Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC([N:4]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=O.O>O1CCCC1>[C:23]1([C@H:21]([NH:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6]2)[CH3:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Yield: 51.7 %

Procedure:
To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+ (6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+ (7) By using 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(OC=C)(=O)C>CCCCCC>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C@@H:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(O)Cc1cccc(C(F)(F)F)c1
Solvent: C=COC(C)=O
Solvent: CCCCCC
Product: C[C@H](O)Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
One gram of 1-(3-trifluoromethylphenyl)-propan-2-ol, (±)-(1), is dissolved in 100 ml of hexane, then is added with 0.5 g of Novozym (lipase from Candida antarctica) and 1 ml of vinyl acetate. The suspension is then incubated at 45° C. in a rotating stirrer (300 rpm). After 1 h, when the reaction mixture contains only two compounds in 1:1 ratio, the reaction is stopped and the solvent is distilled off under vacuum. The resulting residue is subjected to chromatographic separation on silica gel, eluting with ethyl ether/petroleum ether gradient, to yield 0.627 g of (R)-1-(3-trifluoromethylphenyl)-propan-2-ol acetic ester, (−)-(2), (52% yield, 92% ee) and (S)-1-(3-trifluoromethylphenyl)-propan-2-ol, (+)-(1), 0.470 g (47% yield, >98% ee). The (−)-(2) ester is dissolved in 50 ml of hexane containing 1.5 ml of butanol and added with 0.5 g of Novozym. The suspension is then incubated at 45° C. in a rotating stirrer (300 rpm). After 5 h, the reaction is stopped to yield (R)-1-(3-trifluoromethylphenyl)-propan-2-ol, (−)-(1), 0.488 g (94% yield, >98% ee).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:15]3[CH2:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCCOc2cccc3[nH]ccc23)C1
Temperature: 100 °C
Yield: 52.2 %

Procedure:
The above 1-(4-indolyloxy)-3-chloropropane (0.629 g, 3 mmol), 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.595 g, 3 mmol) and sodium carbonate (0.795 g, 7.5 mmol) were mixed together in 15 mL dimethylformamide. This mixture was heated at 100° C. for 18 h. Evaporation of dimethylformamide, dilution with water and crystallization of the resulting precipitate from ethanol provided 0.582 g of yellow crystals. Mp 192°-194° C. Mass spectrum, m+ =371. Anal (C24H25N3O) theory C, 77.60; H, 6.78; N, 11.31; found C, 77.49; H, 6.53; N, 11.29.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 54.7 %

Procedure:
A mixture of methyl thiosalicylate (0.85 g, 5.1 mmol), 2-cyano-6-methylpyridine (0.60 g, 5.1 mmol), triethylamine (1.10 ml, 7.9 mmol) and toluene (1.1 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.71 g, 55%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH2:19])[CH2:13]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1

Procedure:
Using 5-benzoyloxy-2-(tert-butoxycarbonylamino)indan (130 mg, 0.37 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6 ml), a similar procedure to Example 24 was carried out to obtain 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol) having the following physical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[Cl:25]Cl>Cl.C(O)=O.ClCCCl>[Cl:25][C:18]1[C:13]2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: ClCl
Agent: Cl
Solvent: ClCCCl
Solvent: O=CO
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 160 g (0.49 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one in 400 ml of concentrated hydrochloric acid and 400 ml of formic acid is treated while stirring with a solution of 46 g of chlorine gas in 400 ml of 1,2-dichloroethane. The reaction mixture, which consists of two phases, is stirred at room temperature, whereby after 3 days a further 25 g of chlorine gas in 200 ml of 1,2-dichloroethane are added and after 5 days a further 5 g of chlorine gas in 40 ml of 1,2-dichloroethane are added. After 7 days, the mixture is concentrated, treated with ice-water, made alkaline with aqueous ammonia and extracted four times with methylene chloride. The organic extract is concentrated and treated with 600 ml of isopropanol. Subsequently, the residual methylene chloride is removed on a steam-bath and the product is left to crystallise. There is obtained 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 174°-175°.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
3.09 (3), Tyr; 1.02 (1), Phe; 2.99 (3),
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[CH:16][N+:13]([O-:15])=[O:14])[C:3]=1[O:2][CH3:1]
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1OC
Product: COc1cccc(C=C[N+](=O)[O-])c1OC

Procedure:
In close analogy to the procedure described above, 2,3-Dimethoxy-benzaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:20][OH:21].[OH-].[Na+].C(O)C>O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][OH:21])[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 78), 2.4 mmol of hydroxylamine hydrochloride and 4.8 mmol of NaOH are heated under reflux in 10 ml of water and 10 ml of ethanol for 7 hours. The mixture is concentrated under reduced pressure and alkalized with saturated K2CO3 solution, and the crude product is filtered off and washed with water. The product is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.O>CC(C)=O>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-hydroxy-5-nitrobenzoate (0.685 g, 3.5 mmol) was dissolved in acetone (75 mL). Potassium carbonate (1.43 g, 10.4 mmol) and 2-bromomethylnaphthalene (0.77 g, 3.5 mmol) were added, and the whole was stirred under reflux for 5 h. Mixture was cooled to room temperature and poured into basic (NaOH, pH 10-11) water. After 1 h, precipitated solid was filtered, washed with water (3×25 mL), and air-dried. Off-white crystals, yield 0.970 g (82%). 1H NMR (DMSO-d6, 400 MHz), δ: 8.24 (s, 1H); 8.14 (s, 1H); 8.05 (s, 1H); 7.99-7.90 (m, 4H); 7.63 (d, J=7.5 Hz, 1H); 7.57-7.50 (m, 2H); 5.51 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:43]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:46]=[CH:47][S:43][CH:44]=3)=[CH:53][CH:52]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: Nc1ccc(-c2ccsc2)cc1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccsc2)cc1
Reaction time: 0.03 h
Yield: 19.1 %

Procedure:
DMAP (104 mg, 0.85 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (167 mg, 0.47 mmol) in DMF (2 mL) followed by EDCI (90 mg, 0.47 mmol) and HOBT (63 mg, 0.47 mmol). After 2 minutes, 4-thiophen-3-yl-phenylamine (75 mg, 0.43 mmol) was added and stirring was continued at room temperature overnight. Cold water was added and the formed precipitate was collected. Purification by preparative HPLC afforded 42 mg (19.2% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-thiophen-3-yl-phenyl)-propionamide. LC/MS [M+H]+: 512.06, 93.02%. 1H NMR (300 MHz, CDCl3): δ 9.6 (d, 1H), 7.85-7.5 (m, 5H), 7.46-7.34 (m, 4H), 7.34-7.26 (m, 2H), 4.09-3.9 (m, 2H), 3.82-3.64 (m, 4H), 3.58-3.52 (s, 1H), 3.5-3.44 (s, 1H), 3.42-3.32 (m, 1H), 3.3-3.18 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.15 mmol), glycine (2.61 g, 35 mmol) and NaOMe solution (52 mL, 26 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 39 mg of the title compound as a yellow solid. MS: (+) m/z 444.15 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1.CN(C)C=O>CO>[C:9]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 27.9 %

Procedure:
20.2 g (0.297 mol) of imidazole are added to a solution of 9.5 g (0.175 mol) of sodium methylate in 49 ml of methyl alcohol. A slution of 44.3 g (0.135 mol) of 1-(4-biphenylyl)-2-chloro-1-(4-fluorophenyl)-ethanol in 103 mol of dimethylformamide is then added dropwise, and the reaction mixture is heated to 60° C. for 90 minutes. It is concentrated by distilling off the solvent in vacuo, and the residue is stirred with water. The crystals which remain are washed with acetonitrile and recrystallised from ethyl alcohol. 13.5 g (28% of theory) of 1-(4-biphenylyl)-1-(4-fluorophenyl)-2-(imidazol-1-yl)-ethanol of melting point 220° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2C(=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O>>[Br:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:3][CH2:2][NH:1][CH3:9])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Product: CNCCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s, 1H), 8.26 (d, J=1.2 Hz, 2H), 7.47-7.37 (m, 4H), 4.31 (t, J=5.2 Hz, 2H), 2.88 (t, J=5.2 Hz, 2H), 2.39 (s, 3H); MS (ESI) m/z 486.0 (M−H)−; MS (ESI) m/z 487.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][O:10][Si:16]([CH3:18])([CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)ONCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
A stirred solution of 10.0 grams (0.063 mole) of N-(2-chlorophenyl)methylhydroxylamine (Example 1, Step A-2) and 12.9 grams (0.19 mole) of imidazole in 50 ml of dry dimethylformamide was cooled in an ice-water bath. To this stirred solution was added dropwise during a 20 minute period 10.6 grams (0.07 mole) of tert-butyldimethylsilyl chloride in 25 ml of dry dimethylformamide. During the addition the reaction mixture temperature was maintained at 5°. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature at which it was stirred for 18 hours. Most of the dimethylformamide was removed from the reaction mixture under water aspirator pressure. The residue was taken up in 300 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give on cooling a semi-solid residue. A sample of the semi-solid was slurried with hexane and the insolubles collected by filtration. The filtrate was concentrated to give an oil residue. The above procedure was repeated on the remainder of the semi-solid using 75 ml of hexane. The hexane filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled under reduced pressure to give 10.2 grams of [(2-chlorophenyl)methyl]-[dimethyl(1,1-dimethylethyl)silyloxy]amine; bp 88°-89°/0.7 Pa.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH2:24])[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:24][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[N:7]=1
Reactant: NCC1CCCO1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCC2CCCO2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 34.8 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), tetrahydrofurfuryl amine (Aldrich Chemical Company) (0.212 mL, 2.05 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to obtain crude pink solids. Recrystallization from EtOH/MeOH gave 0.044 g (35%) of the title compound as an off-white solid. Mp: 280° C. 1H NMR (CDCl3; 500 MHz): δ 1.59 (m, 1), 1.87 (m, 2), 2.00 (m, 1), 2.39 (s, 3), 3.48 (m, 1), 3.71 (m, 2), 3.86 (t, 1, J=7.3), 4.06 (m, 1), 6.74 (s, 1), 6.95 (s, 1), 7.38 (t, 1, J=7.1), 7.51 (t, 2, J=7.6), 7.80 (d, 2, J=8.0), 11.41 (s, 1). MS m/z: 309 (M+1). Anal. Calcd for C18H20N4O: C 70.11, H 6.54, N 18.17. Found: C 69.88, H 6.51, N 18.03.
Reaction SMILES: [CH:1]([S:4]([O-:6])=[O:5])([CH3:3])[CH3:2].[Na+].CN1CCCC1=O.Cl[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[Cl:22][C:21]1[C:16]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CC(C)S(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)S(=O)(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a mixture of sodium isopropylsulfinate (3.3 g) and N-methyl-2-pyrrolidinone (20 mL), 2,3-dichloronitrobenzene (4 g) was added and stirred overnight at 70° C. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration and washed with diethyl ether to give 3-chloro-2-isopropylsulfonyl-1-nitrobenzene (3.0 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:14][CH2:13]2)=[C:4]([O:26]C)[CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.[OH-].[NH4+]>ClC(Cl)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:17]2)=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(CCNS(C)(=O)=O)CC1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)NCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2O)CC1
Reaction time: 12 h
Yield: 70.7 %

Procedure:
1-[4-Amino-5-chloro-2-methoxyphenyl]-3-{1-[2-(methylsulfonyl) aminoethyl]-piperidin-4-yl}propan-1-one (1.19 g, 2.8 mmol), prepared as in Example 11, was dissolved in dichloroethane (50 mL). Boron tribromide in methylene chloride (4 mL, 1.0 g, 4.0 mmol) was added and the mixture was stirred for approximately 12 hours. The mixture was then poured over ice and methylene chloride (150 mL) and ammonium hydroxide) were added. This bilayer mixture was stirred until a solution had formed in the methylene chloride layer. The aqueous layer was removed and combined with fresh methylene chloride (100 mL) and this bilayer mixture was stirred. The methylene chloride layers were combined and dried over potassium carbonate. Filtration and concentration gave 1-(4-amino-5-chloro-2-hydroxyphenyl)-3-{1-[2-(methylsulfonyl)aminoethyl]piperidin-4-yl}propan-1-one (0.8 g, 2.0 -mmol)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48](F)(F)F)=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([CH3:48])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nn(CC(=O)N2CCN(c3ccncc3)CC2)c(C)c1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d,2H), 5.41 (s, 2H), 3.83 (m,2H), 3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:21])(=O)=O)=CC=1.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([F:21])[S:7][C:6]=2[CH:10]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1cc2ccc(Br)cc2s1
Yield: 32.5 %

Procedure:
Using analogous reaction condition and reagents as described Example 20 for the preparation of I-20a, 6-bromo-benzo[b]thiophene (I-25c: 0.5 g, 2.347 mmol) in dry THF was reacted with N-fluorobenzenesulfonimide (1.33 g, 4.22 mmol), n-butyl lithium (1.76 ml, 3.52 mmol), diisopropyl amine (0.57 ml, 3.99 mmol) to afford crude product. Purification by column chromatography on silica gel (100% hexane) afforded 176 mg of the product (33% yield).