Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[N:3].C([O-])(C)(C)C.[K+].C[O:11][C:12]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=O>C1COCC1>[C:2]([CH2:1][C:12]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][CH2:20]1)=[O:11])#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(C(=O)CC#N)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
CH3CN (0.25 mL, 4.79 mmol) was added to a cold (−78° C.) solution of t-BuO−K+ in THF (1M, 5.0 mL, 5.0 mmol) under Ar and the reaction mixture was stirred for 5 mins. Solution of tert-butyl 4-((3-(methoxycarbonyl)phenoxy)methyl)piperidine-1-carboxylate (1.01 g, 2.86 mmol) in anhydrous THF (7 mL) was added to the reaction mixture and the resulting mixture was stirred at −78° C. for 10 min, then warmed to room temperature over 30 mins. The reaction mixture was quenched with 5% aqueous NaHSO4 and extracted twice with tert-butyl methyl ether. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (20%-80% EtOAc-hexanes gradient) gave tert-butyl 4-((3-(2-cyanoacetyl)phenoxy)methyl)piperidine-1-carboxylate as a white solid. Yield (0.55 g, 54%); 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.51 (m, 3H), 7.23-7.28 (m, 1H), 4.73 (s, 2H), 3.84-4.00 (m, 2H), 3.90 (d, J=6.26 Hz, 2H), 2.60-2.80 (m, 2H), 1.86-1.97 (m, 1H), 1.70-1.78 (m, 2H), 1.38 (s, 9H), 1.08-1.23 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([OH:14])[CH3:13].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)ccc1Br
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.9 %

Procedure:
To a solution of compound 1-(2-bromo-5-(trifluoromethyl)phenyl)ethanol (10.4 g, 44.6 mmol) in the dimethylsulfoxide (50 mL), 2-iodoxybenzoic acid (25 g, 89.2 mmol) at 0° C. The reaction was warmed to 25° C. and stirred at this temperature for 2 hours under a nitrogen atmosphere. Then the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (2×500 mL). Organic part was dried over sodium sulfate, filtered and concentrated under a vacuum to give the crude compound 1-(2-bromo-5-(trifluoromethyl)phenyl)ethanone (15 g), as a brown liquid. 1H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([CH2:49][CH3:50])[CH2:47][NH2:48]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:48][CH2:47][CH:46]([CH3:45])[CH2:49][CH3:50])=[O:22])=[CH:16][CH:15]=1
Reactant: CCC(C)CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC(C)CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-methylbutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-N-(2-methylbutyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH2:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:33]([CH3:37])[C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[CH2:28][O:29][CH2:30][CH2:31][OH:32].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH:16][C:34](=[O:35])[CH:33]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][O:29][CH2:30][CH2:31][OH:32])=[C:22]([F:21])[CH:23]=3)[CH3:37])=[CH:13][C:12]([C:17]([F:18])([F:20])[F:19])=[N:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1)c1ccc(COCCO)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (16 mg, 0.050 mmol, 1.0 eq) in THF/DMF (1/20, v/v, 0.5 mL) was added 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (11 mg, 0.050 mmol, 1 equiv.), HOBt (7 mg. 0.05 mmol, 1 equiv.), TBTU (16 mg, 0.050 mmo, 1 equiv.) and DIPEA (0.033 mL, 25 mg, 0.20 mmol, 4 equiv.) and the mixture was stirred for at room temperature overnight. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:1) as eluent) to give N-((1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanamide (23 mg, 92 N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:36]1[S:37][C:38]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[C:39]=2[N:40]=1.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.O.C(Cl)Cl.C(OCC)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>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:36]4[S:37][C:38]5[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[C:39]=5[N:40]=4)[C:22]([NH2:34])=[N:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: FC(F)(F)c1cccc2sc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (75 mg, 0.16 mmol), 2-chloro-4-trifluoromethyl-1,3-benzothiazole (46 mg, 0.19 mmol), potassium carbonate (66 mg, 0.48 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) in DME (3 mL) and H2O (1 mL) was evacuated and refilled with N2 (3×), then it was heated at 100° C. for 30 min in the microwave reactor. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give a yellow solid. This material was dissolved in DCM (2 mL) and treated with 1M HCl in diethyl ether (3 mL). The resulting mixture was stirred at room temperature overnight. The title compound was collected by filtration as a yellow solid and washed with DCM. MS (ES+): m/z=445.10 [MH+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[C:34]([OH:39])=[N:35][O:36][C:37]=1[CH3:38].O[CH:41]1[CH:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1>O1CCCC1>[Cl:32][C:33]1[C:34]([O:39][CH:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[N:35][O:36][C:37]=1[CH3:38]
Reactant: OC1CN2CCC1CC2
Reactant: Cc1onc(O)c1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(OC2CN3CCC2CC3)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A solution of 7.86 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5° C., and then 5.22 g of diethyl azodicarboxylate were added dropwise to the cooled solution, followed by 4.00 g of 4-chloro-3-hydroxy-5-methylisoxazole. 3.81 g of 3-hydroxyquinuclidine were then added to the resulting mixture, and the mixture was stirred at room temperature for 24 hours. At the end of this time, the solvent was removed from the mixture by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to afford 4.72 g (yield 64.8%) of the title compound as a colorless powder, melting at 37°-38° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32](Cl)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate (500 mg), cyclopropylboronic acid (188 mg), potassium phosphate (1.12 g) in toluene (6.2 mL) and water (0.31 mL) was purge with nitrogen. Tricyclohexylphosphine tetrafluoroborate (79 mg) and palladium acetate (24 mg) were added. The mixture was heated at 90° C. for 16 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated. The residue was purified with flash chromatography (0-30% EtOAc/heptane) to give the product (276 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([N:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:13]=2[CH:12]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH:12]1[C:13]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:14]=2[CH2:15][CH2:16][CH2:17][N:11]1[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid methyl ester (1.17 g, 2.31 mmol), in MeOH (9 ml) and dioxane (12 ml), was added dropwise aqueous NaOH 2N (11 ml, 22 mmol). The resulting yellow homogeneous mixture was then stirred at 45° C. for 8 h. The reaction mixture was then concentrated in vacuo and washed with Et2O (5 ml). The aqueous phase was acidified (pH=1) with HCl 2N and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled carboxylic acid (1.14 g, 2.31 mmol, 100%) as a beige solid (mixture of diastereoisomers).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[Br:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:27][CH2:26][CH2:25][Br:24])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: BrCCCBr
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Yield: 98 %

Procedure:
A mixture of 6.0 g of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 19 ml of 1,3-dibromopropane and 2.0 g of anhydrous potassium carbonate in 175 ml of anhydrous acetone was stirred at reflux for 52 hours. The reaction mixture was concentrated in vacuo to give 8.1 g (98% yield) of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23](Cl)[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:30][CH2:31][CH3:32].[Na+]>C(O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([O:30][CH2:31][CH3:32])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)cccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A solution of Intermediate 25 (230 mg) obtained in Example 36-1 in ethanol (10 ml) was added with sodium ethoxide (204 mg, Aldrich), and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added with saturated brine (10 ml), and extracted three times with ethyl acetate (10 ml for each time), and the combined organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (223 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[CH2:32][CH2:33][CH3:34])[CH:28]=[N:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:35]>CC(O)C>[ClH:35].[NH:15]1[CH2:16][CH2:17][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[CH2:32][CH2:33][CH3:34])[CH:28]=[N:27][CH:26]=[CH:25]3)[CH2:19][CH2:20]1
Reactant: CCCc1cc2cnccc2cc1SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCCc1cc2cnccc2cc1SC1CCNCC1

Procedure:
85 mg (107 mmol) 4-(7-Propyl-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester trifluoroacetate (276) were stirred in 6N HCl in iPrOH for 1 h at RT. After evaporation water was added and lyophilized. 42 mg of 6-(Piperidin-4-ylsulfanyl)-7-propyl-isoquinoline hydrochloride were obtained. Rt=0.94 min (Method B). Detected mass: 287.1 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:16]Br>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: COC(CBr)(CBr)OC
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CC(C#N)(c2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.2 %

Procedure:
To a solution of NaH (1.302 g, 32.6 mmol, 60 wt % in mineral oil) in dry DMF (10 mL) cooled to 0° C., was added dropwise a solution 2-(4-fluorophenyl)acetonitrile (2.0 g, 14.8 mmol) in DMF (10 mL) To the stirred suspension at 0° C. was then added 1,3-dibromo-2,2-dimethoxypropane (3.88 g, 14.80 mmol). The reaction mixture was then heated to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude compound was purified by silica gel chromatography (24 g REDISEP® column, eluting with 20% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 308A as a yellow liquid (1.4 g, 40%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz, 2H), 3.28 (s, 3H), 3.05-3.19 (m, 5H), 2.64-2.72 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1.C=O.[BH3-][C:31]#N.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH3:31])[CH3:27])[CH2:24][CH2:25]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1
Reactant: [BH3-]C#N
Reactant: CNC1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of tert-butyl N-(4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)-N-methylcarbamate (60 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrochloric acid (1 mL, 12 M) at 0° C. and stirred for 1 h at room temperature. The pH value of the solution was adjusted to 9 with sodium carbonate (sat.) and extracted with 3×20 mL of dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 40 mg (84%) of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine as colorless oil which was used directly for next step. To a solution of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine (40 mg, 0.11 mmol, 1.00 equiv) in methanol (2 mL) was added HCHO (37%, 0.07 mL, 1.06 mmol) and stirred for 1 h at room temperature. Then NaBH3CN (20 mg, 0.32 mmol, 3.01 equiv) was added and stirred for addional 1 h at room temperature. The reaction was then quenched by the addition of 20 mL of NH4Cl (sat.) and extracted with 3×20 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (60 mg) was re-crystallized from ethyl acetate to give 15 mg (36%) of pure 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES, m/z): 394 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.08 (s, 1H), 7.68-7.65 (d, 1H), 7.56-7.54 (d, 1H), 7.38-7.25 (m, 3H), 5.45-5.42 (m; 1H), 3.33 (s, 1H), 2.90 (s, 6H), 2.53-2.50 (d, 2H), 2.23-2.20 (d, 2H), 1.82-1.66 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)[CH3:15])[C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: C[C@@H](Oc1nc(Cl)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cn3ncc(C#N)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Crude intermediate 5.65 from the previous step, (3,4-dimethoxyphenyl)boronic acid (34 mg, 0.19 mmol), K3PO4 (79 mg, 0.37 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.3 mg, 0.005 mmol) were taken up in 1,4-dioxane (1.35 mL) and water (0.14 mL) under Ar. The stirred reaction mixture was heated to 100° C. After stirring 16 h, the reaction mixture was partitioned between EtOAc, water, and brine and the resulting emulsion was filtered through a pad of Celite. The Celite was washed with DCM to elute all product and the resulting filtrate was concentrated in vacuo. The concentrate was purified by silica gel chromatography (0-20% MeOH in DCM) to provide 6-(3,4-dimethoxyphenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile 5.66. LCMS-ESI+ (m/z): [M+H]+ calcd for C21H22N5O4: 408.2; found: 407.9. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.68 (s, 1H), 7.70 (dd, J=8.4, 2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.55 (s, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.56-5.45 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.41-3.33 (m, 1H), 3.25-3.15 (m, 1H), 2.93-2.81 (m, 1H), 2.35-2.27 (m, 2H), 1.46 (d, J=6.2 Hz, 3H).
Reaction SMILES: ClC1C=CC(COC2C=CC(N)=CC=2)=CN=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[N:32][CH:33]=1>>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:32][CH:33]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Nc1ccc(OCc2ccc(Cl)nc2)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Br)cn2)cc1

Procedure:
The substituted aniline compounds of formula (I) wherein W is oxygen can be prepared by the reaction of nitrophenol with a substituted pyridylalkyl halide to obtain the corresponding substituted nitrobenzene which is reduced to the desired substituted aniline of formula (I). For example, the reaction of 4-nitrophenol and 6-chloro-3-pyridylmethyl bromide gives 4-(2-chloro-5-pyridylmethyloxy)nitrobenzene which is then reduced to 4-(2-chloro-5-pyridylmethyloxy)aniline of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitrobenzene with a substituted pyridylalkyl alcohol or substituted pyridylalkyl thiol followed by reduction of the nitro group. For example, the reaction of 4-fluoronitrobenzene and 5-bromo-2-pyridine methanol gives 4-(5-bromo-2-pyridylmethyloxy)nitrobenzene which is then reduced using, for example, iron powder to give 4-(5-bromo-2-pyridylmethyloxy)aniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:27](=[O:29])[CH3:28])[CH:15]2[CH2:16][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.2 mmol) in DCM (22 mL) was added DIEA (0.8 mL, 4.6 mmol) and acetic anhydride (0.42 mL, 4.4 mmol). The mixture was stirred (rt, 16 h). After washing the solution with 1 N NaOH and brine, the organic layer was dried and concentrated to an orange oil (1.15 g, 98%). MS (ESI): mass calcd. for C15H26N2O3, 282.19; m/z found, 283.2 [M+H]+.