of iodocyclopentane (2 ml) was added and the mixture was stirred for 1 h. The solvent was evaporated and the residue was partitioned between water and EtOAc. he combined organic extracts were washed with NaOH (2N), brine and dried (Na2SO4). The resulting oil was purified using biotage™ chromatography on silica using cyclohexane as eluant to give the title compound (3.6 g). LCMS RT=4.1 min
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[N:29]([CH3:50])[C:30]3[C:39]4[C:38](=[O:40])[NH:37][C:36]([CH:41](OC(=O)C)[CH:42]=[CH2:43])=[C:35]([CH3:48])[C:34]=4[CH:33]=[CH:32][C:31]=3[N:49]=2)=[C:23]([CH3:51])[CH:22]=1.[N-:52]=[N+]=[N-].[Na+].[OH-].[NH4+]>O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[NH2:52][CH2:43][CH:42]=[CH:41][C:36]1[NH:37][C:38](=[O:40])[C:39]2[C:30]3[N:29]([CH3:50])[C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][C:23]=4[CH3:51])=[N:49][C:31]=3[CH:32]=[CH:33][C:34]=2[C:35]=1[CH3:48]
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN)[nH]c(=O)c3c2n1C
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a 50 mL round bottom flask equipped with a magnetic stir bar was added Pd2(dba)3 (38 mg, 42 μmol), triphenylphosphine (52 mg, 200 μmol) and THF (6.6 mL). The resulting solution was stirred under nitrogen for 20 minutes followed by the addition of acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.288 mg, 0.664 mmol). The resulting red solution was stirred for 20 minutes, then sodium azide (47 mg, 0.72 mmol) was added as a solution in water (0.6 mL). The flask was sealed with a plastic cap and heated to 60° C. for 3 hours. The reaction mixture was cooled to room temperature and triphenylphosphine (165 mg, 0.63 mmol) was added. After stirring at room temperature for 7 hours, ammonium hydroxide was added (0.7 mL) and the reaction was stirred for 12 additional hours. The reaction mixture was diluted with ethyl acetate (50 mL) and the solution dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with MeOH:HCCl3 (10-40%) to give 7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one. 1H NMR (400 MHz, d6-DMSO) δ 11.24 (s, 1H), 10.62 (s, 1H), 8.1-8.0 (m, 2H), 7.77 (d, J=9 Hz, 1H), 7.71 (d, J=9 Hz, 1H), 7.6-7.5 (m, 1H), 6.6-6.45 (m, 2H), 4.18 (s, 3H), 3.75-3.65 (m, 2H), 2.36 (s, 3H), 2.30 (s, 3H); ESMS m/z: found, 392 (M+1)+.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH3:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:17](=[O:19])[CH3:18])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (4.5 g) in anhydrous tetrahydrofuran (70 mL) at 0° C. was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (5.2 g). After stirring at 15° C. for 15 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (10 g) in tetrahydrofuran (30 mL) was added and the resulting mixture heated at 70° C. for 17 hours. The mixture was diluted with saturated aqueous citric acid solution (20 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (2:1 to 0:1 by volume) to afford title compound as a gum, 3.5 g.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Yield: 89 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.50 g), 3-acetamidobenzeneboronic acid (0.38 g) and tetrakis(triphenylphosphine)palladium(0) (0.045 g) in ethanol (1.7 ml), aqueous sodium carbonate solution (2 M, 1.55 ml) and toluene (6.9 ml) with heating at reflux for 1 hour. The residue obtained after work-up was purified by column chromatography over silica eluting with dichloromethane:methanol (92:8) to give the title compound (0.52 g) as an oil which crystallised from ethyl acetate and was recrystallised from isohexane/ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[Br:22]N1C(=O)CCC1=O>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([Br:22])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1C
Temperature: 4 °C
Yield: 75.9 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (204 g), 177 g of potassium carbonate and 1428 mL of acetonitrile were stirred and cooled to 4° C. in an ice bath. N-Bromosuccinimide (228 g) was added in portions with vigorous stirring keeping the temperature below 17° C. The mixture was warmed to 20° C. and 2856 mL of water was slowly added. The mixture was stirred for 30 minutes. The precipitate was collected by vacuum filtration and washed three times with 400 mL of ethanol:water 1:2 each time. The solids were dried under vacuum at 60° C. to give 228 g (76% yield) of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as an off-white solid. 1H-NMR (dimethylsulfoxide-d6) δ 1.26 (t, 3H, CH3), 2.14, 2.17 (2×s, 2×3H, 2×CH3), 4.20 (d, 2H, CH2O), 11.75 (br s, 1H, NH). MS m/z 246, 248 [M+1].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[N+:1]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][S:10][C:14]=2[CH:15]=1)([O-:4])=[O:2]
Reactant: c1ccc2scnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a 30 mL solution of 1:1 mixture of HNO3 --H2SO4 was added benzothiazole (7.0 mL, 53 mmol) slowly over 1 h period at -25° C. and resulting solution was stirred for 12 h. Reaction temperature was allowed to warm up to 25° C. The reaction mixture was poured into ice water to produce a yellow precipitation which was subjected to column chromatography (CHCl3, neat) to yield 7.3 g (41 mmol, 79%) of the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][O:34]C5CCCCO5)[C:30]5[CH:41]=[CH:42][CH:43]=[CH:44][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2.C(O)(=O)C.C1COCC1>O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]4[N:31]([CH2:32][CH2:33][OH:34])[C:30]5[CH:41]=[CH:42][CH:43]=[CH:44][C:29]=5[N:28]=4)[CH2:15]3)=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCO
Temperature: 45 °C

Procedure:
(2R,4R)-tert-butyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (90 mg, 0.15 mmol) was added to a solution of acetic acid (2 mL), THF (1 mL) and water (0.5 mL) (4:2:1), the resulting solution was stirred at 45° C. for over night. The reaction mixture was concentrated to give a yellow oil as title compound (LC-MS: 523.2, t=2.3 min) for the next reaction without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>C([O-])(O)=O.[Na+]>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Nc1ccccc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzyl chloroformate (11 mmol, 58% in toluene) was added drop wise to a stirred solution of 2-aminophenol in NaHCO3 (3M, 3.6 mL). The reaction mixture was further stirred for 15 hours at RT. Then the reaction mixture was washed with NaOH (3M, 20 mL) followed by water (20 mL) and diethyl ether (20 ml×3). Concentrated HCl was added to the aqueous part until precipitation of the targeted product as a light yellow solid (70%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: Fc1cccc(F)c1CCl
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1c(F)cccc1F
Yield: 100.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.35 g of 2,6-difluorobenzyl chloride and 2.00 g of indole-4-carbaldehyde as a starting material to give 3.74 g of 1-(2,6-difluorobenzyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 100%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15](OCC)=[O:16])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OC/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Yield: 90 %

Procedure:
Ethyl (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienoate was treated with diisobutyl aluminum hydride in the same manner as in Reference example 21 to obtain the title compound in a yield of 90%.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.O.[NH2:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.[NH2:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27].[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3
Solvent: O
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]

Procedure:
Apomorphine glutamate solution was prepared by dissolving apomorphine base in 0.1M glutamic acid solution. Water was added to obtain solutions with a molar ratio of 1:1 or 1:1.2, apomorphine:glutamic acid, at a final concentration of 2% apomorphine. The pH of each solution was 4.7 and 4.4, respectively.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19](ON1C(=O)CCC1=O)=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
Under an atmosphere of argon, to a solution of 2,5-dioxopyrrolidin-1-yl O-benzyl-N-t-butoxycarbonyl-L-serinate (4.41 g) in tetrahydrofuran (30 mL) was added sodium borohydride (644 mg) in ice bath and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.30 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH2:38])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)C>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH:38][S:7]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]3)(=[O:9])=[O:8])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(Br)cc3F)c(C)c(=O)n3c2N(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
1-Allyl-cyclopropanesulfonyl chloride (121 mg, 0.001 mol) was added to a stirred solution of 8-amino-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.0003 mol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer concentrated to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 120 mg of the product (60.6% yield).
Reaction SMILES: OC1CCCCCCCCCCCC1=O.C([O:19][CH:20]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:35])(=O)C.C(OC1CCCCCCCCCCCC1=O)(=O)C.OC1CCCCCCCCCCCCCCC1=O>>[OH:35][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:20]1=[O:19]
Reactant: CC(=O)OC1CCCCCCCCCCCCCC1=O
Agent: CC(=O)OC1CCCCCCCCCCCC1=O
Agent: O=C1CCCCCCCCCCCC1O
Agent: O=C1CCCCCCCCCCCCCCC1O
Product: O=C1CCCCCCCCCCCCCC1O

Procedure:
Thirty grams each of 2-hydroxycyclopentadecanone, 2-hydroxycyclotridecanone, 2-acetoxycyclopentadecanone, 2-acetoxycyclotridecanone, and 2-hydroxycyclohexadecanone obtained through acyloin condensation was dissolved in 200 ml of an organic solvent shown in Table 1. The resulting solution was placed in a reaction apparatus equipped with a reflux condener having a water trap, a stirrer, and a dropping funnel, and 40 g of a zinc powder was dispersed therein. The mixture was allowed to react under reflux by adding 150 ml of 12N hydrochloric acid dropwise over a period of 1.5 hours. During the reaction, the aqueous layer in the trap was intermittently withdrawn in the case of using toluene, xylene, or cyclohexane as an organic solvent. In the case of using methyl ethyl ketone, the whole amount of the liquid reserved in the trap (about 90 ml) was intermittently withdrawn.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[NH2:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:11][C:10]=1[C:18]([O:20]C)=O.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:2][NH:3][C:18]([C:10]1[O:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:9]=1[NH2:8])=[O:20]
Reactant: COC(=O)c1oc(C(C)(C)C)cc1N
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1oc(C(C)(C)C)cc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A slurry of methylamine hydrochloride (1.03 g, 15.2 mmol, 3.0 equiv) in anh. toluene (60 mL) at 0° C. was treated with AlMe3 (2M in toluene, 7.6 mL, 15.2 mmol, 3.0 equiv). The resulting solution was stirred at 0° C. for 30 min and allowed to warm to room temp for 40 min. To the aluminum amide solution was then added methyl 3-amino-5-tert-butyl-2-furancarboxylate (1.00 g, 5.1 mmol). The resulting mixture was heated at the reflux temp. for 20 h, cooled to room temp., and a 6N HCl solution was added dropwise. The quenched mixture was made basic with a 1N NaOH solution (approximately 100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure to afford N-methyl-3-amino-5-tert-butyl-2-furancarboxamide as a yellow solid (0.90 g, 91%): TLC (20% EtOAc/CH2Cl2) Rf0.26; 1H NMR (CDCl3) δ1.23 (s, 9H), 2.93 (d, J=4.8 Hz, 3H), 4.51 (br s, 1H), 5.73 (s, 1H).