Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](C3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1.[NH2:35][C:36]1[CH:46]=[CH:45][C:44](Br)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:35][C:36]1[CH:46]=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38](=[O:39])[N:40]([CH3:41])[CH3:42]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(C3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (6.5 g, 14 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide (3.4 g, 14 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (511 mg, 0.7 mmol) in THF/Acetonitrile/saturated NaHCO3 (25 ml/25 ml/30 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (3.7 g, 52% yield).
Reaction SMILES: Br[C:2]1[CH:17]=[C:16]([CH3:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=2)=[C:4]([Cl:19])[CH:3]=1.[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:23])[CH:21]=[CH2:22].C1(CNCC2CCCCC2)CCCCC1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[Cl:19][C:4]1[CH:3]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:17]=[C:16]([CH3:18])[C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc([N+](=O)[O-])cn1
Reactant: C=CC(=O)OCCCC
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)/C=C/c1cc(C)c(Oc2ccc([N+](=O)[O-])cn2)c(Cl)c1

Procedure:
To a 1,4-dioxane (10 mL) solution of 2-(4-bromo-2-chloro-6-methylphenoxy)-5-nitropyridine (1.00 g) and butyl acrylate (0.480 mL) were added N,N-dicyclohexylmethylamine (0.655 mL), tri-tert-butylphosphine tetrafluoroborate (34 mg) and tris(dibenzylideneacetone)dipalladium (0) (40 mg) at room temperature. The resultant mixture was stirred at 70° C. under a nitrogen atmosphere for 4 hours. To the reaction mixture was added water, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 1/1) to afford butyl (E)-3-{3-chloro-5-methyl-4-[(5-nitropyridin-2-yl)oxy]phenyl}prop-2-enoate as a yellow powder (1.05 g).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41]1([C:47]2[CH:48]=[CH:49][C:50]([C:53](O)=[O:54])=[N:51][CH:52]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH3:12][C:11]([CH3:14])([CH3:13])[C@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:8]([N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:52][N:51]=1)=[O:54])=[O:9]
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a 10 ml vial was added N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (100 mg, 0.268 mmol), EDC (128 mg, 0.670 mmol), HOBt (41.0 mg, 0.268 mmol), 5-phenyl-2-pyridinecarboxylic acid (64.1 mg, 0.322 mmol), CH2Cl2 (2.8 ml) and DIEA (0.187 ml, 1.072 mmol). The mixture was stirred at room temperature for 4 h, then diluted with sat. Na2CO3. The organic layer was passed over a phase separator and concentrated and purified by reverse phase HPLC: 30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the resulting aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were combined, dried and concentrated to afford the desired product (123 mg, 0.227 mmol) as an off white solid. LCMS (m/z): 536.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.05 (s, 2H), 1.07 (s, 2H), 1.10 (s, 4H), 1.73-2.09 (m, 2H), 3.37-4.07 (m, 4H), 4.45-5.27 (m, 3H), 6.90-7.25 (m, 2H), 7.26-7.96 (m, 9H), 8.03-8.38 (m, 2H), 8.42-9.10 (m, 1H), 11.55-11.83 (m, 1H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].CO.[CH:21](=O)[CH3:22]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH:21][CH3:22])=[O:14])[CH3:2]
Reactant: CC=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: CO
Solvent: O
Product: CC=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 45 μl of acetaldehyde were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 103 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-ethylidene-1-methylhydrazine ((40-b)-(15)-2).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[OH:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH:16]([N:18]2[C:22]3[N:23]=[C:24]([S:37][CH2:38]CC)[N:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:21]=3[N:20]=[N:19]2)[CH:15]([OH:41])[CH:14]1[OH:42].C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH:16]([N:18]2[C:22]3[N:23]=[C:24]([S:37][CH3:38])[N:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:21]=3[N:20]=[N:19]2)[CH:15]([OH:41])[CH:14]1[OH:42]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
DIBAL-H® (1.5M solution in toluene, 20 ml) was added to an ice-cooled solution of the product of Example 11, step a) (2.00 g) in toluene (30 ml) and the solution stirred at this temperature for 30 minutes before adding ethyl acetate (2 ml). The solution was washed with water and concentrated. The residue (1.8 g) was taken into ethanol and cooled to 4° C. before adding 3-chloroperoxybenzoic acid (50-55%, 2.5 g) and allowing the reaction to stir at room temperature for 18 hours. The solution was washed with aqueous sodium metabisulfite solution (3×10 ml) then dried and concentrated. Purification (SiO2, ether:isohexane, 80:20, as eluent) afforded the subtitle compound (1.8 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].[C:25](=N)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO.C([BH3-])#N.[Na+]>ClCCl.Cl.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(NC(c5ccccc5)c5ccccc5)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (22 mg, 0.07 mmol), in 0.25 mL of dichloromethane was added benzophenone imine (1 eq), followed by 1 drop of 1N hydrochloric acid. The mixture was stirred at room temperature for 1 h, concentrated, and 0.5 mL of methanol and sodium cyanoborohydride (0.14 mmol) followed by two drops of glacial acetic acid was added, and the mixture was stirred for 16 h, diluted with ethyl acetate, rinsed with saturated sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration of the resulting oil from ether/hexanes, 28 mg (83%) of the title compound as a white solid. mp 109°-111°. FDMS: m/e=486. α[D]589 =+46.90 (c=0.49, methanol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[S:41]([CH2:45][C:46](O)=[O:47])([OH:44])(=[O:43])=[O:42].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:46]([CH2:45][S:41]([OH:44])(=[O:43])=[O:42])=[O:47])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)CS(=O)(=O)O
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CS(=O)(=O)O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (17), and 48 μl of diisopropylethylamine in 1 ml of dimethylformamide was added to a solution of 40 mg of sulfoacetic acid, 110 μl of diisopropylcarbodiimide, and 76 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 544.58 (C27H26F2N2O6S1); MS (ESI) 527.10 (M+H+—H2O)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.[Pd].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>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8]
Reactant: O=Cc1sccc1Br
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1sccc1-c1cccs1

Procedure:
To a stirring solution of 3-bromo-thiophene-2-carbaldehyde (0.120 g, 0.6 mmol) and 2-thiopheneboronic acid (0.134 g, 0.75 mmol) in 1,2-dimethoxyethane (4.0 ml) under argon was added sodium bicarbonate solution (1.0 M, 3.0 ml). Tetrakis(triphenylphosphine) palladium (0) (0.022 g, 0.02 mmol) was then added to the reaction mixture. The solution was heated under reflux for 24 hrs, then was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4. The solvent was evaporated to yield [2,3′]bithiophenyl-2′-carbaldehyde as a colorless oil which was used directly in next step, without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:21])C(F)(F)F)=[CH:8]1)[CH2:4][CH2:5][CH3:6].O.P(=O)(O)(O)[OH:24]>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:21])=[O:24])=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: O=P(O)(O)O
Reactant: CCCCn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCn1cc(C(=O)O)c2ccccc21
Temperature: 50 °C

Procedure:
A solution of potassium hydroxide (6.9 kg, 133.7 mol) in 14 mL of methanol was heated to reflux temperature and crude 1-butyl-3-trifluoroacetylindole (11.5 kg) in 35 L of toluene was added slowly. The mixture was heated under reflux for 60 minutes, cooled to approximately 50° C. and 80 L of water was added. The aqueous layer was separated and extracted with 30 L toluene. Phosphoric acid was then added to the aqueous layer until a pH of 7.16 was obtained. Ethyl acetate was then added, followed by additional phosphoric acid until a pH of 2.38 was obtained. The ethyl acetate layer was separated and washed twice with water (2×40 L). The ethyl acetate layer was filtered, heated to 83° C. and combined with 40 L of heptane at which point crystallization occured. The mixture distilled until the mixture heated to 89° C., after which the mixture was cooled slowly. A crystalline product was obtained and isolated by filtration. Drying under nitrogen gave 1-butylindole-3-carboxylic acid (6.64 kg, 30.6 mol), m.p. 124°-126° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH2:9][CH2:8]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C=O)C>[CH:7]1([C:10]2[CH:14]=[CH:13][N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:11]=2)[CH2:9][CH2:8]1
Reactant: c1cc(C2CC2)n[nH]1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(C2CC2)n1
Reaction time: 0.33 h
Yield: 42 %

Procedure:
Potassium carbonate (7.67 g, 55.56 mmol) was added to 3-cyclopropyl-1H-pyrazole (2.0 g, 18.52 mmol) in dry DMF (20 mL) at 25° C. and the mixture was stirred for 20 minutes. Ethyl bromoacetate (2.06 mL, 18.52 mmol) was added then the mixture was stirred for 2 days at room temperature. The reaction mixture was neutralized with aqueous HCl (1.0 M), extracted with ether (40 mL) and the organic extract was washed with brine (30 mL), dried over sodium sulfate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 42% yield, 1.50 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[C:8]1[C:9]([CH2:14]O)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]>C(Cl)Cl>[Cl:3][CH2:14][C:9]1[C:8]([N:7]([CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH2:5][CH3:6])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (470 mg, 288 μL, 3-95 mmol) was added to a stirred solution of ethyl [trans-4-({ethyl[2-(hydroxymethyl)pyridin-3-yl]amino}methyl)cyclohexyl]acetate (132.2 mg, 0.395 mmol) in dry CH2Cl2 (10 mL) at room temperature. The reaction was stirred overnight at room temperature then quenched with pyridine (425 μL) and washed with water. The aqueous layer was extracted with CH2Cl2 (2×20 mL) an the combined extracts were dried (Na2SO4) and concentrated in vacuo to afford ethyl (trans-4-{[[2-(chloromethyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. 1H NMR (500 MHz, CDCl3): δ 8.37 (dd, J=1.2, 4.5 Hz, 1 H); 7.51 (dd, J=1.4, 8.1 Hz, 1 H); 7.23 (dd, J 3.7, 8.3 Hz, 1 H); 4.86 (s, 2 H); 4.10 (q, J=7.1 Hz, 2 H); 3.03 (q, J=7.1 Hz, 2 H); 2.81 (d, J=7.1 Hz, 2 H); 2.14 (d, J=6.8 Hz, 2 H); 1.80-1.67 (m, 5 H); 1.42-1.29 (m, 1 H); 1.23 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.1 Hz, 3H); 0.94-0.86 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1.[CH2:22]1C[O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:24](=[O:25])[CH:23]=[CH2:22])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])=[CH:16][CH:17]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 500 mg (1.47 mmol) 6-amino-4-[(4-bromophenyl)amino]-3-quinolinecarbonitrile in 1 ml hot DMF, added 6 ml THF and chilled to 0° C. under N2. Added 226 μl (1.62 mmol) triethylamine and 135 μl (1.62 mmol) acryloyl chloride. Removed ice bath at 15 minutes. At 1.5 hours, stripped solvent, slurried residue in dilute sodium bicarbonate, collected solids, and dried in vacuo. Boiled solids in ethyl acetate, collected, and dried in vacuo, giving 194 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=393.1, 395.1.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]2)=[CH:25][CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.55 g), benzyl bromide (0.7 ml), potassium carbonate (0.92 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]propionic acid (1.53 g, yield: 84%). This was recrystallized from ethyl acetate-hexane. Melting point: 130–131° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Mg]Br)C.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].Cl>CCOCC.O1CCCC1.COCOC.[Zn].CN(C)P(=O)(N(C)C)N(C)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:26][CH:27]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1
Agent: CC[Mg]Br
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A solution of 2.6 g (4.0 mmol) of dichlorobis(triphenylphosphine) nickel and 2.1 g (8.0 mmol) of triphenylphosphine in 30 ml of ether was cooled to 0° C. in an argon atmosphere. To this solution, 1.8 M ethylmagnesium bromide solution in ether was added in an amount of 4.4 ml (8.0 mmol). The resulting mixture was stirred for 1 hour, and the solvent was then removed by evaporation under reduced pressure. To the residue was added a solution of 4.3 g (16.4 mmol) of 4-bromo-4'-methoxybiphenyl in 20 ml of tetrahydrofuran (THF) and 30 ml of dimethoxymethane, and was also added 10 ml of hexamethylphosphoric triamide (HMPA). Thereto was added at 0° C. a Reformatsky reagent prepared from 10.0 g (60.0 mmol) of ethyl bromoacetate, 6.5 g (100 mmol) of zinc, and 10 ml of dimethoxymethane. The resulting mixture was stirred at room temperature overnight. Thereafter, 50 ml of 3 M hydrochloric acid was added thereto, and this mixture was subjected to extraction with 250 ml of ether. The resulting ether solution was washed with purified water, and then concentrated under reduced pressure. The residue was separated and purified by column chromatography (hexane/ethyl acetate=5/1), thereby obtaining 2.16 g (yield 51%) of ethyl 4-(4-methoxyphenyl)phenylacetate.
Reaction SMILES: C1COCC1.I[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[N:9]([CH3:20])[N:8]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:20][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8]1
Reactant: COC(=O)c1ccc2c(I)nn(C)c2c1
Reactant: OB(O)Oc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(-c3ccccc3)nn(C)c2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a 100-mL egg plant-type flask, PdCl2(dppf) (178 mg, 0.22 mmol) was added to a THF (20 mL)-water (2 mL) mixed solution of methyl 3-iodo-1-methyl-1H-indazole-6-carboxylate (690 mg, 22 mmol), phenylboric acid (399 mg, 3.27 mmol) and K2CO3 (1.35 g, 9.81 mmol), and stirred overnight at 80° C. in an argon atmosphere. This was diluted with ethyl acetate, washed with water and saturated saline water, dried with sodium sulfate, filtered and concentrated. The resulting crude product was purified through silica gel column chromatography to obtain the title compound.