Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[Br-].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:60](Br)(Br)([Br:62])[Br:61].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:60]([Br:62])[Br:61])[CH:15]=[N:14]1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: BrC(Br)(Br)Br
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)c(-n2ncc(C=C(Br)Br)n2)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (3.1 g), in dichloromethane (20 ml) was added to a solution of triphenylphosphonium dibromide at -20° (prepared by mixing a solution of carbon tetrabromide (31.2 g) in dichloromethane (30 ml) with a solution of triphenylphosphine (21 g) in dichloromethane (70 ml)) and the mixture stirred for 1 hour. Hexane was added and the mixture filtered. The filtrate was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,2-dibromo-vinyl)-2H-1,2,3-triazole. 89°-91° . (Compound 24)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridine-2(1H)-one (200 mg, 0.63 mmol) in DMSO (5 mL) was added Cs2CO3 (1.03 g, 3.15 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (0.15 mL, 0.66 mmol). After stirring overnight at ambient temperature under argon, the reaction mixture was filtered through a layer of Celite and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one (90 mg, 29%). To a solution of 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one in THF (3 mL) was added TBAF (0.75 mL, 0.75 mmol, 1.0 M). After the reaction was complete, the mixture was treated with H2O, extracted with CH2Cl2, and the combined organics were concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-hydroxypropyl)-1H-indazol-5-yl)pyridin-2(1H)-one (50 mg, 88%) as a white solid. In accordance with the procedure of Example 1, the HCl salt was made to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.33 (dd, J=9.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.50 (t, J=7.0 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.01-1.96 (m, 2H); ESI MS m/z 376 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([O:28][C:26]1[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (30 mg, 67 μmol) in N,N-dimethylformamide (0.5 mL) is added pyridine (12 μL, 0.17 mmol) and acetyl chloride (10 μL). The reaction mixture is shaken overnight at room temperature and then purified by reverse-phase high performance liquid chromatography to give 6-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2,2-dimethyl-1,3-benzodioxol-4-yl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[C:4]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.[H-].[Na+].Br[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1>CN(C=O)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:4]2[C:5]3[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=3[N:15]=[C:2]([NH:1][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)[C:3]=2[C:28]#[N:29])[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=1)[CH3:27]
Reactant: CCOc1cc(OCC)cc(-c2c(C#N)c(N)nc3c2c(=O)n(C)c(=O)n3C)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)cc(-c2c(C#N)c(NCc3ccc4ccccc4c3)nc3c2c(=O)n(C)c(=O)n3C)c1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 56d (100 mg, 0.25 mmol) in DMF (3 mL) was treated with 60% NaH (12 mg, 0.3 mmol). After the mixture was vigorously stirred for 30 min, a solution of 2-(bromomethyl)naphthalene (55 mg, 0.25 mmol) was added. The mixture was stirred at rt for 20 min, and 50° C. for 2 h. After which the solution was suspended in 200 mL of EtoAce and was washed with brine, 3×200 mL. The organic layer was dried over Na2SO4 and evaporated in vacuuo. The residue was purified by prep HPLC to give 5-(3,5-diethoxyphenyl)-1,3-dimethyl-7-(naphthalene-2-ylmethylamino)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (56e, 87 mg). MS [m+H] calc'd for C31H29N5O4, 536.22; found 536.22
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:18](C1C=CC=CC=1)(=[O:25])[C:19]1C=CC=C[CH:20]=1.C(Cl)(=O)C=C>O>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:25])[CH:19]=[CH2:20]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 g quantity of 4-hydroxybenzophenone was added to 500 ml of water containing 22.0 g of sodium hydroxide. The solution was stirred until all of the benzophenone had dissolved. After the solution had cooled to 5°-10° C., there was added 45.5 g of acrylyl chloride over a period of 30 minutes, to yield a white solid which was recovered by filtration after the solution had been stirred for 2 hours at 5°-10° C. and an additional hour at room temperature. The white solid was recrystallized from ethanol and found to have m.p. 44°-46° C. Infrared and NMR spectra confirmed the structure of 4-acryloxybenzophenone.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Reactant: CCC(C)c1ccc(N)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(NC(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution of N-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) in chlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenyl amine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butyl aniline and 1.0 M HCl-ether) was added and continued reflux. After 2 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.45 g, 65%) as a syrup. TLC: Rf=0.22 (CH2Cl2:CH3OH; 10:1); 1H NMR (CD3OD): δ 7.27 (d, 4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, —NCH3), 2.69-2.58 (m, 2H, 2×—CH), 1.68-1.57 (m, 4H, 2×—CH2)1, 1.25 (d, 6H, 2×—CH3), 0.85 (t, 6H, 2×—CH3); HRMS: 337.2484 (337.2528 Calcd. for C22H31N3); HPLC: (CH3CN:H2O; 50:50 with 0.1% TFA): 98% pure.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:8]=[N:9][C:10]([NH:15][CH3:16])=[N:11][C:12]=2[CH2:13][CH2:14]/1)[CH3:3].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2C(N)=[CH:28][CH:27]=[N:26]2)=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:12]5[N:11]=[C:10]([NH:15][CH3:16])[N:9]=[CH:8][C:7]=5[C:6]=4[C:28]=3[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CNc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Solvent: CC(C)O
Product: CNc1ncc2c(n1)CCc1cnc3c(cnn3Cc3ccc(OC)cc3)c1-2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a mixture of (E)-6-((dimethylamino)methylene)-2-(methylamino)-7,8-dihydroquinazolin-5(6H)-one (2.8 g, 12 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2.69 g, 13 mmol) was added trifluoroacetic (1 mL). The reaction mixture was heated at 100° C. for 16 hours. The reaction was then cooled to room temperature followed by addition of isopropanol (20 mL). The reaction mixture was the stirred for 30 minutes and the supernatant decanted. The residue was dried under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 100 hexanes to 15% EtOAc in hexanes) to give desired product (1.0 g, 22%) as solid. 1H NMR (CDCl3, 400 MHz): δ 9.32 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.52-5.48 (m, 1H), 5.62 (s, 2H), 3.76 (s, 3H), 3.18-3.04 (m, 5H), 3.0-2.88 (m, 2H); LCMS [M+H]: 373.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:21]=O)=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>N1CCCCC1.C(O)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:19]1[NH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([C:9](=[O:10])[CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]=3[CH:20]=1)/[C:34](=[O:40])[NH:35]2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Reactant: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(-c3c(F)cccc3F)c2/C1=C/c1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Yield: 60.3 %

Procedure:
4-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (80 mg, 0.26 mmol) was condensed with 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (61 mg, 0.25 mmol) and piperidine (1 drop) in ethanol (3 mL) at rt for over the weekend. The precipitate was filtered, washed with ethanol and dried to give 80 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCc2ccccc2)nn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)nn2)cc1

Procedure:
3-Benzyloxy-6-chloropyridazine (411 mg, 1.86 mmol) was reacted with N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide in analogy to example 1b.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[B:19]1(B2OCC(C)(C)CO2)[O:24]CC(C)(C)C[O:20]1.C([O-])(=O)C.[K+]>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]2)=[CH:3][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(I)c2)C1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(B(O)O)c2)C1
Temperature: 80 °C

Procedure:
A mixture of methyl trans-3-(3-iodo-4-methoxyphenyl)cyclopentanecarboxylate (Step C) (64 mg, 0.178 mmol), bis(neopentyl glycolato)diboron (48.2 mg, 0.213 mmol), potassium acetate (100 mg, 1.019 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.012 mmol) in DMSO (3 ml) was degassed flushing with nitrogen and heated at 80° C. for 1 hour. Then, added ethyl acetate and washed with water followed by brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J=2.5 Hz, 1H); 7.29 (m, 1H); 6.85 (m, 1H); 6.10 (s, 2H); 3.90 (s, 3H); 3.70 (s, 3H); 3.19 (m, 1H); 3.02 (m, 1H); 2.35 (ddd, J=13.3, 8.0, 4.6 Hz, 1H); 2.19-2.11 (m, 2H); 2.01-1.85 (m, 2H); 1.72-1.63 (m, 1H).
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:18]([F:21])([F:20])[F:19])[O:11][C:10]2[CH:12]=[CH:13][C:14](C=O)=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][CH:2]([C:7]1([C:18]([F:21])([F:19])[F:20])[O:11][C:10]2[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:9]=2[O:8]1)[C:3]([F:4])([F:5])[F:6]
Reactant: O=Cc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
50 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-(trifluoromethyl)-5-formyl-1,3-benzodioxole were dissolved 500 ml of methylene chloride, and 53 g of 70% strength by weight m-chloroperbenzoic acid were added. The mixture was stirred under reflux for 6 hours. It was then cooled, and the precipitate which had separated out was filtered off. The filtrate was washed with 5% strength by weight aqueous sodium hydrogen sulphide solution and with saturated aqueous sodiumbicarbonate solution and concentrated on a rotary evaporator. The residue which remained was dissolved in 300 ml of diethyl ether, and 100 ml of 1N sodium hydroxide solution were added at room temperature. When the reaction had ended, the phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried with magnesium sulphate and subjected to fractional distillation in vacuo. The yield was 26 g (=54% of theory), and the boiling point was 95° C. under 0.07 mbar. 19F-NMR: -68.6 and -81.6 ppm. 1H-NMR: 4.70 ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[O:29]
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCOCC(N)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC(NC(=O)CCCCBr)C1
Reaction time: 1 h

Procedure:
To an ice bath stirring solution of tert-butyl 6-amino-1,4-oxazepane-4-carboxylate 38.4 (1.01 g, 4.67 mmol) and Et3N (1.95 mL, 14.0 mmol) was added 5-bromo-pentanoyl chloride (0.62 mL, 4.7 mmol). The ice bath was removed and the solution was stirring for 1 h and then diluted with water and extracted with DCM. The organic phase was washed with diluted citric acid, water, sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford an oil which was purification by flash column chromatography (gradient EtOAc/hexanes). LCMS m/z 324.1 & 325.1 [M-tBu]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:4]2[CH:3]=1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.61 g, 2.0 mmol) in N,N-dimethylformamide was added cyclopentyl guanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrous potassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heated at 80° C. for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from acetonitrile, 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.6 g, 74%) as a white solid. 1H-NMR (CDCl3): δ8.54 (broad s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28 (d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4-2.2 (m, 8H); 19F-NMR (CDCl3): δ−112.5; MS m/z 408 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].O.[CH3:20]N(C=O)C>>[CH3:20][O:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCC1CCNCC1

Procedure:
To a solution of 825 mg (3.6 mmol) of 1-t-butoxycarbonyl-4-hydroxyethylpiperidine in 2.5 mL of DMF was added 0.21 g (7.2 mmol) of NaH (80% dispersion in mineral oil) in 3 portions over a period of 30 min. After 16 h 10 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][CH:48]=1)[CH2:18][N:19]1[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[C:43]([OH:45])=[O:44]>>[CH3:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]3[N:21]=[C:20]([C@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]4[C:43]([OH:45])=[O:44])[N:19]([CH2:18][C:17]4[CH:46]=[C:47]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=5)[CH:48]=[CH:15][CH:16]=4)[C:23]=3[CH:24]=2)=[N:31][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4cccc(Br)c4)c3c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4cccc(-c5ccc(C(F)(F)F)cc5)c4)c3c2)nc1

Procedure:
The title compound was prepared using similar methods to those in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and racemic cis-2-{1-(3-bromobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid. MS (ESI): mass calcd. for C35H32F3N3O3, 599.24; m/z found, 600.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (dd, J=8.1, 2.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.35 (d, J=8.0 Hz, 1H), 7.04 (dd, J=8.8, 2.3 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 5.36 (s, 2H), 5.14 (s, 2H), 3.25-3.09 (m, 1H), 3.09-2.97 (m, 1H), 2.65-2.53 (m, 1H), 2.28 (s, 3H), 1.87-1.71 (m, 3H), 1.70-1.58 (m, 2H), 1.51-1.31 (m, 2H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30](O)=[O:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH2:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:44]2)=[C:36]2[S:42][CH:41]=[CH:40][C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([NH:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])[CH2:44]2)=[C:36]2[S:42][CH:41]=[CH:40][C:37]2=[N:38][CH:39]=1)=[O:31])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccsc23)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (76.1 mg, 0.570 mmol) in THF (1.0 mL) was added slowly to a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6, 76.1 mg, 0.214 mmol) in THF (0.5 mL). The mixture was stirred at room temperature for 5 h. A solution of tert-butyl [(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (62.3 mg, 0.179 mmol) in THF (2.0 mL) was then added, followed by pyridine (135.3 mg, 1.710 mmol), and the mixture was stirred at room temperature for a further 2 h. The mixture was then concentrated under reduced pressure and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a dark semi-solid (78.5 mg, 64%). LCMS calc. for C32H37F2N6O5S2 (M+H)+: m/z=687.2. found 687.2.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[CH3:21]O>O.Cl>[CH3:21][O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:5])[OH:6])[NH2:1]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The α-L-aspartyl-L-phenylalanine (20 g, 0.071 mole) is dissolved in the mixture of water (12.2 ml) and methanol (9.5 ml) and concentrated hydrogen chloride (26 ml) is added while stirring for 48 hours at room temperature to obtain as a precipitate the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester (20.3 g, 0.055 mole). After filtration, the cake of precipitate is dissolved in 355 ml of water. Then, the mixture is adjusted to a pH of 4.8 with 50% caustic solution (3.8 ml) and kept overnight at 5° C. to obtain a precipitate and separated by filtration. The filtered precipitate is washed with water (13 ml) at 5° C. and dried to obtain α-L-aspartyl-L-phenylalanine methyl ester (12.4 g, 0.042 mole).