Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][CH:7]=1.[C:19]([NH:29][CH2:30][C:31]#[CH:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(NC(C)C)(C)C.C(OCC)(=O)C.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.[Cu]I>[C:14]([O:13][C:12]([NH:11][CH2:10][C:9]#[C:8][C:5]1[N:6]=[CH:7][C:2]([C:32]#[C:31][CH2:30][NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Br)cn1
Reactant: C#CCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of tert-butyl 3-(5-bromopyridin-2-yl)prop-2-ynylcarbamate (3-1) (1.44 g), N-Cbz propargylamine (1.09 g), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (25 mL) was heated under reflux under a nitrogen atmosphere for 3 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate (70 mL). The precipitates were filtered and rinsed with ethyl acetate (30 mL). The filtrate and washings were combined, concentrated under reduced pressure, and purified by silica gel column chromatography using a mixture of MTBE and hexanes (2:3 to 4:1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was crystallized from MTBE. Crystals were filtered, washed with MTBE, and dried to give 6-1 (1.07 g). An additional 120 mg of 6-1 was isolated from the mother liquors and washings.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:24]=[CH:23][C:22]=2[CH3:33])=[O:19])=[N:16][CH:17]=1>CN1C(=O)CCC1>[CH:30]1([NH:29][C:27]([C:25]2[CH:24]=[CH:23][C:22]([CH3:33])=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:17][N:16]=3)=[O:19])[CH:26]=2)=[O:28])[CH2:32][CH2:31]1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To 2-pyridinylmethanol (300 μL) was added sodium hydride 60% dispersion in oil (20 mg, 1.39 mmol) under inert atmosphere and the mixture stirred at room temperature for 10 minutes. NMP (600 μL) was then added followed by 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-pyrazinecarboxamide (100 mg, 0.303 mmol) and the resulting mixture stirred for 48 hours. The solvent was evaporated under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate and DCM. Evaporation of DCM, precipitation with diethyl ether and isohexanes and filtration gave the title compound as a solid (25 mg, 20%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.31 (s, 3H), 2.86 (m, 1H), 5.59 (s, 2H), 7.36 (m, 2H), 7.55 (m, 1H), 7.62 (d, 1H), 7.86 (m, 1H), 8.08 (m, 1H), 8.37 (m, 1H), 8.58 (m, 2H), 8.89 (s, 1H), 9.76 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.C(OCC)C>O1CCCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: BrCCCOC1CCCCO1
Reactant: C#CC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C#CCCCOC1CCCCO1
Temperature: -78 °C
Yield: 40.7 %

Procedure:
0.81 g of tert-butylacetylene was dissolved in 19 ml of tetrahydrofuran, and 6.1 ml of a 0.55M n-butyllithium-hexane solution was added dropwise with stirring at -78° C. After the mixture was stirred at this temperature for 1 hour, 2.2 g of 3-bromo-1-(2-tetrahydropyranyloxy)propane was added. The solution was warmed to the room temperature, and then heated at 80° C. with stirring for 8 hours. The reaction mixture was poured into the ice water, and ethyl ether was added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1] to give 0.90 g of 6,6-dimethyl-1-(2-tetrahydropyranyloxy)- 4-heptyne.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=5)[N:18]([S:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)(=[O:28])=[O:27])[CH:17]=4)[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([C:14]3[CH:13]=[N:12][N:11]([CH:8]4[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]4)[CH:15]=3)=[CH:17][N:18]2[S:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c2ccc(F)cc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 3-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 47; 500 mg; 1.04 mmol) in THF (20 mL) was added HCl (0.35 mL; 35%). The reaction mixture was stirred overnight, concentrated, and purified by reverse phase flash chromatography to afford 197 mg (43%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>C(O)C>[N:16]1([C:14]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[O:15])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: COc1ccc2nccc(N)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Product: COc1ccc2nccc(NC(=O)n3ccnc3)c2c1
Reaction time: 1 h

Procedure:
A suspension of 4-amino-6-methoxyquinoline (406a) (2.0 g, 11 mmol) in ethanol-free chloroform (60 ml) was treated with 4-N,N-dimethylaminopyridine (1.4 g, 11.4 mmol) and 1,1′-carbonyl diimidazole (2.6 g, 15.9 mmol). The suspension became clear over 1 hour then precipitation occurred. After a further 2 hours, filtration afforded the product as a white solid which was dried in vacuo (1.8 g, 59%).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(O)C.C(=O)([O-])[O-].[NH4+:49].[NH4+]>ClCCl.C(O)C>[ClH:41].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:49])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 25 from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 61% of theory, C33H34N6O2 (546.7); Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=547; (M+H+Na)++=285.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]=O)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:29][C:20]3[CH:19]=[C:18]([CH3:17])[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1-c1ccccc1
Yield: 65.4 %

Procedure:
Compound 74 was prepared using the same method as Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].[H][H]>[Pd].N1C=CC=CC=1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2ccccc2F)cc1

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 29.6 g., was reduced in a Parr Instrument Company Series 3910 Low-Pressure Shaker-Type Apparatus, using 450 ml. of pyridine, and 0.3 g. of five percent palladium on barium sulfate; reduction was carried out at room temperature for 30 minutes and at an initial hydrogen pressure of 30 psig. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was vacuum distilled to give 20.5 g. of solid which was recrystallized from methanol to give 4-(2 -fluorophenyl)-1-vinylbenzene, mp 38°. The material contained traces of pyridine and 1-ethyl-4-(2-fluorophenyl)benzene, as shown by nuclear magnetic resonance analysis. The following elemental analysis was obtained:
Reaction SMILES: C([NH:11][CH2:12][CH:13]([N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C)(OCC1C=CC=CC=1)=O.[C:32]([OH:35])(=[O:34])[CH3:33]>C(O)C.[Ni]>[C:17]([OH:19])(=[O:18])[CH3:16].[C:32]([OH:35])(=[O:34])[CH3:33].[C:28]([O:27][C:25]([CH2:24][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]([NH2:11])[CH3:32])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(CNC(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(N)CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of N-carbobenzyloxy-N′,N′-bis-(t-butoxycarbonylmethyl)-propylenediamine 35 (5.3017 g, 12.144 mmol) in ethanol (75 mL) was filtered through a bed of Raney nickel into a solution of acetic acid (2.1 mL, 3 equiv) in ethanol (75 mL). The filtrate was degassed with nitrogen and treated with 10% palladized charcoal (0.4 g). The mixture was hydrogenated at 50 psi on a Parr apparatus for 16 h and then the catalyst was filtered off on a bed of celite. The filtrate was concentrated in vacuo and the residue flushed with chloroform (150 mL). The crude product was carried on without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>C1COCC1.O>[C:7]1([CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=CCOCCc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-allyloxyethylbenzene (5. g; 30.8 mmol) dissolved in THF (75 ml) is slowly added a 0.5M THF solution of 9-BBN [9-borabicyclo [3.3.1]nonane] (68 ml; 34 mmol) and the reaction mixture warmed to room temperature and stirred for 4 hours. The reaction mixture is then cooled to 0° C. and 5 ml H2O is added followed by slow addition of 6N NaOH (30 ml; 7.2 g/30 ml). After stirring for 5 minutes, 30% H2O2 (20 ml) is added over 15 min. The reaction mixture warms significantly but is kept from refluxing. After addition is complete, it is stirred for 15 minutes allowing the mixture to come to room temperature. It is then diluted with. Et2O, washed with H2O 2×, Na2S2O3 2×, NaHCO3 and brine, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using Et2O to obtain 3-(2-phenylethoxy)-1-propanol which is used directly in Step C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]([Cl:10])=[C:8]([Cl:11])[S:7][C:6]=1[CH2:12][C:13](O)=[O:14])(O)=[O:2].B.C1COCC1>C1COCC1>[Cl:10][C:9]1[C:5]([CH2:4][CH2:1][OH:2])=[C:6]([CH2:12][CH2:13][OH:14])[S:7][C:8]=1[Cl:11]
Reactant: O=C(O)Cc1sc(Cl)c(Cl)c1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCCc1sc(Cl)c(Cl)c1CCO
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of the product from step (d) (2.5 g, 9.33 mmol) in THF (85 ml) was cooled to 0° C. and a 1M solution of BH3-THF (46.6 ml, 46.6 mmol) was added dropwise over 10 min. and stirred for an additional 20 minutes after the addition was complete. The reaction was warmed to 22° C. and stirred for 2 hours. The reaction was poured into ice cold sat. NaHCO3 (150 ml) and extracted with EtOAc. The crude was passed through a plug of silica gel washing with EtOAc. Concentration of the eluent provided 1.99 g (88%) of the subtitle compound.
Reaction SMILES: N[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.N1CC[C@H]([OH:30])C1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[OH:30][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCN3CC[C@H](O)C3)cc2)cc1
Yield: 61 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (180 mg, 0.65 mmol), (3S)-3-pyrrolidinol (57 mg, 0.65 mmol), potassium carbonate (140 mg) and potassium iodide (180 mg) in 20 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (61 % yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)[CH:5]=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[CH3:18][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(S(C)(=O)=O)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O[C@H]2CCN(S(C)(=O)=O)C2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8b (30 mg, 0.05 mmol) was dissolved in 2 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (0.1 mL, 0.10 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, 1M hydrochloric acid was added dropwise to adjust the pH to 5 and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2-((S)-6-((2′,6′-dimethyl-4′-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 8 (28 mg, yield 94.2%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: c1cc[nH]c1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cccc4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and pyrrole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:46](=[O:47])[C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=[N:42]2)=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:48]([C:45]2[C:46](=[O:47])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=[CH:43][CH:44]=2)=[O:49])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=3)[N:9]=[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (143.2 mg, 0.322 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (377.3 mg, 1.61 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (308.8 mg, 1.61 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (217.7 mg, 1.61 mmol), N-ethyl-N-isopropylpropan-2-amine (208.2 mg, 1.61 mmol) and CH2Cl2 (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (127 mg, 59.67%). LRMS (APCI pos): >99% purity, 254 nm, m/e 661 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[CH2:2]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10](=[O:19])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccccc1NC(=O)OC1CN2CCC1CC2
Yield: 72 %

Procedure:
Using general procedure E, quinuclidin-3-yl2-bromophenylcarbamate, 2-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (102 mg, 72%). 1H NMR (500 MHz, CDCl3) δ 7.95 (br s, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.72 (br s, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.23 (m, 1H), 2.90-2.64 (m, 5H), 1.98-2.08 (m, 1H), 1.81-1.63 (m, 2H), 1.60-1.50 (m, 1H), 1.42-1.30 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 156.2, 153.8, 135.6, 132.1, 130.9, 129.7, 128.3, 127.1, 123.8, 121.5, 111.3, 71.8, 55.7, 55.5, 47.3, 46.5, 25.3, 24.5, 19.4 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.48 min; (M+1) 353.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:17]2=[O:20])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]3)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[O:20]=[C:17]1[C:7]2([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH2:6][C:5]2[C:18]1=[CH:19][C:2]([C:27]1[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:21]#[N:22])=[CH:3][CH:4]=2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12CCc1ccccc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCc4ccccc4C2)C3)c1
Yield: 20 %

Procedure:
6-Bromo-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (163 mg, 0.5 mmol), 3-cyanophenylboronic acid (147 g, 1 mmol) in [1,4]-dioxane (12 mL), Cs2CO3 (2 N, 3.2 mL), then Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) was added under Ar2, the mixture was refluxed for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by TLC to give 3-(1-oxo-1,3,3′,4′-tetrahydro-1′H-spiro[indene-2,2′-naphthalene]-6-yl)benzonitrile (35 mg, 6%).
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O+]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33]([C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(O)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:33]([C:45]1[CH:46]=[CH:47][C:48]([N+:49]2[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:50][CH:51]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
A 2.3-g portion (0.005 mole) of 2,4,6-triphenylpyrylium triflate is placed in a 500-ml round-bottom flask. To this, 200 ml of ethanol is added and then 1.3 g (0.005 mole) of p-dodecylaniline is added. The mixture is refluxed for about 20 hours. The ethanol is removed by evaporation to give a yellow waxy substance. This material is washed with ether which causes some yellow crystals to precipitate.