Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCCN(CCC)CC1CCc2ccc(NC(C)=O)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCC)CC1CCc2ccc(NCC)cc21

Procedure:
A solution of the free base of compound 2a (5.0 g) in dry THF (25 ml) was added dropwise to a suspension of 1 g LiAlH4 in dry 50 ml THF at 20°-25° C. The mixture was refluxed for 2 hours, excess LiAlH4 was destroyed by cautiously adding 2 ml diluted aqueous NaOH solution. Inorganic salts were filtered off and the crude 6-ethylamino-1-(N,N-dipropylaminomethyl)indan was isolated as a viscous oil upon evaporation of the solvents. Yield: 3.0 g. All off the thus obtained ethylaminoindan derivative was dissolved in 60 ml dichloromethane and 2.3 ml triethylamine was added. The mixture was cooled to 0° C. and a solution of 1 ml acetylchloride in 10 ml dichloromethane was added dropwise at 5°-10° C. The mixture was stirred for another hour at room temperature. Water (100 ml) was added and the organic phase was subsequently separated and worked up. The remaining oil was dissolved in acetone and oxalic acid was added. The oxalate salt of the title compound 14a crystallized and was filtered off and dried in vacuo. Yield: 2.5 g. Mp: 129°-130° C.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].ClC1C=CC(N([C@H]2C3C(=CC=CC=3)N(C(=O)C3C=CC(OC)=CC=3)[C@@H](C)C2)C(=O)C)=CC=1>>[C:1]([N:4]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:30][CH:31]=2)=[O:16])[C@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Agent: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@H]1C[C@@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21

Procedure:
4-(4-{[(2R,4S)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid was prepared following the procedure to prepare 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro-quinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid, substituting N-(4-chlorophenyl)-N-[(2R,4S)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide for N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CC2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), cyclopropylboronic acid (78.5 mg, 0.914 mmol), saturated aqueous sodium carbonate solution (3 ml), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.0172 mmol) in dimethoxyethane (5 ml) was stirred at 90° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (70.0 mg, 39.8%) as an oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:23]5[S:30][CH:29]=[CH:28][C:24]=5[N:25]([CH3:27])[N:26]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:23]5[S:30][CH:29]=[CH:28][C:24]=5[N:25]([CH3:27])[N:26]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (131 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 83 mg (83%) of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS (M+Na)+=457; mp=310-320° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (br. s., 1H), 9.07 (s, 1H), 8.46 (d, J=11.0 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 4.42-4.77 (m, 3H), 4.13-4.21 (m, 1H), 4.12 (s, 3H), 3.97-4.08 (m, 1H), 3.76-3.89 (m, 1H), 1.51 (dd, J=6.8, 2.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1(C(OCC)=O)[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12>C(O)C.O>[NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12
Reactant: CCOC(=O)C1(N)N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)-n1c(C)nnc1C(N)N=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
In a mixture of 180 ml of ethanol and 60 ml of water was dissolved 15.1 g of ethyl 6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-carboxylate. To the solution was added 6.0 g of crystals of barium hydroxide·8 hydrate, and the mixture was stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, 200 ml of water and 100 ml of benzene were added and the mixture was stirred fully. The water layer was separated, adjusted to pH 2 with 1N hydrochloric acid and left standing still for 24 hours. Thereafter, the mixture was neutralized with sodium carbonate, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in chloroform and insoluble matters were filtered off. After the solvent was distilled off under reduced pressure, the residue was recrystallized from ethanol to give 10.7 g of 6-amino-4-( 2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine, m.p. 130°-131° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:27]=[CH:26][C:20]2[O:21][C:22]([F:25])([F:24])[O:23][C:19]=2[CH:18]=1.[Cl:28]C(Cl)(F)C(Cl)(F)F.[NH4+].[Cl-]>O1CCCC1.O.C(OCC)C>[Br:16][C:17]1[CH:27]=[CH:26][C:20]2[O:21][C:22]([F:25])([F:24])[O:23][C:19]=2[C:18]=1[Cl:28]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: FC1(F)Oc2ccc(Br)c(Cl)c2O1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
2,2,6,6-Tetramethylpiperidine (2.1 mL, 1.8 g, 12 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to −75° C. and treated with n-butyllithium (n-BuLi, 2.5 M; 4.8 mL, 12 mmol), and the mixture was stirred for 30 min at −75° C. 5-Bromo-2,2-difluorobenzo[d][1,3]dioxole (2.0 g, 8.4 mmol) was added, and the mixture was stirred for 2 h at −75° C. 1,1,2-Trichloro-1,2,2-trifluoroethane (2.4 mL, 3.8 g, 20 mmol) was added and stirring was continued for 1.5 h. Saturated NH4Cl (10 mL) was added, and the mixture was shaken with diethyl ether (30 mL) and water (20 mL). The ether phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated under vacuum. The residue was purified by chromatography on silica with hexane and then repurified by reverse-phase HPLC using 75% acetonitrile to give the title compound as a clear liquid (640 mg, 28%): 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J=8.5, 5.1 Hz, 1H), 6.90 (dd, J=9.0, 4.7 Hz, 1H); EIMS m/z 332.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[CH3:20].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])=[CH:14][C:13]=1[CH3:20]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Cc1cc(C=O)ccc1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(C)c1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (310 mg, 2.17 mmol) in methanol (10 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.27 mL, 2.17 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (340 mg, 5.42 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). Two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (460 mg, 1.73 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.68 (2H, m), 1.89 (3H, m), 2.04 (1H, m), 2.28 (3H, d, J=2.0 Hz), 2.97 (1H, m), 3.31 (1H, m), 3.71 (3H, s), 3.72 (2H, m), 6.93 (1H, t, J=8.4 Hz), 7.07 (1H, m), 7.11 (1H, m).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:16]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[OH:25])=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:16]([C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][C@H:20]1[OH:25])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=NC1CCNCC1O
Reactant: O=[N+]([O-])c1cc(F)cc(-n2cnnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1CCN(c2cc(-n3cnnc3)cc([N+](=O)[O-])c2)C[C@H]1O
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A mixture of 4-(3-fluoro-5-nitrophenyl)-4H-1,2,4-triazole (200 mg, 0.96 mmol), 4-azidopiperidin-3-ol (164 mg, 1.15 mmol) and K2CO3 (199 mg, 1.44 mmol) in DMSO was heated at 100° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc (two times). The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography, (SiO2, 24 g column, 0-12% MeOH/DCM) to give Intermediate 33A (135 mg, 43%) as a yellow solid. HPLC: Rt=1.722 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=331 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 13.5 mmol) in anhydrous DMF (20 mL) was stirred at 0° C. Sodium hydride (60% in mineral oil, 0.8 g, 20.3 mmol) was added portion-wise and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.4 g, 20.3 mmol) was added to the solution dropwise and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was concentrated in vacuo, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography on silica gel (eluting with 1% EtOAc in petroleum ether) to give 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 70%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.08 (d, J=10.0 Hz, 2H), 4.67 (m, 1H), 4.6 (d, J=12.8 Hz, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.8 Hz, 3H), 0.95 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [N+:1]([CH:4]([CH3:16])[CH2:5][O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8]1([CH3:15])[CH3:14])([O-])=O>CO.[Ni]>[NH2:1][CH:4]([CH3:16])[CH2:5][O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8]1([CH3:15])[CH3:14]
Reactant: CC(COC1C(C)(C)CCC1(C)C)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(N)COC1C(C)(C)CCC1(C)C

Procedure:
1-(2-Nitropropoxy)-2,2,5,5-tetramethylcyclopentane is dissolved in methanol and hydrogenated at 50 psi with Raney nickel T-1 as a catalyst. The reaction mixture is filtered through Celite and evaporated to yield 1-(2-aminopropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>O1CCCC1.CO.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 (12.0 g) obtained in Example 120-(1) was dissolved in tetrahydrofuran (120 ml) and methanol (360 ml), and added thereto were triethylamine (24.2 ml) and 10% palladium carbon catalyst (wet, 3.6 g), and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere under normal pressure. The insoluble materials were filtered off, washed with tetrahydrofuran, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3(2-thienylmethyl)benzene (7.79 g) as colorless crystals. APCI-Mass m/Z 536 (M+NH4).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[NH2:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=1.CC1NC2C(C=1)=CC(O)=CC=2>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Nc1cc(O)ccn1
Agent: Cc1cc2cc(O)ccc2[nH]1
Product: COC(=O)c1ccc(F)cc1Oc1ccnc(N)c1

Procedure:
The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and 2-aminopyridin-4-ol for 2-methyl-5-indolol in EXAMPLE 3A, except here heating was at 130° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:29][C:30]([NH2:32])=[NH:31])=[N:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[C:5]([NH:29][C:30]([NH2:32])=[NH:31])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@@H](C(=O)O)CC3)cc12
Yield: 390.1 %

Procedure:
t-Butyl cis-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (55 mg, 0.121 mmol) was suspended in a solution of EtOAc saturated with HCl (50 mL) and the mixture heated at reflux. The mixture was cooled, the white solid was collected by filtration, with EtOAc washing, and then dried to give cis-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylic acid hydrochloride (110 mg, 0.236 mmol).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[Cl:28][C:29]1[C:36]([N:37]([C:39](=[O:56])[CH2:40][NH:41][C:42](=[O:55])[CH:43]=[CH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:54])[NH:52][CH3:53])=[CH:47][CH:46]=2)[CH3:38])=[CH:35][CH:34]=[C:33]([Cl:57])[C:30]=1[CH2:31]Br>O>[Cl:28][C:29]1[C:36]([N:37]([C:39](=[O:56])[CH2:40][NH:41][C:42](=[O:55])[CH:43]=[CH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51](=[O:54])[NH:52][CH3:53])=[CH:49][CH:50]=2)[CH3:38])=[CH:35][CH:34]=[C:33]([Cl:57])[C:30]=1[CH2:31][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To an ice-cooled mixture of sodium hydride (40% in oil, 9 mg) and anhydrous N,N-dimethylformamide (1 ml) was added 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (53 mg), and the mixture was stirred at the same temperature for 30 minutes. To this mixture was added 2,6-dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyl bromide (103 mg), and the mixture was stirred at ambient temperature for 2.5 hours. Water (2 ml) was slowly added to the reaction mixture under ice-water cooling and the precipitates were collected by vacuum filtration and washed with water and diethyl ether. The crude product was purified by a preparative thin layer chromatography (chloroform-methanol-ammonium hydroxide) followed by trituration with ethyl acetate to give 8-[2,6-dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (77 mg) as a pinkish powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:24]=1)[C:20]#[N:21]
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3cc(F)cc(C#N)c3)nc2)cs1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (30 mmol, 7.02 g) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (30 mmol, crude material, above procedure), dichlorobis(triphenylphosphine)palladium(II) (1.5 mmol, 1.05 g), and potassium carbonate (120 mmol, 16.6 g) were added to deoxygenated DME:water (1:1, 300 mL) at room temperature. The reaction was warmed to 80° C. and stirred overnight under nitrogen, then partitioned in a separatory funnel with EtOAc (500 mL) and water (300 mL). The organic layer was washed with one additional portion of water (100 mL) and the combined aqueous layers back extracted with EtOAc (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 30% EtOAc in hexanes, to afford the title compound as a tan solid. 1H-NMR (CDCl3, 500 MHz) δ 8.89 (m, 1H), 8.17 (dd, 1H), 8.04 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.42 (m, 1H), 2.79 (s, 3H). MS (ESI) 320.0 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH3:18])[C:7]([OH:9])=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH3:18])[C:7]([O:9][C@@H:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: CCc1ccccc1NC(C(=O)O)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(2-ethylphenylamino)acetic acid (I43) (875 mg, 2.81 mmol), HOBT (430 mg, 2.81 mmol), and DCC (1.16 g, 5.62 mmol) in THF (28 ml) was stirred at r.t. for 30 minutes. Then (R)-quinuclidin-3-ol (715 mg, 5.62 mmol) was added, and the reaction mixture was stirred at r.t. overnight. The solvent was evaporated, and the crude product was partitioned between EtOAc and sat. Na2CO3. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=3/1) to collect (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(2-ethylphenylamino)acetate (86 mg, 7.3% yield over two steps)