Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1[O:5][C@H:6]([CH2:12][OH:13])[C@@H:7]([OH:11])[C@H:8]([OH:10])C=1)(=O)C.[CH3:14][O-:15].[Na+].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.[CH3:30][OH:31]>>[O:15]=[CH:14][C@@H:30]([C@H:12]([C@@H:6]([C@@H:7]([CH2:8][OH:10])[OH:11])[OH:5])[OH:13])[OH:31]
Reactant: CC(=O)C1=C[C@@H](O)[C@H](O)[C@@H](CO)O1
Reactant: C[O-]
Reactant: CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: c1c[nH]cn1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
To a solution of the crude acetyl glucal 3 (12.5 g, 45.9 mmol) in dry MeOH (150 mL) was added a solution of sodium methoxide (NaOMe, 4.59 mmol) in dry MeOH (1 mL) at room temperature. The reaction mixture was stirred for 30 min and evaporated to dryness. The residue was dissolved in dry N,N-dimethylformamide (DMF, 150 mL) at 0° C. and to this solution was added imidazole (9.4 g, 137.7 mmol) and tert-butyldimethylsilyl chloride (10.4 g, 68.9 mmol). The reaction mixture was stirred for 3 h at room temperature, diluted with icewater, and extracted with 50% ethyl acetate (AcOEt)-hexane. The organic extract was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel (200 g) using 50% AcOEt-hexane to yield 4 (7.15 g, 65% from D-glucose).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]([C:13]2[C:14](=O)[O:15][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[N:20]([CH3:32])[CH:19]=2)=[CH:3]1.CO.C[Si](C)(C)[NH:39][Si](C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]([C:13]2[C:14](=[O:15])[NH:39][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[N:20]([CH3:32])[CH:19]=2)=[CH:3]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)OC2=O)c2ccc(C#N)cc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-Methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-furan-3-yl]-1H-indole-6-carbonitrile (0.16 g, 0.36 mmol) was dissolved in dry DMF (5 mL, dried over 3A° molecular sieves) in a 50 mL round bottom flask. To this was added methanol (0.1 mL) and 1,1,1,3,3,3 hexamethyldisilazane (0.9 mL). The purple solution was stirred at room temperature overnight. Methanol (0.03 mL) and 1,1,1,3,3,3 hexamethyldisilazane (0.27 mL) were added and stirred for 3 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine. The aqueous layer was back extracted with ethyl acetate (2×50 mL). The combined organic extracts were diluted with an equal volume of hexanes, dried (MgSO4), and passed over a pad of silica gel. The silica gel was washed a with 1:1 ethyl acetate/hexanes (150 mL), and the filtrate was concentrated. Chromatography of the residue over silica gel using 25%-40% EtOAc/hexanes gave 1-methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl]-1H-indole-6-carbonitrile (71 mg, 44%) as a purple solid.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>CO.N1C=CC=CC=1>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([Cl:25])=[O:12])[CH:2]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Cl)c1cnn2ccccc12
Reaction time: 8 h

Procedure:
Pyrazolo[1,5-a]pyridine-3-carboxylic acid (9.72 g) was dissolved in hot anhydrous methanol (225 ml) and treated with a solution of potassium hydroxide (3.73 g) in dry methanol (45 ml) with stirring. The resulting orange solution was evaporated to dryness under reduced pressure, to give a colourless solid. This solid was treated with dry toluene (300 ml) and the mixture was stirred and treated with oxalyl chloride (10.2 ml), with stirring, at room temperature. After further stirring for a period of 15 minutes the mixture was treated with pyridine (45 drops), and the mixture was vigorously stirred overnight. The mixture was then filtered and the filtrate was evaporated under reduced pressure, to give pyrazolo[1,5-a]pyridine-3-carbonyl chloride (10.6 g), m.p. 119°-120° C. (in a sealed tube).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(S(C)(=O)=O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-methylsulfonylphenyl boronic acid were reacted to give 146. MS: (ESI+) 524.1
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12](/[OH:17])=[CH:13]/[CH2:14][CH2:15][CH3:16].[H-].[Na+].Cl>>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:17]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH3:16])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: CCC/C=C\O
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCC1=C(C)C(O/C=C\CCC)CC1=O
Reaction time: 1 h

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), 2-cis-pentenol (5 parts) and sodium hydride (1/30 part) were charged, and the mixture was stirred at a temperature of 10° to 15° C. for 1 hour. After completion of the reaction, the mixture was neutralized with 1N HCl and extracted with toluene. Toluene was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-(2-cis-pentenyloxy)-2-cyclopentenone, which was purified by chromatography. Yield, 97%. nD20 1.4946.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:18]([O:25][CH2:26][C:27](N(OC)C)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][CH2:26][C:27]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)COCc1ccccc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)COCc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-benzyloxy-N-methoxy-N-methylacetamide. The product is used in crude form in the following reaction.
Reaction SMILES: [Br-].C1(=O)[N:6]([CH2:7][CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]C(=O)C3C=CC=CC=3)[CH:10]=2)C(=O)C2=CC=CC=C12.[ClH:30]>>[ClH:30].[Cl-:30].[NH2:6][CH2:7][CH2:8][N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([SH:15])[CH:10]=1
Reactant: O=C(Sc1ccc[n+](CCN2C(=O)c3ccccc3C2=O)c1)c1ccccc1
Agent: Cl
Agent: [Br-]
Product: NCC[n+]1cccc(S)c1
Product: [Cl-]
Temperature: 25 °C

Procedure:
A suspension of 1-(2-phthalimidoethyl)-3-benzoylthiopyridinium bromide (40 g) in 6N hydrochloric acid (510 ml) was heated under reflux for 10 hours and cooled to room temperature. The resulting precipitates were filtered off and washed with water. The filtrate and the washings were combined and washed with chloroform. The separated aqueous layer was evaporated to dryness under reduced pressure. The residue was triturated in acetone, and the resulting precipites were collected by filtlation and dried in vacuo to give 1-(2-aminoethyl)-3-mercaptopyridinium chloride hydrochloride (18.1 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:48])[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:17][CH2:16][O:15]1>C(OCC)(=O)C>[CH3:48][C:14]1([CH3:13])[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:32][CH:33]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:17][CH2:16][O:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.25 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6](SC)[CH2:5]2.[S:14]([O:18]OS([O-])(=O)=O)(O)(=O)=[O:15].[K+].[CH2:25](O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:14]([CH3:25])(=[O:18])=[O:15])[CH2:5]2
Reactant: O=S(=O)([O-])OOS(=O)(=O)O
Reactant: CSC1Cc2cc(Cl)ccc2C1=O
Reactant: CCO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 g of 5-chloro-2-methylsulfanylindan-1-one was dissolved in 10 ml of dry ethanol. At 0° C., a solution of 4.33 g of potassium hydrogenpersulfate (2 KHSO5×KHSO4×K2SO4; “Oxone”) in 10 ml of water was added dropwise and the reaction mixture was then stirred at room temperature for 5 h. The alcohol was distilled off under reduced pressure at room temperature. 20 ml of dichloromethane and 10 ml of water was added to the residue, and the mixture was stirred for 10 min. The organic phase was separated off, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was dried. This gave 5-chloro-2-methylsulfonylindan-1-one of melting point 196° C.
Reaction SMILES: [H-].[Na+].C([Si](C)(C)[O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[C:16]3[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=3[S:14][CH2:13][C:12]2=1)(C)(C)C.Cl[CH2:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1>CN(C=O)C>[N:37]1([CH2:36][CH2:35][O:34][C:33]2[CH:43]=[CH:44][C:30]([CH2:29][N:18]3[C:17]4[C:16]5[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=5[S:14][CH2:13][C:12]=4[C:11]4[C:19]3=[CH:20][CH:21]=[C:9]([OH:8])[CH:10]=4)=[CH:31][CH:32]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2SC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 144 mg, 1.317 mmoL) was added into 8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (440 mg, 1.197 mmoL) in DMF (5 mL) at 0° C. After 10 minutes, 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (382 mg, 1.317 mmoL) was added dropwise into the reaction at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layers from the two extractions were combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, first EtOAc then CH2Cl2:MeOH 4:1 as eluent) to yield 8-(tert-butyl-dimethyl-silanyloxy)-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine as a pale foam and 11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11 dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol as a yellow solid.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=O>C(O)CC.[Ni]>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[CH:2]1
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Ni]
Solvent: CCCO
Product: O=c1[nH]cnc2nc[nH]c12
Yield: 70.2 %

Procedure:
2.18 g (4.5 mM) of xanthine (B.) and 2.6 g of Raney-nickel (treated with 0.1% aqueous acetic acid) were refluxed in 30 ml of 1-propanol for 2.5 hr. The nickel was filtered off and the solution evaporated in vacuo to dryness. The residue was dissolved in 40 ml of ethyl acetate and extracted with sodium bicarbonate solution. The formed solid is filtered off and the organic phase evaporated in vacuo to dryness (1.95 g). A dichloromethane solution, comprising 2% of methanol, was purified on 19 g of silicagel in a column. Crystallization from ethyl acetate gave 1.37 g (67.2%) of hypoxanthine with mp 159-161° C., a second crop gave 0.4 g (2.0%) of hypoxanthine.
Reaction SMILES: [F:1][C:2]([CH:4](O)[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3].S(Cl)([Cl:14])=O>CCCCCC.CN(C)C=O>[F:1][C:2]([CH:4]([Cl:14])[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3]
Reactant: C=C(F)C(O)C#CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=C(F)C(Cl)C#CC(C)(C)C
Yield: 90.4 %

Procedure:
Ten grams (0.064 mole) of 2-fluoro-3-hydroxy-6,6-dimethylhept-1-ene-4-yne was dissolved in 100 ml of hexane, and to 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 11.42 g (0.095 mole) of thionyl chloride were added to the resulting solution. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 10.1 g of 2-fluoro-3-chloro-6,6-dimethylhept-1-ene-4-yne.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:9]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc[n+]([O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
3-Methoxypyridine (20.08 g, 209 mmol) was dissolved in 100 mL of acetic acid. 30% H2O2 (28.3 mL, 275 mmol) was added and the reaction mixture was heated at 70° C. for six h. The cooled reaction mixture was concentrated and the residue dissolved in CH2Cl2 and stirred overnight with 20 g of solid potassium carbonate. The mixture was filtered and concentrated to give compound 762A (25.2 g, 100%) as a light yellow solid which was characterized by 1H NMR and carried on to the next step.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][OH:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:18][CH:19]=[O:20])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CC=O)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred solution of Compound (2) (278 mg) in DCM (6 mL) was added Dess-Martin periodinane (400 mg, 0.94 mmol). The mixture was stirred at room temperature for 1 h and then diluted with DCM (10 mL) and washed with aq. saturated NaHCO3 solution (10 mL) and water (10 mL). The organic phase was filtered to remove insoluble impurities, dried (MgSO4) and concentrated in vacuo to afford (i) (276 mg) which was used in the next step without further purification. ESI-MS m/z calculated for [M+MeOH]+: 474.2; found: 474.2.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)ccc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.42 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.85 g, 21 mmol) was added to a solution of tert-butyl 7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (5.0 g, 14 mmol) in DMF (75 mL). After 25 min, ethyl bromoacetate (3.1 mL, 28 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 3 h and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography with heptane/EtOAc (3:1) to give 6.0 g (96%) of a white foam: mp 118.5-119.5° C.; IR (diffuse reflectance) 2976, 1747, 1674, 1477, 1457, 1420, 1405, 1370, 1366, 1344, 1254, 1200, 1165, 1111, 930 cm−1; MS (EI) m/z 440 (M+), 386, 384, 339, 310, 305, 300, 298, 224,57, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H. 5.94; N, 6.35; found: C, 57.27; H, 6.01; N, 6.22.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH2:10][CH3:11]
Reactant: CCCBr
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(C)nc1
Yield: 42.5 %

Procedure:
A mixture of 16.5 g (0.15 mol) of 5-hydroxy-2-methylpyridine (commercially available), 18.8 g (0.15 mol) of n-propyl bromide and 8.00 g (0.06 mol) of anhydrous potassium carbonate with 100 ml of acetone was refluxed for 24 hours, the solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:4) to give 9.63 g of an oily product (yield 42.1%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8].[NH2:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8]
Reactant: O=C=NCCCCBr
Reactant: CCOC(=O)CC(C)(C)N
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)NC(=O)NCCCCBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 4-bromobutylisocyanate (15.1 g) in methylene chloride (50 ml) is added to a stirred solution of ethyl 3-amino-3-methylbutanoate (12.3 g), dissolved in methylene chloride (50 ml) at -20° C. The mixture is stirred for 30 minutes at -20° C. and then for an additional 2 hours at room temperature. Evaporation of the solvent yields a residue of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (26 g).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH:13](/B(O)O)=[CH:14]\[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.CCOC(C)=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2](/[CH:13]=[CH:14]/[CH3:15])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C/C=C/B(O)O
Reactant: N#Cc1c(I)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: C/C=C/c1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A suspension of 2-iodo-6-nitrobenzonitrile (Example 130d) (1.52 g, 5.53 mmol), tetrakis(tiphenylphosphine)palladium(0) (0.64 g, 0.55 mmol), trans-1-propen-1-ylboronic acid (0.95 g, 11.06 mmol), sodium carbonate (0.65 g, 6.08 mmol) and water (10.0 mL) in dimethoxyethane (DME) (40.0 mL) was heated at reflux for 15 h, under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (100 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined extract was washed with brine and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (7:3), to give 0.98 g (94%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.16-8.24 (m, 2H), 7.83-7.89 (m, 1H), 6.71-6.84 (m, 2H), 1.90-2.02 (m, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=CN=1)[NH2:2].[C:9]([CH2:17][C:18]([O:20]CC)=O)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:23](OCC)(=O)[CH2:24][C:25]([CH3:27])=O>>[CH3:6][C:7]1[CH:8]=[C:3]([N:1]2[C:18](=[O:20])[CH:17]=[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:2]2)[CH:23]=[CH:24][C:25]=1[CH3:27]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccn1
Product: Cc1ccc(-n2[nH]c(-c3ccccc3)cc2=O)cc1C

Procedure:
Following the procedure of Example 22a), except substituting 3,4-dimethylphenylhydrazine for 2-hydrazinopyridine and ethyl benzoylacetate for ethyl acetoacetate, the title compound was prepared (16.0 g; 61%). MS(ES) m/z 265 [M+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O1CCN(CC2CCC(N)C2)CC1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CN2CCOCC2)C1
Agent: NC1CCC(CN2CCOCC2)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@H](CN2CCOCC2)C1

Procedure:
Tert-butyl (1R,3S)-3-(morpholinomethyl)cyclopentylcarbamate (Step 4, 0.6) was treated with trifluoroacetic acid (2 ml) and the obtained compound of 3-(morpholinomethyl)cyclopentanamine was used directly for synthesizing final compounds given in example section without further purification.