Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH3:28])=[C:17]([O:21][C:22]4[CH:23]=[N:24][CH:25]=[N:26][CH:27]=4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([O:31]CC)=[O:30])=[N:10][CH:9]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH3:28])=[C:17]([O:21][C:22]4[CH:27]=[N:26][CH:25]=[N:24][CH:23]=4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([OH:31])=[O:30])=[N:10][CH:9]=1
Reactant: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C)c(Oc3cncnc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2[nH]c3c(C(=O)O)ncc(-c4ccccc4F)c3c2cc1Oc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of ethyl 4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.08 g, 0.181 mmol) and 1N aqueous NaOH (0.814 mL, 0.814 mmol) in methanol (3.01 mL) was refluxed. After 1 hr, the reaction was cooled to room temperature and concentrated in vacuo. Water was added, and the solution was acidified to pH ˜4 by litmus paper. The precipitate was filtered, washed with water, and dried over Drierite to give the desired product (0.0456 g, 0.110 mmol, 60.9% yield) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:33])[CH2:11][N:12]1[C:20]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][C:38]([N:40]([O:42][CH3:43])[CH3:41])=[O:39]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([O:33][CH2:37][C:38]([N:40]([O:42][CH3:43])[CH3:41])=[O:39])[CH2:11][N:12]1[C:20]([C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)CBr
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)COC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-(6-(3-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9a, step 1) (280 mg, 0.597 mmol) in THF (5975 μL) was added sodium hydride (60% in mineral oil) (71.7 mg, 1.792 mmol) at 0° C. The resulting red solution was warmed to room temperature and stirred for 20 minutes, before being cooled to 0° C. 2-Bromo-N-methoxy-N-methylacetamide (Example 13, step 1) (141 mg, 0.777 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature over 3 hours and then cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution (5 mL). DCM (10 mL) was added to the biphasic solution. The aqueous phase was separated and extracted with DCM (3×10 mL); the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford a yellow oil. The oil was purified using Teledyne ISCO (12 g, SiO2) eluting with 0-65% EtOAc/hexanes to afford the title compound as an amorphous white solid.
Reaction SMILES: CO.S(Cl)(Cl)=O.[CH2:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:9][NH2:10].[C:15](OC(NC(=NC(OC(C)(C)C)=O)SC)=O)(C)(C)C>C(Cl)Cl>[CH3:15][O:13][C:12]([CH2:11][CH2:7][CH2:8][CH2:9][NH2:10])=[O:14]
Reactant: NCCCCC(=O)O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCN
Reaction time: 0.5 h
Yield: 153.4 %

Procedure:
Methanol (15 mL) was cooled to 0° C., combined with thionyl chloride (1.25 mL, 17.1 mmol) and stirred further for 30 minutes. This reaction solution was combined with 5-amino-n-valeric acid (500 mg, 4.3 mmol) and stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in methylene chloride (10 mL), combined with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.85 g, 6.4 mmol) and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to a column chromatography to obtain 5-amino-n-valeric acid methyl ester (compound 102; yield: 865 mg).
Reaction SMILES: [Li]C.[CH3:3]COCC.[C:8]([O:12][C:13]([N:15]1[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[N:32]=[CH:31][CH:30]=[N:29]3)[CH:23]=2)[CH2:19][O:18][CH2:17][C:16]1=[O:33])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:29]=[CH:30][CH:31]=[N:32]2)[CH:23]=1)[CH2:19][O:18][CH2:17][C:16](=[O:33])[CH3:3])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@H]1Cc1cccc(-n2nccn2)c1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)COC[C@@H](Cc1cccc(-n2nccn2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
MeLi 1.6 M in Et2O (3.6 mL, 5.82 mmol) was added dropwise to a −78° C. solution of (R)-3-oxo-5-(3-[1,2,3]triazol-2-yl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester I-5 (1.49 g, 4.16 mmol) in THF (15 mL) and the resulting mixture was stirred at −78° C. for 3 h. The reaction mixture was quenched with sat. aq. NH4Cl, warmed to RT and the solvent was removed in vacuo. The remaining aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (eluting with 20% to 50% EtOAc in hexane) to give the title compound as a yellow solid. LC-MS B: tR=0.81 min; [M+H-Boc]+=259.17.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:41])([F:40])[C:13]1[CH:14]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH2:31][OH:32])[C@@H:27]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:24])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH:31]=[O:32])[C@@H:27]2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH3:24])[CH:14]=[C:13]([C:12]([F:41])([F:11])[F:40])[CH:18]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 86.7 %

Procedure:
To a solution of 0.248 mL of oxalyl chloride in 8 mL of methylene chloride cooled to −70° C. was added dropwise 0.40 ml of DMSO. The reaction was stirred for 10-15 minutes and then a solution of 510 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(hydroxymethyl)-cyclopentane from Example 19, Method A or B in 5 mL of methylene chloride was added dropwise at −70° C. The reaction was stirred for 1 hour before dropwise addition of 2.0 mL of DIPEA in 3 mL of methylene chloride. After 5 minutes, the dry ice/acetone bath was removed and the reaction was allowed to warm to room temperature over 1 hour. The reaction was then diluted with methylene chloride and water containing 5 mL of 2N hydrochloric acid and the layers were separated. The aqueous layer was reextracted with methylene chloride and the organic layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (10% ethyl acetate/hexanes) to give 440 mg of title compound as a waxy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([Mg]Br)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: Br[Mg]c1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: c1ccc(COc2ccc3[nH]cc(Cc4cccnc4)c3c2)cc1

Procedure:
The above mentioned compound was prepared similarly to the procedure described in Arch. Pharm. 308, 209 (1975) from 5-benzyloxy-indolyl-magnesium bromide and 3-chloromethyl-pyridine. After recrystallization from acetonitrile, the desired compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.C([C:39]([NH2:41])=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:39]=[NH:41])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Reactant: CCC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNC=N)n1)c1csc(N)n1)C(=O)O
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (100 mg, 0.159 mmol) and ethylformamidate hydrochloride (17.4 mg, 0.159 mmol) in DMF (1 mL) was added DIPEA (41 mg, 0.32 mmol). After 2 h of stirring, more ethylformamidate hydrochloride (9.0 mg, 0.082 mmol) and DIPEA (20 mg, 0.16 mmol) was added. After an additional 4 h the solution was concentrated and washed with ether. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (15.5 mg, 18%) as mixture of amidine tautomers. LCMS: m/z=556.8 (M−1); 1H NMR (400 MHz, D2O): δ 7.73 (s, 0.4H), 7.65 (s, 0.6H), 7.57 (m, 1H), 6.83 (s, 1H), 5.37 (d, J=5.6 Hz, 1H), 4.80-4.61 (m, 3H assumed; obscured by solvent residual peak) 4.48 (s, 0.4H), 4.45 (s, 0.6H), 1.17 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH3:27]
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and acetyl chloride (22 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.O1CCCC1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+]>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:1][O:2][CH3:3])=[CH:15][N:16]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(Br)nc1

Procedure:
Methoxymethyl chloride (73 ml) was added to a tetrahydrofuran (1.3 L) solution of the obtained 6-bromo-3-pyridinol (129 g), and sodium hydride (30% liquid paraffin added) (32 g) was added at an inner temperature not to be over −10° C. Water was added, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 8/1) to obtain the entitled compound (105 g) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1
Reactant: Cc1cnc(F)c(-c2c[nH]c(=O)[nH]c2=O)c1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cc(C)cnc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 5-(2-fluoro-5-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep99, 300 mg, 1.16 mmol), and K2CO3 (241 mg, 1.7 mmol) in DMF (5 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (234 mg, 1.3 mmol) was added and stirring was continued for three days. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (95:5:0.5) to give 200 mg of the final compound as oil (53% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][NH:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][N:18]([C:8](=[O:10])[CH3:9])[CH:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:13]
Reactant: CCOC(=O)CCNC1c2ccccc2-c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCN(C(C)=O)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.51 mg of triethylamine and 0.28 ml of acetyl chloride were added under ice-cooling to a solution of 0.77 g of N-(9-fluorenyl)-β-alanine ethyl ester in 25 ml of methylene chloride. The resultant mixture was stirred at 0° C. for 0.5 hour and, then, at room temperature for 3 hours. The reaction solution was poured into ice-cold 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: chloroform-methanol) to give 0.85 g of N-acetyl-N-(9-fluorenyl)-β-alanin ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=3[Cl:30])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: C[C@H]1C[C@@H](Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 4-(3-amino-phenoxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 39, 0.29 g), triethyl amine (95 mg), and 2-chloro-4-fluorobenzoyl chloride (0.201 g) in THF (10 mL) and stir at room temperature. After 18 hr., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and dry in vacuum to give the title compound (0.464 g). Mass spectrum (electrospray) m/z=461 (M−1); 1H NMR (CDCl3): 7.87 (br s, 1H), 7.72 (dd, 1H), 7.37 (t, 1H), 7.19 (dd, 1H), 7.13 (dd, 1H), 7.02 (ddd, 1H), 6.97 (dd, 1H), 6.64 (dd, 1H), 4.63 (m, 1H), 4.28 (m, 1H), 3.81 (m, 1H), 3.20 (m, 1H), 1.88 (m, 2H), 1.81 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.24 (d, J=7.1 Hz, 3H). (file: mn4-a01246-76).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:57][CH:58]([CH2:63][CH2:64][CH2:65][C:66]([F:69])([F:68])[F:67])[C:59]([CH3:62])([OH:61])[CH3:60]>CN(C=O)C.O>[F:1][C:2]1([F:22])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([NH:57][CH:58]([CH2:63][CH2:64][CH2:65][C:66]([F:67])([F:68])[F:69])[C:59]([OH:61])([CH3:62])[CH3:60])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1
Reactant: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(O)C(N)CCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)NC(CCCC(F)(F)F)C(C)(C)O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.32 mmol) of 8-[(3,3-difluorocyclobutyl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 107A and 135 mg (0.35 mmol) of HATU were initially charged in 2 ml of DMF. 0.16 ml (0.96 mmol) of N,N-diisopropylethylamine and 70.6 mg (0.354 mmol) of rac-3-amino-7,7,7-trifluoro-2-methylheptan-2-ol hydrochloride Example 103A were then added, and the mixture was stirred at RT overnight. 7 ml of water were added, and the reaction solution was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed with 15 ml of water and with 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative RP-HPLC (acetonitrile-water+0.1% formic acid) and the product fractions were combined and concentrated to dryness. This gave 86 mg of the target compound (55% of theory).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)[CH2:2][CH3:3].[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:1][CH2:2][CH3:3])=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCCNCc1nc2c(c(=O)[nH]1)COCC2
Product: CCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (37.3 mg) from 2-((propylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C25H31FN4O4 470.5. found 471.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.89-8.08 (m, 2H) 7.19 (t, J=8.34 Hz, 2H) 4.60 (s, 2H) 4.42-4.57 (m, 2H) 4.27 (br. s., 2H) 3.85-4.01 (m, 3H) 3.81 (br. s., 1H) 3.57 (br. s., 1H) 3.39 (br. s., 1H) 3.31 (br. s., 2H) 3.12-3.28 (m, 1H) 2.72 (br. s., 1H) 2.13 (s, 4H) 1.58-1.80 (m, 1H) 1.40-1.58 (m, 1H) 0.76-1.00 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1.[CH3:30][NH2:31]>O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:16]=3[N:15]=[C:14]([NH:31][CH3:30])[C:13]=2[CH2:12][CH2:11]1
Reactant: CN
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OCC(F)(F)F)cccc4c32)c(C)c1
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(OC)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.42 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) in the pressure tube, and the reaction mixture was refluxed at 180° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:2) to obtain 450 mg of desired compound as solid in 76% of yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:16]1[CH:15]=[C:14]([C:7]2[C:6]3[C:10](=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCn1nc(-c2ccc(OC)c(F)c2)c2cccc(Cl)c21
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc(-c2ccc(OC)c(F)c2)c2cccc(-c3ccccc3)c21
Temperature: 80 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 7-chloro-3-(3-fluoro-4-methoxyphenyl)-1-propyl-1H-indazole (0.38 g, 1.18 mmol) in anhydrous dioxane (6 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.022 g, 0.024 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene HCl (0.02 g, 0.047 mmol). Phenylmagnesium bromide (0.71 mL, 1.40 mmol, 2M in diethyl ether) was added and the reaction heated to 80° C. for 18 hours. The reaction mixture was treated with 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (3/1) to provide the title compound as a white solid (0.28 g, 0.78 mmol, 66%). This material was used directly in step 2.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccccc1
Yield: 57.4 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and benzoic acid (40 mg, 0.33 mmol) as starting materials. The title compound (69 mg, 49.3%) was isolated as off white solid; MS (ESI): 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]#[N:13])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])O.[Na+]>>[C:12]([CH2:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[CH:4][C:5]=2[O:9]1)#[N:13]
Reactant: CCOC(=O)Cl
Reactant: N#CCCC1Cc2cc(N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc2c(c1)CC(CCC#N)O2
Yield: 87.8 %

Procedure:
Starting from 2.6 g (14 mmol) of 5-amino-2-cyanoethyl-2,3-dihydrobenzofuran, 1.45 ml (15.2 mmol) of ethyl chloroformate and 1.7 g (21 mmol) of sodium hydrogencarbonate treated under the conditions described in step 6 of Example 1, 3.2 g of product were obtained.