Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:36][CH3:37])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:28]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ccc(F)cc1B(O)O
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: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (100 mg, 0.23 mmol, example 25, intermediate a) and 5-fluoro-2-methoxybenzeneboronic acid (CAS RN 179897-94-0) (59.7 mg, 0.35 mmol) in dry DMF (3 mL) was added potassium carbonate (129.4 mg, 0.94 mmol) at 25° C. in a sealed tube and the reaction mixture was purged with argon for 10 min. Then Pd(PPh3)4 (27.05 mg, 0.023 mmol) was added and again purged with argon for 15 min. The reaction mixture was heated at 100° C. for 16 hours. The reaction mass was cooled to 25° C., filtered through a bed of celite and washed with EtOAc. The solvent was evaporated and the residue was dissolved in EtOAc and washed with water. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The resulting crude product was purified by preparative HPLC. Off-white solid (55 mg, 50%). MS (ESI): m/z=473.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH3:26])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Li+].C(O)C>O>[CH2:1]([N:5]([CH3:26])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(C(=O)N(C)CC(C)C)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylate (165 mg, 0.467 mmol), lithium hydroxide (55 mg, 2.3 mmol), ethanol (10 mL), and water (1 mL) was stirred at room temperature for 5 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield the product as white foam. LC-MS: 326.0 [M+1]+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:24]=[CH:25][CH:26]=2)=[C:13]([CH2:29][CH2:30][C:31]([F:33])([F:32])[F:34])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9]
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.45 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-{3[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-aniline and 4.3 ml of triethanolpropy amine in 90 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 5 hours, the mixture is poured onto water and extracted with methylene chloride. Evaporation of the extracts and recrystallisation of the residue from ether gives methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S1(=O)CCCO1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (2.58 g, 12.1 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.06 g, 8.6 mmol). The mixture was stirred at reflux for 2 h. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound N, 2.85 g (71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (110 mg, 0.25 mmol) (from example 70, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.066 mL, 0.25 mmol) dissolved in water (0.500 mL) was added. After 20 min at −40° C., hydroxylamine (50% by weight in water, 7.71 μL, 0.25 mmol) was added and stirring continued for 4 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (1.299 mL, 7.80 mmol) and stirred for 1 h. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (7.00 mg, 6.85%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.90-2.01 (m, 1H), 2.06 (dt, 1H), 2.56 (d, 1H), 2.76 (t, 1H), 2.89 (t, 1H), 3.78 (s, 3H), 4.13-4.47 (m, 1H), 5.46-5.74 (m, 1H), 5.68 (s, 1H), 6.89 (d, 2H). MS m/z 407 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:4]=[N:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+]>CN(C)C=O.O>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH:4]=[N:3][CH:2]=1
Reactant: ClCCCCCCc1cncnc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCc1cncnc1
Yield: 71.1 %

Procedure:
A solution of 22.3 g of 6-(5-pyrimidinyl)hexyl chloride, 41.6 g of potassium phthalimide, and 1.8 g of potassium iodide in 180 ml of dimethylformamide was heated to a bath temperature of 130° C. for 1 hour. The mixture was diluted with water and was extracted with dichloromethane. The combined organic layers were washed with water and were dried over potassium carbonate. The residue obtained after evaporation was crystallized from ethyl acetate-hexane to give 24.7 g (71%) of 2-[6-(5-pyrimidinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 124°-126.5° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:16])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:16])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:19][N:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(Cl)s1
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-(2-chloropyridin-4-yl)ethanone (15.8 mmol) in 10 mL N,N-dimethylformamide, was added N,N-dimethylformamide dimethyl acetal (53.7 mmol). The mixture was refluxed for 2 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate:heptane 6:4 to 1:0) to afford 3.3 g (60% yield) of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(2-chloropyridin-4-yl)prop-2-en-1-one.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: N
Reactant: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (4.8 g, 20.34 mmol) in dioxane (30 ml) was added 30% w/w water solution of ammonia (60 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 97/3).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[C:18]([CH3:26])=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1>CN(C=O)C>[CH3:26][C:18]1[C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[N:19]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 1.4 g, 36 mmol)) in DMF (50 mL) was added tert-butyl ethyl propanedioate (6.8 g, 36 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 3-chloro-2-methyl-6-nitropyridine (4.8 g, 28 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. and stirred for 5 h. Cooled to ambient temperature, poured to ice/water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography to give title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][NH2:13].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:3]3[C:4]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:25])[N:23]=2)[CH:20]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1c(Cl)cccc1C(F)(F)F
Product: O=C(NCc1c(Cl)cccc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: Oc1ccc(Cl)cc1
Product: COc1cccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Chloro-phenoxy)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: N(CC1CCCC1)=[N+]=[N-].[CH:10]1([CH2:15][N:16]=[C:17]=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[CH:10]1([CH2:15][NH:16][C:17]([NH:22][CH2:21][CH2:19][OH:20])=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCO
Reactant: S=C=NCC1CCCC1
Agent: [N-]=[N+]=NCC1CCCC1
Product: OCCNC(=S)NCC1CCCC1
Yield: 63 %

Procedure:
The intermediate azidomethylcyclopentane was obtained from commercially available cyclopentanemethanol as described in General Procedure D. Spectroscopic data: 1H NMR (CDCl3, 300 MHz) δ 3.18 (d, J=10.0 Hz, 2H), 2.23-2.05 (m, 1H), 1.87-1.74 (m, 2H), 1.68-1.55 (m, 4H), 1.30-1.15 (m, 2H). The azide was then converted into cyclopentylmethyl isothiocyanate, which was reacted with ethanolamine to afford the title compound (12.68 g, 63%) according to General Procedure A. Spectroscopic data: 1H NMR (D6, DMSO, 300 MHz) δ 7.46 (br s, 1H), 7.31 (br s 1H), 4.72 (br s, 1H), 3.5-3.38 (m, 4H), 3.25 (br s, 2H), 2.03 (quintet, J=6.4 Hz, 1H), 1.70-1.57 (m, 3H), 1.55-1.41 (m, 3H), 1.20-1.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH:9]=2)=[C:4]([CH3:23])[CH:3]=1.ClCCCl.C([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:41][CH:38]4[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]4)=[CH:3][C:4]=3[CH3:23])[NH:13][C:12](=[O:14])[CH:11]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)c2)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(-c2cc(-c3ccc(NCC4CCNCC4)cc3C)[nH]c(=O)c2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyridin-2(1H)-one (76 mg, 0.25 mmol), 1,2 Dichloroethane (5.0 mL), acetic acid (0.1 mL), and N-Boc-4-Formyl piperidine (0.65 mg, 0.30 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (85 mg, 0.40 mmol). Stirring was continued at room temperature for 10 min. The reaction was then concentrated down under reduced pressure. The resulting oil was then dissolved in 4N HCl/dioxane (5.0 mL) and stirred at 45° C. for 1 h. The resulting slurry was cooled down to room temperature and the precipitate was filtered off. The resulting solid was then dissolved in MeOH and purified by preparatory HPLC (15-40% gradient of NH4OAc/ACN) to give 4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4-ylmethyl)amino]phenyl}pyridin-2(1H)-one as the acetate salt (16 mg, 14% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 7.47 (s, 1H), 7.39 (dd, 1H), 7.06 (d, 1H), 6.85 (d, 1H), 6.45 (m, 2H), 6.36 (s, 1H), 6.27 (s, 1H), 5.95 (t, 1H), 2.98 (m, 2H), 2.91 (t, 1H), 2.48 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.72 (m, 4H), 1.09 (m, 1H); MS (EI) for C25H29N3O2: 404 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Reactant: CNC
Product: CN(C)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Yield: 48 %

Procedure:
Mesylate (205) prepared as described in example 174 (70 mg, 0.16 mmol) was reacted with aqueous dimethylamine solution according to the procedure described in example 179 to give amine (209) (30 mg, 48%) as a yellow powder, mp 283–286° C. 1H NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.33 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 4.55 (t, J=6.5 Hz, 2H), 2.62 (t, J=6.5 Hz, 2H), 2.19 (s, 6H). Found: C, 71.92; H, 5.16; N, 10.55. C24H21N3O3 requires: C, 72.17; H, 5.30; N, 10.52.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[C@H:30]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:31]=3[C:28]([CH2:29]2)=[CH:27][NH:26]4)[CH2:19][C:18](=O)[CH2:17]1>[Pd]>[CH3:15][N:16]1[C@H:30]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:31]=3[C:28]([CH2:29]2)=[CH:27][NH:26]4)[CH2:19][CH:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][CH:10]=2)[CH2:17]1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Product: CN1CC(Nc2ccc(Oc3ccccc3)nc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-phenoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C)CCN(C)C.C([Li])(CC)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(OCC)C.O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:31]([O:33][CH3:34])=[O:32])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Reactant: COC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (5 g, 22.8 mmol) and N,N,N′,N′-tetramethyl-1,2-ethanediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl ether (300 mL) and cooled to −78° C. in an acetone/dry ice bath. Sec-butyl lithium (1.4 M solution in cyclohexanes, 17.6 mL, 24.6 mmol) was added dropwise over 10 minutes and the reaction left stirring for 90 minutes at this temperature. Methyl chloroformate (8.8 mL, 10.8 g, 0.1 mol) was added to the mixture and the reaction was allowed to warm up to room temperature over 1 hour. Water was added carefully to the mixture and the organic layer separated and washed 3 times with more water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.91 g) as a gummy yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:39][CH:38]([OH:40])[CH2:37]1>>[OH:40][CH:38]1[CH2:39][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:33])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: OC1CNC1
Agent: Cl
Product: CC(C(=O)N1CC(O)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood and Cat. No. 013898). LCMS (M+H)+: m/z=529.2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([O:36][CH3:37])=[C:29]([OH:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>CN(C)C=O.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>[OH:35][C:29]1[C:30]([O:33][CH3:34])=[C:31]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])[CH:32]=[CH:27][C:28]=1[O:36][CH3:37]
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Reactant: COc1ccc(Br)c(OC)c1O
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: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Temperature: 85 °C
Yield: 41 %

Procedure:
A stirring solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (3 g, 12.87 mmol) in dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (12.58 g, 38.61 mmol), Pd (PPh3)4 (743 mg, 0.64 mmol) and 3-bromo-2,6-dimethoxyphenol (3.32 g, 12.87 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (1.5 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][C:11](O)=[O:12])[C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:6]=2[CH:14]=1
Reactant: O=C(O)Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1coc2ccc(F)cc12
Yield: 100.7 %

Procedure:
A solution of 5-fluorobenzofuran-3-ylacetic acid (4.6 g, prepared as described in Example 2) in dry tetrahydrofuran (200 mL) was added dropwise to a suspension of lithium aluminium hydride (4.5 g) in dry tetrahydrofuran (150 mL) at room temperature. After reflux for 2 h the reaction was quenched by successive additions of water (9.2 mL), 15% aq. sodium hydroxide (4.6 mL), water (23 mL). Filtration and removal of solvent in vacuo gave an oil, 2-(5-fluorobenzofuran-3-yl)ethanol (4.3 g).