Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:19][CH2:18]1.CC(NC(C)C)C>C(O)C>[N:23]1([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: Cc1nc2n(C)c(C)cn2c(=O)c1CCBr
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: Cc1nc2n(C)c(C)cn2c(=O)c1CCN1CCC(n2ccc3ccccc32)CC1
Yield: 62 %

Procedure:
A mixture of 6-(2-bromoethyl)-1,2,7-trimethyl-1H,5H-imidazo[1,2-a]pyrimidin-5-one (8.85 g), prepared as described in EP-0,378,255, 1-(4-piperidinyl)-1H-indole (2 g) and N-(1-methylethyl)-2-propanamine (1.2 g) in ethanol (100 ml) was stirred and refluxed for 6 hours. The solvent was evaporated and the residue was stirred in water and subsequently extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/DIPE and the precipitate was filtered off and dried, yielding 2.5 g (62%) 6-[2-[4-(1H-indol-1-yl)-1-piperidinyl]ethyl]-1,2,7-trimethylimidazo[1,2-a]pyrimidin-5(1H)-one (compound 9; mp. 165.7° C.).
Reaction SMILES: [Cl-].[Si:2]([O:9][CH2:10][C@@H:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[BH4-].[Na+]>CO>[Si:2]([O:9][CH2:10][C@@H:11]1[CH:16]=[CH:15][C@H:14]([OH:17])[CH2:13][N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a stirred solution of cerious chloride (4.36 g, 11.71 mmol) and (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 50, 4.00 g, 11.71 mmol) in 50 mL MeOH at 0° C., NaBH4 (0.443 g, 11.71 mmol) was added as a solid. The mixture was stirred at ambient temp for 15 minutes. The mixture was concentrated and diluted with 10% citric acid (aq), H2O and ethyl acetate. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to give a residue which was purified by silica gel column (25 g, 20-40% Hex/EA) to give the desired product (2.6 g) as a colorless oil.
Reaction SMILES: [SH2:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]>COCCOCCOC>[CH2:13]([SH:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: S
Reactant: C=CCCCCCCCCCC
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCS

Procedure:
Under the conditions of Example 3, with an input of 38 liters per hour of hydrogen sulphide, 67.7 mmoles of dodecene-1 dissolved in diglyme at a concentration of 0.564 mole per liter were irradiated at 11° C. After 3 minutes of irradiation, 48.2 mmoles of n-dodecyl mercaptan were formed.
Reaction SMILES: [CH3:1][C:2]([C:17]#[N:18])([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:12][C:11]([CH3:13])([CH2:14][NH2:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:16])[CH2:17][NH2:18])[CH:5]=1
Reactant: CC(C)(C#N)Cc1cccc(CC(C)(C)C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(CN)Cc1cccc(CC(C)(C)CN)c1
Temperature: 25 °C

Procedure:
In a 1-liter flask equipped with a paddle stirrer, a reflux condenser capped with a nitrogen bubbler, and an addition funnel, was placed 7.50 g of 1,3-bis(2-methyl-2-cyanopropyl)benzene and 250 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 107 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 1 hr. The mixture was refluxed for 17 hrs 15 min. The mixture was then worked up as described in Example 1(b). Upon distillation of the isolated product through a small Vigreux still, there was otained 3.51 g of 1,3-bis(2,2-dimethyl-3-aminopropyl)benzene as a colorless liquid distilling at 105° to 110°/0.05 mm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COCC1(Nc2ccccc2)CCNCC1

Procedure:
A mixture of 10 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.5 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][S:34][C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=12>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([S:34][CH2:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=5)[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCc3ccccn3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCc5ccccn5)c4s3)[C@H](C)[C@H]12
Yield: 11.3 %

Procedure:
The procedure of Example 1a) was repeated, except that 807 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.255 g of 7-(pyridin-2-yl)methylthio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 149 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)methylthioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [NH2:1]N.[C:3]1(=[O:24])[N:7](CCCCON=C(OCC)C)[C:6](=[O:19])[C:5]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:4]12>>[C:3]1(=[O:24])[C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6](=[O:19])[N:1]=[N:7]1
Reactant: CCOC(C)=NOCCCCN1C(=O)c2ccccc2C1=O
Reactant: NN
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
Briefly, N-(4-bromobutyl)phthalimide was treated with the anion of ethyl N-hydroxyacetimidate in tetrahydrofuran to yield ethyl N-[(4-phthalimidobutyl)oxy]acetimidate. The product was then treated with hydrazine to release the desired amine, ethyl N-[(4-aminobutyl)oxy]acetamidate, from the phthalimide. The desired amine was isolated from the crude product by removal of phthalazine-1,4-dione by filtration, and was coupled to biotin using dicyclohexyl carbodiimide and N-hydroxy succinimide in dimethylformamide. Acidic hydrolysis of the coupled product, ethyl N-[(4-biotinamidobutyl)oxy]acetamidate, gave the final product, N-(4-aminooxybutyl)biotinamide, V. Other analogous aminooxy linkers may be prepared by variations of the above synthetic procedure. The synthesis of biotin aminooxy linker V is described in more detail and summarized in the reaction scheme presented in Example 1.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[CH2:12][CH2:11][N:10]([C:15](OCC)=O)[CH2:9][C:8]=2[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:15][N:10]1[CH2:11][CH2:12][C:13]2[S:14][C:6]([CH2:4][OH:3])=[CH:7][C:8]=2[CH2:9]1
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2sc(CO)cc2C1
Temperature: 23 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
6,7-Dihydro-4H-thieno[3,2-c]pyridine-2,5-dicarboxylic acid diethyl ester (46 gram, 163 mmol) was dissolved in 200 ml THF. The solution was injected LAH (1M, THF) 300 ml at 23° C. Then it was stirred at 23° C. for 18 hrs. The reaction was quenched with 10 ml water and dried directly over sodium sulfate. Filter and concentrate yielded 29.3 gram (160 mmol, 98%) crude product.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([N:17]([CH3:19])[CH3:18])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:3]>C(OCC)(=O)C>[CH3:3][CH:2]([CH2:4][C@H:5]([N:17]([CH3:18])[CH3:19])[C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:1]
Reactant: CC(C)CC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
12.3 g of racemic sibutramine was dissolved in 85 ml of ethyl acetate, L-DBTA dissolved in 85 ml of ethyl acetate was added thereto. The reaction mixture was heated under reflux, cooled to room temperature and then filtered to obtain crystals (ee: about 85%). And then, the crystals were suspended in 220 ml of ethyl acetate, and heated under reflux to obtain solids. The solids were recrystallized from 450 ml of isopropyl alcohol to obtain L-DBTA salt of (−)-sibutramine (ee: ≧99.3%). The L-DBTA salt of (−)-sibutramine was neutralized with saturated sodium bicarbonate, and then extracted with chloroform to obtain (−)-sibutramine free base.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21].Cl.O>CO>[OH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 15 h
Yield: 46.5 %

Procedure:
Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g) in methanol (18 ml) containing concentrated hydrochloric acid (1.2 ml) and water (0.8 ml) and allow the mixture to stand at room temperature for 15 hours. Add water and extract the mixture with ether. Wash, dry and evaporate the ethanol solution and dissolve the residue in a little benzene. Filter through a column of alumina (25 g) with benzene-ether (7.3). Evaporate the eluates and recrystallize the residue from etherhexane to obtain the title compound (372 mg), m.p. 123°-124.5° or in an alternate form, m.p. 131°-132°; ultraviolet absorption maximum at 241 mμ (ε16,600); infrared absorption peaks at 6μ, 7.9 μ, 9.4 μ.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38](=[N:40]O)[NH2:39])=[N:35][C:34]=1[CH3:42])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.ClCCl>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]2[N:40]=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][N:39]=2)=[N:35][C:34]=1[CH3:42])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(C(N)=NO)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2noc(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of phenylacetic acid (0.05 g, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (0.14 g, 0.83 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, and N-benzyl-2-(N′-hydroxy-carbamimidoyl)-4-methylthiazole-5-carboxamide (0.12 g, 0.41 mmol) was added. The reaction mixture was stirred for 17 hours, diluted with dichloromethane, washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white powder (0.01 g, 6%): mp 124-125° C.; 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 10H), 6.16 (t, J=5.6 Hz, 1H), 4.60 (d, J=5.6 Hz, 2H), 4.29 (s, 2H), 2.76 (s, 3H); MS (ES+) m/z 391.5 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([NH:34][C@H:35]([C:39](O)=[O:40])[C@@H:36]([CH3:38])[OH:37])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:34][C@@H:35]([C@H:36]([OH:37])[CH3:38])[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:40]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](N)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 200 mg (0.47 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 113 mg (0.52 mmol) of N-(tert-butoxycarbonyl)-L-threonine. The protecting group was cleaved off as already described using HCl in dioxane. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:16]1[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=1[CH3:25].O>CN(C)C=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:12][C:16]2[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]=2[CH3:25])=[CH:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCn1ncc(Cl)c(C)c1=O
Reactant: CC(C)(C)c1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(SCc2ccc(C(C)(C)C)cc2)c(C)c1=O
Yield: 56.2 %

Procedure:
To 3 ml of dry N,N-dimethylformamide was added 0.024 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 1 g of p-t-butylbenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 0.67 g of 5-chloro-2-ethyl-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was allowed to stand over night. The resulting solution was poured into 30 ml of water and extracted twice with 30 ml of diethyl ether. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.42 g of a crude product. The crude product was separated and purified by thin layer chromatography (silica gel, benzene) to obtain 0.69 g of 5-(p-t-butylbenzylthio)-2-ethyl-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: Br.C(O)(=O)C.C(OC(=O)[NH:15][C:16]1[N:17]([CH2:34][C:35]2[CH:43]=[CH:42][C:38]3[O:39][CH2:40][O:41][C:37]=3[CH:36]=2)[C:18](=[O:33])[C:19]2[C:24]([C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:23][C:22]([Br:32])=[CH:21][CH:20]=2)C1C=CC=CC=1>>[NH2:15][C:16]1[N:17]([CH2:34][C:35]2[CH:43]=[CH:42][C:38]3[O:39][CH2:40][O:41][C:37]=3[CH:36]=2)[C:18](=[O:33])[C:19]2[C:24]([C:25]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:23][C:22]([Br:32])=[CH:21][CH:20]=2
Reactant: O=C(Nc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Nc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 119 %

Procedure:
25% Hydrogen bromide-acetic acid solution (10.0 ml) was added to [2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl]carbamic acid benzyl ester (3.6 g), and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound (3.3 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([OH:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.[N:21]1C2C(=CC=CC=2)C(C=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([OH:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:21]=[CH:9][CH:8]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Product: COc1cccc(C(O)c2ccnc3ccccc23)c1

Procedure:
The compound 26 was prepared by following the synthesis procedure as described for compound 1, but substituting 1-naphtaldehyde for 4-quinolinecarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:16][CH3:17])[CH:4]=1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(Br)ccc1Cl
Temperature: 55 °C
Yield: 99 %

Procedure:
To a solution of 2-chloro-5-bromophenol (WO98/003464 which is incorporated herein by reference, 3.43 g, 16.5 mmol) and K2CO3 (4.57 g, 33.0 mmol) in DMF (20 mL) was added ethyl iodide (1.78 mL, 22.3 mmol) at rt. The mixture was heated at 55° C. for 3.0 h. After cooling to rt, the reaction was diluted with ether, washed with water and brine, and dried over MgSO4. The crude residue was purified by flash column chromatography to give 3.85 g (99%) of 31A as viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.03 Hz, 3H) 4.08 (d, J=7.03 Hz, 2H) 7.03 (m, 2H) 7.22 (d, J=6.15 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](O)=[O:13].S(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Solvent: CSC
Product: O=[N+]([O-])c1ccc(CCO)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.8 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (1 g, 5.02 mmol) in tetrahydrofuran (10 mL) was added BH3.S(CH3)2 (7.5 mL, 7.53 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature for 10 h. Then reaction mixture was cooled to 0° C. and the excess of borane was quenched with methanol (10 mL). The reaction mixture was concentrated under reduced pressure to obtain a crude compound which was purified by CC (eluent: ethyl acetate/n-hexane (1:1)) to give 2-(2-fluoro-4-nitrophenyl)ethanol (0.89 g, 95%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=1.O>C(O)C>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:23][C:22]([C:18]1[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=1)=[O:24])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(C)ccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(C)ccn1
Reaction time: 0.17 h

Procedure:
Diethyl oxalate (4.42 mL) was added to sodium ethoxide (2.22 g) in ethanol (22 mL), and the mixture was stirred for 10 minutes. The above-obtained 1-(4-methyl-2-pyridyl)ethanone (2.20 g) in ethanol (22 mL) was added to the mixture, followed by stirring at room temperature for 20 minutes. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether, and then the aqueous layer was partitioned by use of saturated aqueous ammonium chloride and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(4-methyl-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester as an oily product (2.84 g, 74%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:14]([NH:21][C:22]([NH2:24])=[NH:23])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:17]([O:16][C:14]([N:21]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)=[CH:11][N:23]=[C:22]1[NH2:24])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N=[N+]=[N-])cc2)cnc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
To a solution of 1-(4-azidophenyl)-2-bromoethanone (1.50 g, 6.24 mmol) in anhydrous DMF (20 mL) was added Boc-guanidine (3.00 g, 18.7 mmol). The reaction was stirred at ambient temperature for 48 hours upon which the mixture was partitioned between EtOAc (150 mL) and water (75 mL). The organic layer was successively washed with water (3×50 mL) and brine (2×50 mL) before being dried (Na2SO4) and evaporated to dryness. The resulting crude oil was purified via flash column chromatography (10-50% EtOAc/Hexanes) to obtain the target 2-amino-5-(4-azidophenyl)imidazole-1-carboxylic acid tert-butyl ester (1.84 g, 58%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, 2H, J=8.1 Hz), 7.36 (s, 1H), 7.10 (dd, 2H, J=0.9, 8.1 Hz), 6.61 (br s, 2H), 1.58 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 148.9, 137.6, 136.2, 130.5, 126.2, 119.1, 106.2, 84.7, 27.5; HRMS (ESI) calcd for C8H6BrN3O (M+) 300.1335. found 300.1329.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][CH2:36][NH2:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:37][CH2:36][CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3cccs3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with thiophene-2-ethylamine (0.023 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(2-(thiophen-2-yl)ethylaminomethyl]indol-2-yl)isoindolinone.