Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[NH:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=[N:33]1
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: N#Cc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 100 °C

Procedure:
4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(tiphenylphosphine) palladium (0) as the catalyst and heating at 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. 1H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br.s).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.O>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Temperature: 100 °C
Yield: 62 %

Procedure:
To a solution of Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) in dioxane (2 mL) was added 4-chlorobenzene boronic acid (66 mg, 422 μmol), ethyl-di-isopropyl-amine (120 μL, 636 μmol), water (500 μL) and palladium tetrakis(triphenylphosphine) (25 mg, 20 μmol). The reaction mixture was degassed and stirred at 100° C. in a sealed tube. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was passed through a pad of Celite. The organic filtrate was washed with water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated in vacuo to yield the crude product. The residue was purified by flash chromatography eluting with ethyl acetate in heptane (0-6%) to give the title compound as a white semi-solid, 60 mg, in a 62% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (s, 9 H), 1.45-1.48 (m, 1 H), 1.62-1.73 (m, 3 H), 1.78-1.82 (m, 2 H), 2.71 (s, 3 H), 2.78-2.81 (m, 2 H), 3.66 (s, 3 H), 4.99 (s, 1 H), 7.18-7.21 (m, 1H), 7.39-7.42 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:4]2[C:3](=[O:2])[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(C=O)cn1
Product: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Yield: 67.8 %

Procedure:
According to Scheme 2: The title compound was prepared from 6-methoxynicotinaldehyde (1 eq, 13.4 mmol, 1.83 g) and 4-chloro-benzylbromide (2 eq, 26.8 mmol, 5.50 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 17 hours under reflux. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 95/5 as eluent to afford 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (9.08 mmol, 2.25 g, 68%) as an orange solid.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([OH:12])[CH2:9][CH:10]=[CH2:11]>>[CH2:8]([O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])[CH2:9][CH:10]=[CH2:11]
Reactant: C1CCC2OC2C1
Reactant: C=CCCO
Product: C=CCCOC1CCCCC1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of cyclohexene oxide (3-1) (10.0 g, 102 mmol) in 3-buten-1-ol (17.4 mL, 204 mmol) cooled to 0° C. was added FeCl3 (1.65 g, 10.2 mol) The mixture was removed from the ice bath and stirred at rt for 1 hr. The reaction was quenched with water and extracted ether. The combined organics were washed with brine, dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (400 MHz, CDCl3) δ 5.77-5.88 (m, 1H), 5.00-5.15 (m, 2H), 3.69-3.76 (m, 1H), 3.39-3.44 (m, 2H), 2.98-3.05 (m, 1H), 2.74 (s, 1H), 2.30-2.39 (m, 2H), 1.94-2.11 (m, 3H), 1.61-1.79 (m, 3H), 1.06-1.37 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 39-4 (770 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][CH:6]=[CH:5][CH:4]2[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:13][CH2:12]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:27]1[CH2:1][O:2][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=3)[CH2:15][CH2:16]2)[O:26]1
Reactant: [H][H]
Reactant: Fc1cc(C2CCC(CCC3C=CCCC34OCCO4)CC2)cc(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC(CCC3CCCCC34OCCO4)CC2)cc(F)c1F
Yield: 92 %

Procedure:
Pd/C (5% ) (1 g) was added to a solution of 1,1-ethylenedioxy -(2'-(4"-(3'",4'",5'"-trifluorophenyl)cyclohexyl)-ethyl)-3-cyclohexene (6.7 g) in ethanol (200 ml), followed by carrying out catalytic reduction in a hydrogen gas atmosphere, filtering off the catalyst after completion of the reaction and distilling off the solvent from the organic layer under reduced pressure, to obtain 1,1 -ethylenedioxy-(2'-(4"-(3'",4'",5'"-trifluorophenyl)cyclohexyl)ethyl)cyclohexane (6.2 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 16 mmol) in CH2Cl2 (80 mL) was treated with Et2N (2.5 mL, 17.6 mmol), N-tert-butoxycarbonylglycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (2.16 g, 16 mmol). After the reaction mixture was stirred at 25° C. for 16 h, 2 N NaOH solution (80 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired (R)-3-{N-(tert-butoxycarbonyl)glycyl}amino 1-(4-chlorobenzyl)pyrrolidine (5.40 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[C:4]([C:13]#[N:14])[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=3)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.208 g, 0.839 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.18 g, 1.1 mmol) according to method A to yield 0.16 (65%) of a light yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 214-216° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.23-7.32 (2H, m), 7.37 (1H, d, J=2.24 Hz), 7.65-7.70 (1H, m), 7.79 (1H, dd, J=2.22 Hz, J=13.10 Hz), 8.03 (1H, d, J=8.96 Hz), 8.41 (1H, d, J=1.86 Hz), 8.50 (1H, d, J=1.43 Hz), 10.55 (1H, s); MS (ESI) m/z292 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=3[N+:17]([O-])=O)[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1N>CC(N(C)C)=O>[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:17][C:12]1[CH:11]=[CH:10][C:9]([OH:20])=[C:8]2[C:13]=1[C:14](=[O:16])[C:15]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]=1[C:7]2=[O:21]
Reactant: Cc1ccccc1N
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1Nc1ccc(O)c2c1C(=O)c1c(O)ccc([N+](=O)[O-])c1C2=O
Yield: 32.8 %

Procedure:
A 25 g of 1,5-dihydroxy-4,8-dinitroanthraquinone and a 25 g of 2-methylaniline were dissolved in 250 ml of dimethylacetamide. The solution was heated and allowed to react at an inner temperature of 140 degrees Celsius for 4 hours. The reaction solution was cooled, and then extracted with adequate amounts of ethyl acetate and 1N-hydrochrolic acid to separate into two layers. The extracted organic layer was dried with magnesium sulfate and then concentrated. The concentrated solution was purified by silica gel chromatography to give a 9.7 g of 8-(2′-methylanilino)-1,5-dihydroxy-4-nitroanthraquinone in a 33% yield.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:15]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])(=O)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.COC(C)(C)C>[CH2:21]([N:28]1[CH2:6][CH2:7][C:8]2([CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: O=C1NCCCC12CCN(Cc1ccccc1)C2

Procedure:
A solution of 1 mmol of methanesulphonic acid 3-(2-methanesulphonyloxy-ethyl)-2-oxo-piperidin-3-ylmethyl ester and 3 mmol of benzylamine in 5 ml of dioxane is heated at 60° C. for 30 hours. The reaction mixture is diluted with tert-butyl methyl ether and washed with brine. The organic phase is dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([C:5]34[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]3[C:3]([NH:2][C:6]4=[O:7])=[O:12])=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1NC(=O)C2(c3ccnc4cc(Cl)ccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4,7-dichloro-quinoline were reacted to form 0-(7-chloro-4-quinolyl)-phthalimide melting at 225° C. and the latter is reacted to obtain 0-(7-chloro-4- quinolyl)-hydroxylamine melting at 175° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12](C3C=C(OC)C(OC)=C(OC)C=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1csc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanol (400. At −78° C., to a solution of 38f (2.5 mmol) in 5 mL THF under argon protection was added a solution of LiAlH4 in THF (1N, 1.42 mL) and stirring continued at 1 h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). 1H NMR (CDCl3) δ 9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H), 7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI) m/z 210.9 (M+Na)+. To a solution of 5-phenylthiophene-3-carbaldehyde (0.195 g, 1.04 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40f. (70.5%). 1H NMR (CDCl3) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H), 7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85 (s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M−OH)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[CH:11]=1)([O-])=O.Cl.C(OCC)(=O)C>[Pd].CO>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:15])([CH3:16])[CH2:14][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:11]1
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC1(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(c2ccccc2N)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene (450 mg, 1.83 mmol) produced in Example (54b), 10% palladium on carbon (200 mg, wet) and methanol (40 mL) was stirred for 3 hours and 30 minutes at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered, 10% palladium on carbon (200 mg, hydrous) and a 4N solution of hydrogen chloride in ethyl acetate (0.915 mL, 3.66 mmol) were added to the filtrate, and then stirring was continued for 13 hours and 30 minutes at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 295 mg of the title compound as a brown oil.
Reaction SMILES: [Cl-:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11](=[O:26])[C:12](=[O:25])[C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22]C)[CH:20]=3)[N:15]([CH3:24])[CH:14]=1)[CH2:3]2.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl-:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11](=[O:26])[C:12](=[O:25])[C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[N:15]([CH3:24])[CH:14]=1)[CH2:3]2
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)N[C@@H]1CN3CCC1CC3)cn2C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)N[C@@H]2CN3CCC2CC3)c2cc(O)ccc21
Temperature: -70 °C
Reaction time: 96 h
Yield: 68.2 %

Procedure:
(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-5-methoxy-α-oxo-3-indoleacetamide chloride (750 ml; 2.2 mmol) in 30 ml of methylene chloride was stirred and cooled to -70° C. A 1M solution of boron tribromide in methlene chloride (8.0 ml; 8.0 mmol) was added via a syringe. The solution was allowed to warm to ambient temperature and then stirred continuely for 4 days. The reaction mixture was then stirred for 1 hour with ice-cold water containing an excess of potassium carbonate. The layers were separated and the phenolic product was extracted from the methylene chloride layer into 5% aqueous sodium hydroxide. The aqueous layer was stirred and sodium bicarbonate was added until saturated. The product that precipitated was extracted into methylene chloride. The methylene chloride solution was dried over potassium carbonate, filtered and concentrated to leave 500 ml (1.5 mmol) of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-5-hydroxy-α-oxo-3-indoleacetamide chloride, m.p. 282°-284° C., [α ]D25 -7.8° (H2O).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>CN(C1C=CN=CC=1)C.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:21])=[O:20]
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccccc1Cl
Yield: 60.3 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 2-chlorobenzenesulfonyl chloride (300 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 58%) after trituration from n-hexane.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:12]=1)[CH2:5][CH3:6].[CH3:30]I>CS(C)=O>[CH3:30][O:3][C:4]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:12]=1)[CH2:5][CH3:6]
Reactant: CI
Reactant: CCC(O)(c1cncc(OCc2ccc3ccccc3c2)c1)c1nccs1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(OC)(c1cncc(OCc2ccc3ccccc3c2)c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Powdered potassium hydroxide (0.155 g) was added to a solution of 2-[1-hydroxy-1-[5-(naphth-2-ylmethoxy)pyrid-3-yl]propyl]thiazole (0.218 g) in dimethylsulphoxide (2 ml) and the mixture was stirred at ambient temperature for 5 minutes. Methyl iodide (0.073 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between water and methylene chloride (3×20 ml). The organic extracts were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of petrol (b.p. 60°-80° C.) and ethyl acetate to give 2-[1-methoxy-1-[5-(naphth-2-ylmethoxy)pyrid-3-yl]propyl]thiazole (0.14 g, 62%), m.p. 93°-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 0.05 mol) was taken into anhydrous pyridine (51 mL). The reaction was cooled to 0° C. and p-toluenesulfonyl chloride (10.42 g, 0.055 mol) in anhydrous pyridine (25 mL) was added dropwise over 10 min. The reaction ran at 0° C. for 2 h. and then allowed to warm to room temperature overnight. The mixture was concentrated to dryness and the residue was taken into ethyl acetate (200 mL) and washed with 0.5N HCl (50 mL). The ethyl acetate was then washed with aqueous sodium bicarbonate (100 mL), brine, dried over sodium sulfate and concentrated to dryness to obtain the title product (17.55 g, 0.049 mol, 99% yield); MS; m/z 355. found 356 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 1.28 (s, 9H), 1.72 (s, 3H), 1.90 (s, 1H), 2.42 (s, 3H), 3.14-3.23 (m, 2H), 3.84 (s, 1H), 3.97-4.06 (m, 2H), 7.49 (d, J=8.0, 2H), 7.78 (d, J=8.0, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].C(=O)(O)[O-].[Na+].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[N:6][C:5]=1[NH2:10]
Reactant: COC(=O)c1cccnc1N
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cnc1N
Temperature: 0 °C
Reaction time: 19 h
Yield: 35 %

Procedure:
2-Amino-nicotinic acid methyl ester (1.00 g, 6.57 mmol) described in Preparation Example A-2 was dissolved at 0° C. in a mixed solution of nitric acid (0.7 mL) and sulfuric acid (2.6 mL), which was stirred at 0° C. for 40 minute and at room temperature for 19 hours, then, further stirred at 70° C. for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0° C., which was extracted with ethyl acetate and tetrahydrofuran, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. Methanol was added to the residue, the precipitated solid was filtered to obtain the title compound (459 mg, 2.33 mmol, 35%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH2:13]([O:20][CH2:21]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][CH2:21][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCOCc1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2c1ccn2COCc1ccccc1
Yield: 95.2 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (20 g, 131 mmol) was dissolved in hydrous DMF (200 mL), and sodium hydride (60%, 6.0 g, 150 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 30 minutes, and then benzyloxymethyl chloride (26.8 g, 171 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 1 hour and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and saturated brine (200 mL). The aqueous layer was further extracted with ethyl acetate (300 mL). The combined organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica-gel column chromatography (manufactured by Fuji Silysia, BW300 1500CC, n-hexane:EtOAc=4:1) to give 34 g of 1-benzyloxymethyl-4-chloro-1H-pyrrolo[2,3-b]pyridine as a light-yellow syrup (yield: 95%).