Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(#N)C>[C:8]([N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]cn1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing 1 g (10.4 mmol) of 1H-imidazole-4-carbaldehyde and 3.18 g (11.4 mmol) of trityl chloride suspended in 28 ml of acetonitrile are added dropwise 2.5 ml (17.7 mmol) of triethylamine. After stirring for 2 hours at room temperature, 30 ml of water are added and the crude reaction product is filtered. 3.2 g in the form of a beige-coloured powder are obtained and used in the following step without further purification.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.CN.C(Cl)C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:6]([NH:3][CH3:4])[CH:7]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: ClCC=Cc1ccccc1
Agent: CN
Solvent: CO
Product: CNCC=Cc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Triethylamine (0.66 g; 6.55 mmol) was added to 40% solution of methylamine in methanol (20 ml). While the mixture was stirred at room temperature, cinnamyl chloride (1.00 g; 6.55 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 20 hours at room temperature, and excess methylamine and methanol were removed under reduced pressure. The residue was taken up in a mixture of diethyl ether and 2N hydrochloric acid (100 ml-100 ml), and the aqueous layer was neutralized with aqueous sodium hydroxide solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 0.80 g of the target compound as yellow oily matter (yield: 83.0%).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrC1N2N=C(N)N=C2C=CC=1.IC1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3[O:61][C:60]4[C:55](=[CH:56][CH:57]=[CH:58][C:59]=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O.[Cl-].[Na+].O>O1CCOCC1>[C:12]1([NH:11][C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:58]4[CH:59]=[C:60]([OH:61])[CH:55]=[CH:56][CH:57]=4)[N:7]3[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc2nc(Nc3ccccc3)nn12
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CC(C)(C)[O-]
Agent: Nc1nc2cccc(Br)n2n1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: Ic1ccccc1
Solvent: O
Product: Oc1cccc(-c2cccc3nc(Nc4ccccc4)nn23)c1
Temperature: 100 °C
Yield: 48 %

Procedure:
5-Bromo-N-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. To a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2 g, 9.39 mmol) in 100 mL of dioxane was added iodobenzene (3.83 g, 18.78 mmol), sodium tert-butoxide (1.804 g, 18.78 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.086 g, 1.878 mmol) and tris(dibezylideneacetone)palladium (0.903 g, 0.986 mmol) at room temperature under nitrogen. The reaction mixture was heated at 100° C. for 2 h. Upon completion of the reaction, as indicated by LCMS, the reaction mixture was poured into water/brine, and extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by silica gel column chromatography (eluting with 0-80% ethyl acetate in hexanes) to give the title compound as a brown solid (1.3 g, 48% yield). 1H NMR (400 MHz DMSO-d6) δ (ppm) 9.84 (s, 1H), 7.74-7.71 (m, 2H), 7.62-7.60 (m, 1H), 7.52-7.48 (m, 1H), 7.40-7.38 (m, 1H), 7.32-7.28 (m, 2H), 6.92-6.88 (m, 1H); MS (ESI) m/z 290.13 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10]CC2C=CC=CC=2)[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]>O1CCCC1.ClC1C=CC=CC=1Cl.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COc1c(OCc2ccccc2)cc(Cl)c(Nc2ccccc2CC(=O)O)c1Cl
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: COc1c(O)cc(Cl)c(Nc2ccccc2CC(=O)O)c1Cl

Procedure:
The 2-[(2,6-dichloro-3-methoxy-4-benzyloxyphenyl)amino]phenylacetic acid (10 g) from example 37 was hydrogenated with Pd-C (1 g, 5%) in tetrahydrofuran (100 ml) and 1,2-dichlorobenzene (10 ml) at normal pressure for 25 min at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to leave the final product 2-[(2,6-dichloro-3-methoxy-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[F:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1[OH:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29](F)[CH:30]=1)[C:26]#[N:27].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C.O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:21][C:14]2[C:15]([F:20])=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[F:12])[CH:30]=1)[C:26]#[N:27]
Reactant: Cc1ccc(F)c(O)c1F
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 135 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
A 1M solution KOtBu in THF (4.41 mL, 4.41 mmol) was added to a solution of 2,6-difluoro-3-methylphenol (3 g, 20.82 mmol) in DMSO (10 mL) at 0° C. under an atmosphere of nitrogen. After 10 min, 3-chloro-5-fluorobenzonitrile (3.24 g, 20.82 mmol) and 18-CROWN-6 (0.550 g, 2.082 mmol) were added and the solution was heated to 135° C. After 6 h, the brown solution was cooled to RT and water (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated, washed with water (2×150 mL), brine (150 mL), dried over MgSO4, filtered and concentrated. The residue was purfied on silica gel (hexanes/ethyl acetate) to give the title compound (4.05 g, 70%) as a white solid (N4011-11-100). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.36 (t, 1H), 7.20 (t, 1H), 7.05-7.14 (m, 2H), 6.93-7.00 (m, 1H), 2.31 (s, 3H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7]1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:8]3[CH2:9][CH:6]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:7]3)[S:11][C:12]=2[CH:18]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OC1CN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2nc(N3CC(N4CCCCC4)C3)sc2c1
Temperature: 92.5 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-yl methanesulfonate (Reference Example 12b, 61.7 mg, 0.17 mmol), piperidine (0.250 mL, 2.5 mmol), and potassium carbonate (0.062 g, 0.44 mmol) in N,N-dimethylformamide (1 mL) was stirred at 90-95° C. for two days. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (2×4 mL). The combined organic extracts were washed with water (2×5 mL), then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (90:10:0 to 88:10:2 dichloromethane/ethyl acetate/methanol). A second column was run with the same eluent gradient. Fractions containing product were combined and concentrated under reduced pressure to give 6-bromo-2-(3-(piperidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.58 (m, 2H), 1.64 (pentet, J=5 Hz, 1H), 2.35-2.45 (m, 4H), 3.36-3.46 (m, 1H), 4.02-4.08 (m, 2H), 4.24 (t, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.42 (dd, J=2, 8 Hz, 1H), 7.83 (d, J=2 Hz, 1H); MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:15][CH3:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1cc2ccc(Br)cc2cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CNc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol), methylamine hydrochloride (139 mg, 2.06 mmol), and potassium carbonate (456 mg, 3.30 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) was heated to 150° C. and stirred for 60 hours. Additional methylamine hydrochloride (100 mg, 1.5 mmol) and potassium carbonate (200 mg, 1.4 mmol) were added and heating was continued for another 40 hours. The reaction was cooled to room temperature and diluted with water. The mixture was stirred for 30 minutes. The resulting solid was filtered off, rinsed with water and dried under vacuum. Purification by flash column chromatography (10-30% ethyl acetate/heptanes) gave the title compound (82 mg) as a pale yellow solid. −APCI (M−H+1) 237.8; 1H NMR (400 MHz, CDCl3, δ): 8.70 (s, 1H), 7.84 (d, J=1.95 Hz, 1H), 7.48 (dd, J=8.97, 2.15 Hz, 1H), 7.38 (d, J=8.97 Hz, 1H), 6.39 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCN(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.95 mL bromacetylbromide was dropped to 11.68 mL 1-pyridin-2-yl-piperazine and 11.23 mL triethylamine in 300 mL DCM at 0° C. The reaction was stirred 2 h at 0° C. The reaction mixture was added to water and extracted with DCM. The organic layer was dried with magesium sulfate and evaporated The residue was purified by chromatography on silica gel (DCM/MeOH 0-20%; 0.1% ammonia) to yield 23.6 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:34])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH3:32])[N:15]=3)[C@H:10]([CH3:33])[CH2:9]2)=[N:6][CH:7]=1.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[C:4]([CH3:34])=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=4)[CH2:9][C@H:10]3[CH3:33])[CH:19]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg, 1.33 mmol) and Zn(CN)2 (94 mg, 0.799 mmol) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:35][C:36]([F:40])([F:39])[CH2:37][OH:38]>>[CH2:37]([OH:38])[C:36]([F:40])([F:39])[F:35].[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:32][CH2:33][CH2:34]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Solvent: OCC(F)(F)F
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 2,2,2,-trifluoroethanol (CAS Reg. No. 75-89-8 99) to give the title compound as colorless solid. MS (ESI): m/z=586.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
88 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-phenylpiperazine (0.039 mL, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]([NH2:24])=[O:23])[CH:17]=[CH:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1>[Pd].CO>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[CH:17]=[CH:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)/C=C/c1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CCc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Reaction time: 23 h
Yield: 21.7 %

Procedure:
A mixture of (E)-3-{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-acrylamide (111 mg, 0.27 mmol) and 10% palladium on carbon (14 mg) in MeOH (10 mL) was stirred under a hydrogen atmosphere for 23 h, additional palladium on carbon (14 mg) was added and the reaction was stirred under a hydrogen atmosphere for 6 h. The resulting mixture was filtered. The resulting solution was concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8 min., gradient to 95% CH2Cl2: 5% MeOH over 5 min.; 95% CH2Cl2: 5% MeOH for 4 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 6.2 min.) to give 3-{2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yl}-propionamide (24 mg, 17%):
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:26]([NH2:27])=[N:25][NH:24][C:21]2=[N:22][CH:23]=1>CN1C(=O)CCC1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]([NH:27][C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([F:17])[CH:19]=3)[NH:24][N:25]=2)[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1nc(-c2ccccc2Cl)nc(Cl)c1C
Reactant: Nc1n[nH]c2ncc(F)cc12
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2ccccc2Cl)nc(Nc2n[nH]c3ncc(F)cc23)c1C
Temperature: 135 °C

Procedure:
A mixture of 4-chloro-2-(2-chlorophenyl)-5,6-dimethylpyrimidine (31.14 g, 123 mmol) and 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (19.65 g, 129 mmol) in NMP (200 mL) was heated at 135° C. for 3 h 30 min. Then the mixture was concentrated in vacuo to around 100 mL. Then added sat aq. NaHCO3, water and EtOAc but a precipitate appeared in the organic layer. Filtered off this whole mixture and washed the residue with sat aq. NaHCO3, water and EtOAc and ether. Boiling ethanol was added to the residue with stirring and the pure target compound was filtered. The liquors were concentrated and this trituration procedure repeated 4 times to give the target (25 g, 55%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:19]([O:21]C)=[O:20])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:19]([OH:21])=[O:20])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2oc(=O)cc(-c3ccc(F)cc3)c2cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1C(=O)O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylate (0.722 g, 2.31 mmol) in THF (23 mL) was added a 1 N solution of LiOH (11.6 mL, 11.6 mmol), and the mixture was heated at 65° C. for 16 h. At room temperature, the mixture was neutralized with 1 N HCl and concentrated. The residue was stirred with THF (25 mL) and 2 N HCl (50 mL) for 16 h. The precipitate produced was collected by filtration, rinsed with water and dried, affording the title compound that was used without further purification. 1H NMR (500 MHz, DMSO-d6): δ 13.40 (br s, 1H), 7.80 (s, 1H), 7.64 (m, 2H), 7.44 (m, 2H), 7.32 (s, 1H), 6.54 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:10][CH:11]=1)=[O:16]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1ccc(OCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
4-(4-Formylphenoxy)butyric acid ethyl ester (19.6 g, 75 mmol) was dissolved in methanol (250 mL) and 1N sodium hydroxide (100 mL) was added and the resulting mixture was stirred at room temperature for 16 hours. The organic solvent was evaporated in vacuo (40° C., 120 mBar) and the residue was acidified with 1N hydrochloric acid (110 mL). The mixture was filtered and washed with water and dried in vacuo to afford 14.3 g (91%) 4-(4-formylphenoxy)butyric acid as a solid. 1H-NMR (DMSO-d6): δ 1.99 (2H, p), 2.42 (2H, t), 4.13 (2H, t), 7.14 (2H, d), 7.88 (2H, d), 9.90 (1H, s), 12.2 (1H, bs). HPLC-MS (Method A): m/z=209 (M+1); Rt=2.19 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)=[CH:4][C:3]=1[O:45][CH3:46].FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)=[CH:4][C:3]=1[O:45][CH3:46]
Reactant: COc1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)ccc1O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)ccc1O
Yield: 45.3 %

Procedure:
(S)-2-(1-((5-(4-Hydroxy-3-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.10 mmol) was treated with trifluoroacetic acid (1.26 ml, 16.36 mmol) and a solution of ammonia (7N in methanol, 1.26 ml, 8.82 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 6% n-hexane-ethyl acetate) to obtain 23 mg (46% yield) of the title compound.
Reaction SMILES: [C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([O:20]CC)=[O:19])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CSc1nnnn1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio)acetate (269 mg, 0.86 mmol), aqueous sodium hydroxide solution (10%, 5 mL) and methanol (10 mL) was stirred at reflux for 2 hours. The reaction was then cooled to room temperature and the methanol removed. Water was added, neutralized with aqueous HCl solution (1N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded compound 2-(1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio)acetic acid as a solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][CH:47]([CH2:50][CH3:51])[CH:48]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]([CH3:48])[CH2:50][CH3:51])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)C=O
Product: CCC(C)CN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3piperidylmethyl)pyrrolidine-2-carboxamide and 2-methylbutanal. The compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH2:20][CH2:21][OH:22]>C(O)C.C1C=CC=CC=1>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:20][CH2:21][OH:22])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O

Procedure:
Using the equipment described in Example I, 2,6-ditertiary butyl-4-mercaptophenol (50 grams) was dissolved in 90 millimeters of ethanol (denatured alcohol) and 30 millimeters of benzene. A solution of 12 grams of KOH in 60 millimeters of ethanol was added under a nitrogen blanket. 2-Chloroethanol (19 grams) was slowly added dropwise at room temperature. The combination was reacted for three hours and then diluted with benzene and washed with water. The volatiles were then stripped off.