Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5 %

Procedure:
A mixture of 5.0 g (50 mmol) 2-aminothiazole, 10.0 g (50 mmol) tert-butyl 4-aminopiperidine-1-carboxylate, 21.2 g (100 mmol) sodium triacetoxyborohydride and 5.7 ml (100 mmol) acetic acid in THF (100 ml) was stirred for 24 h at RT. Subsequently, a further 10.6 g (50 mmol) sodium triacetoxyborohydride and 2.85 ml (50 mmol) acetic acid were added and stirring took place for a further 2 d at RT. The solvent was removed in vacuo and the residue was taken up by chloroform and washed a plurality of times with 10% aq. NaOH soln and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, Chloroform/EtOH 20:1) was carried out on the residue, yielding 712 mg (2.5 mmol, 25%) tert-butyl-4-(thiazol-2-ylamino)piperidine-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:12](OC)(=[O:20])[CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[C:4]1([C:1](=[O:3])[CH2:2][C:12]([CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCCC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)CCCC(=O)CC(=O)c1ccccc1

Procedure:
Other hindered beta-diketones may be prepared by the method of Example A of U.S. Pat. No. 4,065,502. Alternatively, a preferred method of preparation is the condensation of acetophenone with an appropriate methyl ester in an aromatic hydrocarbon solvent using excess sodium hydride as base. Thus, methyl neooctanoate is condensed with acetophenone to give 1-phenyl-3-neoheptyl-1,3-propanedione, and methyl 2,2-dimethyl octanoate is condensed with acetophenone to give 1-phenyl-4,4-dimethyl-1,3-decanedione, in which the product is a mixture of branched chain isomers.
Reaction SMILES: Br[C:2]1[CH:29]=[C:5]2[N:6]=[C:7]([CH3:28])[C:8]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21]C)=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.Br[C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][N:32]=1.C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC.O[Li].O>O1CCOCC1.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.O.CO>[C:24]([O:23][C@@H:18]([C:8]1[C:7]([CH3:28])=[N:6][C:5]2[N:4]([N:3]=[C:2]([C:31]3[CH:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:34]=[CH:33][N:32]=3)[CH:29]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]1)[C:19]([OH:21])=[O:20])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3cc(-c4ccccc4)ccn3)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.107 mmol, 1 equiv) in dioxane (1.0 mL) was added 2-bromo-4-phenylpyridine (0.030 g, 0.128 mmol, 1.2 equiv), hexabutyldistannane (0.12 mL, 0.235 mmol, 2.2 equiv), and Pd(PPh3)4 (0.012 g, 0.011 mmol, 0.1 equiv). The reaction was heated at 85° C. for 72 h. The reaction temperature was then lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (26 mg, 1.07 mmol, 10 equiv) added and heating was continued for 2 h. Upon completion of the saponification, the reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column. Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to provide (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(4-phenylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (3.5 mg, 6%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.75 (d, J=4.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.06 (s, 1H), 5.72 (br. s., 1H), 3.61-3.55 (m, 4H), 2.53 (s, 3H), 1.65 (br. s., 2H), 1.50 (br. s., 2H), 1.18 (s, 9H), 1.11 (br. s., 6H). LCMS (ESI, M+1): 528.3.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[CH:13][S:12][C:11]=2[C:22]=1[Cl:23])C.[OH-].[Na+]>C(O)C>[Cl:23][C:22]1[C:11]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3F)csc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccccc3F)csc2c1Cl

Procedure:
A mixture of 7.2 g of ethyl{[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetate, 150 ml of 20% sodium hydroxide solution and 150 ml of 95% ethanol is stirred under reflux for 90 minutes. The reaction mixture is evaporated under reduced pressure, 200 ml of water is added and the solution is acidified with concentrated hydrochloric acid. The mixture is extracted with four 200 ml portions of ether. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to give a crystalline material. Recrystallization from acetone-hexane provides {[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetic acid as needles, mp 163°-164° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:2]2.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:2]2[C@@H:3]([C:8]([NH:10][C:11]3([C:14]4[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=4)[CH2:12][CH2:13]3)=[O:9])[CH2:4][CH2:5][CH:6]3[CH:1]2[CH2:7]3)=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D142) (6.8 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((3R)-2-azabicyclo[4.1.0]heptane-3-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D101) (17.5 mg) and 4-(trifluoromethyl)-benzylbromide (0.01 ml). (Cs2CO3: 1.5 eq; Reaction time: 20 hrs; RT).
Reaction SMILES: [Cl:1][C:2]([Cl:51])([Cl:50])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:34][C:35](=[O:48])[C@@H:36]([NH:40]C(OC(C)(C)C)=O)[CH:37]([CH3:39])[CH3:38])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:51][C:2]([Cl:1])([Cl:50])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:34][C:35](=[O:48])[C@@H:36]([NH2:40])[CH:37]([CH3:39])[CH3:38])[CH2:15][O:16][Si:17]([C:30]([CH3:32])([CH3:33])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](N)C(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (450 mg, 0.57 mmol) in anhydrous dichloromethane (10 mL) at 0° C. and under an atmosphere of nitrogen, was added trimethylsilyl trifluoromethanesulfonate (156 μL, 0.86 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (410 μL, 2.30 mmol) and then concentrated in vacuo to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[OH-].[Na+:16]>O.C(O)C>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[Na+:16]
Reactant: C=CCNc1cccc(CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCNc1cccc(CC(=O)[O-])c1

Procedure:
A mixture of 3.62 g. of 3-(allylamino)phenylacetic acid and 25 ml. of ethanol water (9:1) containing 0.400 g. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml. of ethanol-water (9:1) and dried in vacuo for 24 hours to yield sodium 3-(allylamino)phenylacetate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]=1[F:18].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH:10][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]=1[F:18]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1F
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cn2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.9 %

Procedure:
5-Amino-2-fluoro-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (560 mg, 1.9 mmol) was dissolved in 20 mL methylene chloride, and the mixture was cooled to 0° C. Isobutyryl chloride (221 mg, 2.1 mmol) and triethyamine (575 mg, 5.7 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 690 mg (99%) of 2-fluoro-5-isobutyrylamino-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:22]I.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]([CH3:22])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccnc(Br)c2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccnc(Br)c2)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
2-Bromo-4-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine (250 mg, 0.79 mmol) is dissolved in DMF (5.0 mL) and 60% NaH (38 mg, 0.94 mmol) is added. The mixture is stirred for 30 min and methyl iodide (0.098 mL, 1.6 mmol) is added. The reaction is continued for another 1.5 hrs before Saturated NH4Cl aqueous solution (10 mL) is added. The resulting mixture is extracted with EtOAc (3×25 mL). The organic layers are combined and concentrated to give the crude product which is used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].BrC1C=CC=C2C=1[C:27]1([C:38]3=CC4OCOC=4[CH:45]=[C:37]3[O:36][CH2:35]1)C(=O)N2>>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:45][C:37]1[O:36][C:35]([C:2]([F:23])([F:22])[F:1])=[CH:27][CH:38]=1)[C:11]3=[O:19]
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (82%) as a white solid: mp 78-80° C.; 1H NMR (300 MHz, CDCl3) δ 7.33 (td, 1H), 7.21-6.98 (m, 3H), 6.86-6.73 (m, 2H), 6.67 (s, 2H), 6.42 (d, 1H), 5.09 (d, 1H), 5.04 (d, 1H), 4.88 (d, 1H), 4.77 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 176.7, 161.7, 151.9, 150.6, 141.5, 131.7, 129.5, 127.5, 124.2, 124.2, 124.0, 114.1, 112.8, 112.8, 109.6, 109.2, 104.3, 80.7, 57.6, 37.1; MS (ES+) m/z 470 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([N:1]=[CH:26][C:24]2[O:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: O=[N+]([O-])c1ccc(-c2ccc(C=Nc3cc([N+](=O)[O-])ccc3O)o2)cc1

Procedure:
Using 2-amino-4-nitrophenol and 5-(4-nitrophenyl)furan-2-carbaldehyde, 4.10 g of 4-nitro-2-{[5-(4-nitrophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCNCc1cccnn1
Product: CNC(=O)NCCNCc1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with methyl isocyanate by the procedure of Example 24, then concentrating and separating the residue by column chromatography gives the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=O)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.[CH3:32][O:33][NH2:34]>CO.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[N:34][O:33][CH3:32])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C=O)cc23)C1
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2ccccn2)C[C@@H](NC(=O)OC(C)C)C1
Yield: 27.2 %

Procedure:
Dissolve (S)-(7-formyl-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (181 mg, 0.48 mmol) in methanol (10 mL) and 1.0 N sodium hydroxide (2.4 ml, 2.4 mmol). Add methoxyamine hydrochloride (120 mg, 1.44 mmol) and stir at room temperature overnight. Dilute with ethyl acetate, wash with 10% potassium carbonate, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product on a 12 g silica gel column eluting with 30% ethyl acetate/dichloromethane to obtain the pure title compound (53 mg, 27%). LCMS 407.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:17][C:16]=2[C:31]#[N:32])=[CH:11][C:10]=1[C:33]#[N:34])C1C=CC=CC=1.B(O)(O)O.C(C1C=C(C2C=C(C=CN=2)C(OC)=O)C=CC=1OS(C(F)(F)F)(=O)=O)#N.[H][H]>C1COCC1.CO.[C].[Pd]>[C:31]([C:16]1[CH:17]=[C:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:33]#[N:34])[CH:11]=1)#[N:32]
Reactant: COC(=O)c1ccnc(-c2ccc(-c3ccc(OCc4ccccc4)c(C#N)c3)c(C#N)c2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Agent: OB(O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(-c3ccc(O)c(C#N)c3)c(C#N)c2)c1
Yield: 47.5 %

Procedure:
1.32 g of methyl 2-[4′-(benzyloxy)-2,3′-dicyanobiphenyl-4-yl]isonicotinate, which had been obtained in the same manner as in Example 1(1) using 4-(benzyloxy)-3-cyanophenyl]boric acid and methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate, was dissolved in a mixture of 50 ml of THF and 50 ml of methanol, and 0.5 g of palladium-carbon was added, followed by stirring in a hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.5 g of methyl 2-(2,3′-dicyano-4′-hydroxybiphenyl-4-yl)isonicotinate.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[O:17][C:10]3=[C:11]([O:15][CH3:16])[N:12]=[CH:13][CH:14]=[C:9]3[CH:8]=2)[CH2:3][CH2:2]1>C(O)C.[Ni]>[CH3:16][O:15][C:11]1[N:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[O:17][C:10]=12
Reactant: COc1nccc2cc(C3=CCOCC3)oc12
Agent: [Ni]
Solvent: CCO
Product: COc1nccc2cc(C3CCOCC3)oc12
Yield: 99.1 %

Procedure:
A solution of the alkene (1.0 g) in ethanol (50 ml) was treated with Raney Nickel and hydrogenated at atmospheric pressure for 4 hours. The mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound (1.0 g) as a creamy oil.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: BrCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCc1ccccc1Br
Temperature: -78 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of acetonitrile (49 g, 1.20 mol, 9.96 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of BuLi (72 mL, 1.50 equiv) dropwise with stirring at −78° C. Stirred at −78° C. for 1 h. To this was added a solution of 1-bromo-2-(bromomethyl)benzene (30 g, 120.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 1 h at −78° C. The reaction was quenched by the addition of 100 mL of water at −78° C. The resulting aqueous solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The crude product was purified by distillation under reduced pressure (2 mm Hg) and the fraction was collected at 98-107° C. This resulted in 13.21 g (52%) of 3-(2-bromophenyl)propanenitrile as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[NH:18][C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=3)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
Approximately forty oven dried 3 Å molecular sieves were added to a solution of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one (66 mg, 0.292 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (122 mg, 0.583 mmol) in toluene (3 mL) at room temperature. The reaction was heated in a 120° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and sodium borohydride (44 mg, 1.2 mmol) was added. The solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 25 mg (20%) of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[F:10][C:4]1[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cc1F

Procedure:
The title compound was prepared by reacting 4-bromo-2-fluoroanisole (10 g, 0.049 moles) with n-butyl lithium (23.4 mL of 2.5 M solution in hexane, 0.059 moles) followed by triisopropyl borate (45.2 mL, 36.9 g, 0.196 moles) according to Method A to yield 7.1 g (85.2%) of a white solid: MS (ESI) m/z 169 (M−H)−.
Reaction SMILES: O1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([NH2:24])[C:18]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:17]3)[CH:10]=[CH:11][CH:12]=1.[CH3:32][C:33]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[C:34]=1[CH2:35][NH2:36].[OH-].[Na+]>C(O)(=O)C>[O:29]1[CH2:30][CH2:31][CH:26]([CH2:25][C:18]2[C:19]([NH2:24])=[N:20][C:21]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:2][NH:36][CH2:35][C:34]4[C:37]([CH3:42])=[CH:38][C:39]([CH3:41])=[CH:40][C:33]=4[CH3:32])[CH:8]=2)=[CH:23][CH:22]=3)[CH2:27][CH2:28]1
Reactant: Cc1cc(C)c(CN)c(C)c1
Reactant: Nc1nc2ccc(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNCc2cccc(Sc3ccc4nc(N)c(CC5CCOCC5)cc4c3)c2)c(C)c1
Reaction time: 1.5 h

Procedure:
6-(3-[1,3]Dioxan-2-yl-phenylsulfanyl)-3-(tetrahydro-pyran-4-ylmethyl)-quinolin-2-ylamine (40 mg, 0.1 mmol) was dissolved in acetic acid (1 mL) and then 2,4,6-trimethylbenzyl amine (0.1 g, 0.67 mmol) was added. The resulting mixture was subjected to μwave @ 300W, 100° C. for 12 min. The resulting mixture was evaporated under reduced pressure (high vacuum) overnight. Methanol (2 mL) was added, followed by addition of NaBH4 (0.2 g, 5.2 mmol, portionwise) over 1.5 h. The solvent was removed to yield a residue, to which was added 0.1 N NaOH (5 ml). The resulting mixture was extracted with chloroform (3×). The organic layers were combined and dried with MgSO4 and then filtered. The solvent was removed to yield the title compound as a residue, which was purified by reverse phase chromatography (10-90% CH3CN/H2O/0.1% TFA). The product containing fractions were treated with 1N HCl (1 mL) to yield the title compound, 3-(tetrahydro-pyran-4-ylmethyl)-6-{3-[(2,4,6-trimethyl-benzylamino)-methyl]-phenylsulfanyl}-quinolin-2-ylamine, as a residue.