Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[N:4][NH:3]1.[N:22]1(C(OC(C)(C)C)=O)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>Cl.C(O)C.O.CC(N(C)C)=O>[N:22]1([C:16]([C:15]2[CH:14]=[C:13]([CH:21]=[CH:20][CH:19]=2)[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][N:4]=2)=[O:18])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCNCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.8 %

Procedure:
3-(4-Oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A)(5.0 g, 0.17 mol), tert-butyl 1-piperazinecarboxylate (3.9 g, 0.21 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (8.6 g, 0.22 mol) and N,N,-diisopropylethylamine (6.7 ml, 0.38 mol) were added to dimethylacetamide (40 ml) and stirred for 18 hours. Water (100 ml) was added and the reaction mixture was heated to 100° C. for 1 hour. The suspension was cooled to room temperature, filtered and dried to yield a white solid. The solid was dissolved in a solution of 6M HCl and ethanol (2:1, 50 ml) and stirred for 1 hour. The reaction was concentrated, basified with ammonia to pH 9, and the product was extracted into dichloromethane (2×50 ml). The combined organic layers were washed with water (2×50 ml), dried over MgSO4, and evaporated in vacuo to yield 4-[3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one (1) as a yellow crystalline solid (4.0 g, 77%); m/z [M+1]+ 349 (97% purity), δH 2.6-3.8 (8H, m), 4.4 (2H, s), 7.2-7.5 (4H, m), 7.7 -8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: BrCC1CCCCO1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of diisopropylamine (0.67 mL, 4.82 mmol) in tetrahydrofuran (30 mL) cooled to −78° C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (1.93 mL, 4.82 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (1.00 g, 4.38 mmol) in tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 2-bromomethyl-tetrahydro-pyran (0.67 mL, 5.26 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 70/30 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (157 mg, 11%) as a colorless oil: EI-HRMS m/e calcd for C16H22O5S (M+) 326.1188, found 326.1189.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:4].[CH3:15][NH:16][C:17](=[O:29])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH2:19]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C:7]([C:8]([NH:19][CH:18]([C:17]([NH:16][CH3:15])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:10])=[CH:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CC=C(CC(C)C)C(=O)O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(=CCC(=O)OC)CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
N,N-Dicyclohexylcarbodiimide (515 mg, 2.5 mmol) was added to an ice-cooled solution of 4-methoxycarbonyl-2-(2-methylpropyl)but-2-enoic acid (500 mg, 2.5 mmol) and O-methyl-L-tyrosine N-methylamide (520 mg, 2.5 mmol) in dry dichloromethane (30 ml), and the mixture was stirred at room temperature for 18 h. The precipitated solid was filtered off and washed with a little dichloromethane, then the organic solution was washed successively with 1 N hydrochloric acid (20 ml), 1 N sodium bicarbonate (20 ml), and water. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography (30 g silica) of the residual solid, eluting with 5% methanol/dichloromethane gave the title compound (520 mg, 53%), m.p. 142°-144° C. (dichloromethane/pentane).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1)=[O:2]
Reactant: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C

Procedure:
Formic acid (2.5 mL, 66.3 mmol) and acetic anhydride (5 mL, 52.9 mmol) were mixed, and the mixture was stirred with heating at 50° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and cooled to 0° C. To the reaction mixture was added a solution of N-(3-aminophenyl)-3-(trifluoromethyl)benzamide (5.65 g, 20.2 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at the same temperature for 16 hr, during which the reaction temperature was allowed to gradually warm to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (50 mL) and ethyl acetate (250 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated aqueous ammonium chloride solution (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide as a yellow amorphous substance. To a solution of N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide produced above in tetrahydrofuran (100 mL) was added a 1.9M solution (21 mL, 39.9 mmol) of borane-dimethylsulfide complex in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hr. Since the starting materials were not completely consumed, a 1.9M solution (2 mL, 3.8 mmol) of borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was further stirred at room temperature for 1 hr. Methanol (30 mL) and acetic acid (10 mL) were added to the reaction solution and the mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL), washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (5.54 g, total yield of 2 steps 93%) as yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:6]1=[O:22].O.[OH-].[Li+]>C1(C)CCC(C(C)C)C(O)C1>[O:22]=[C:6]1[C:7](=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)CN1C(=O)C(=C(C)c2ccccc2)c2ccccc21
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=C1C(=O)N(CC(=O)O)c2ccccc21)c1ccccc1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid methyl ester (50 mg, 0.16 mmol) was dissolved in menthol 1 ml; then 0.1 ml water was added. Finally, lithium hydroxide (10 mg) was added. The mixture was stirred overnight. The reaction was monitored by HPLC. When the reaction was finished, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give [2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid as white powder (11 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.82 (s, 3H) 4.61 (s, 2H) 6.20 (d, J=7.58 Hz, 1H) 6.66-6.73 (m, 2H) 7.14 (t, J=7.58 Hz, 1H) 7.31 (s, 2H) 7.46-7.54 (m, 3H). MS calcd. for C18H15NO3 293, obsd. (ESI+) [(M+H)+]294.1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([O:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[N:16]=1>CN(C)C(=O)C.[Cu]I>[CH3:22][N:21]([CH3:23])[C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[CH:18]=1
Reactant: CN(C)c1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution of meta-trifluoromethylphenol (1.27 g, 0.0020×4.0 mol) in 20 ml of dry N,N-dimethylacetamide, sodium hydride (0.313 g, (ca.60% in mineral oil), 0.0020×4.0 mol) was added. After the bubbling ceased, a solution of 2-chloro-4-dimethylamino-6-(3-thienylmethyloxy)pyridine (0.526 g, 0.0020 mol) in 20 ml of dry N,N-dimethylacetamide was added dropwise, then CuI (0.186 g, 0.0020×0.5 mol) was added thereto and the resultant solution was stirred for 24 hours at the temperature of 170° to 180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@@:8]2([CH3:28])[N:13](CC3C=CC(OC)=CC=3OC)[C:12](=[O:25])[CH2:11][S:10](=[O:27])(=[O:26])[CH2:9]2)[CH:7]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@@:8]2([CH3:28])[NH:13][C:12](=[O:25])[CH2:11][S:10](=[O:27])(=[O:26])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)CS(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=O)N1
Temperature: 23 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (251 mg, 516 μmol, Eq: 1.00) and trifluoroacetic acid (5.88 g, 3.98 ml, 51.6 mmol, Eq: 100) was stirred at 23° C. for 16 hours. Poured into 1 M Na2CO3-sol. and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was chromatographed on 5 g silica gel with dichloromethane/ethyl acetate 9:1 to give (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (116 mg, 345 μmol, 66.9% yield) as a white solid. MS (ISN): m/z=334.0 [M−H]− and 336.0 [M+2−H]−.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:47][CH:46]5[CH2:44][CH2:45]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-propylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.66, 2.40 Hz, 2H) 0.70 (dd, J=6.95, 2.15 Hz, 2H) 1.50-1.77 (m, 6H) 1.88-1.97 (m, 2H) 2.82 (td, J=7.33, 3.54 Hz, 1H) 3.17 (s, 3H) 3.92 (s, 3H) 3.99-4.08 (m, 3H) 4.75 (d, J=8.84 Hz, 1H) 7.40-7.51 (m, 2H) 7.96 (s, 1H) 8.26 (d, J=8.34 Hz, 1H) 8.35 (d, J=4.04 Hz, 1H). [M+H] C24H28F2N6O3 calc'd for, 487. found 487.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.O=C(C1C=CC=CC=1)C[O:43][C:44](=[O:72])[C@H:45](O)[CH2:46][N:47]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[NH:48][C:49]([C:51]1[O:55][N:54]=[C:53]([OH:56])[CH:52]=1)=[O:50].CCN(C(C)C)C(C)C.CC(O)=O>[Zn]>[C:44]([C@H:45]([O:8][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[CH2:46][N:47]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[NH:48][C:49]([C:51]1[O:55][N:54]=[C:53]([OH:56])[CH:52]=1)=[O:50])([OH:72])=[O:43]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)O[C@H](CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid (9.6 mg, 54.5 μmol) and HATU (23.5 mg, 62 μmol) were stirred in DCM (1.0 mL, 16 mmol) for 10 minutes. (R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) and DIPEA (31.7 μL, 182 μmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and purified by flash chromatography (EtOAc/hexanes=0-100%). Zinc (119 mg, 1.8 mmol) and AcOH (0.5 mL, 9 mmol) were added. The mixture was stirred for 2 hours and filtered. The solids were washed with AcOH (1 mL) and filtered. The combined filtrates were purified by reverse phase preparative HPLC to yield the title compound (0.8 mg). MS m/z [M+H]+ calc'd for C27H29ClN4O9, 589.16. found 589.3.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Li][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:9][C:7]1[S:8][C:4]([C:1]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([OH:3])[CH3:2])=[C:5]([CH3:10])[N:6]=1
Reactant: [Li]c1cccnc1
Reactant: CC(=O)c1sc(C)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1nc(C)c(C(C)(O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Acetyl-2,4-dimethylthiazole (2.5 g) in dry diethylether (10 ml) was added dropwise to a stirred solution of 3-lithiopyridine (from 3.5 g 3-bromopyridine) in diethylether at -70° C. After 3 hours the mixture was allowed to warm to room temperature. After a further 1 hour, aqueous sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with diethylether. The material obtained from the combined organic layers was purified by flash chromatography to give the title compound, m.p. 107.5°-109° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)(=[O:21])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(O)C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
26.0 g (0.2 mol) of piperidine-4-carboxylic acid were dissolved in 250 ml of pyridine and the solution was treated with 47.6 g (0.2 mol) of 2-naphthylsulfonyl chloride in portions at room temperature. The whole was stirred at room temperature for about 5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 2 M hydrochloric acid. The organic phase was dried and concentrated under reduced pressure. 48.5 g (75%) of the product were obtained.
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][N+]([O-])=O)=[O:6])(=[NH:3])[NH2:2].N[CH2:12][C:13]([OH:15])=[O:14].Cl>O>[C:1]([NH:4][C:5](=[O:6])[NH:7][CH2:12][C:13]([OH:15])=[O:14])(=[NH:3])[NH2:2]
Reactant: N=C(N)NC(=O)N[N+](=O)[O-]
Reactant: NCC(=O)O
Agent: Cl
Solvent: O
Product: N=C(N)NC(=O)NCC(=O)O
Temperature: 10 °C

Procedure:
The pH of a mixture of 29.4 g (0.2 mole) of N-guanyl-N'-nitrourea and 7.5 g. (0.1 mole) of glycine in 200 ml. of water is adjusted to 6.0 and the resulting solution heated to reflux. During the 2 hrs. of reflux (95°-97° C.) the pH of the reaction is maintained between 6 and 7 by the addition of 10% hydrochloric acid. The reaction, after 2 hours reflux, is cooled to 10° C. and the pH adjusted to 6.9. The precipitate is filtered, washed with 500 ml. of water and dried to give 14 g. of the desired intermediate, m.p. 202° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1O)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1>CO>[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:3]2[C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[O:1][CH2:2]2)=[CH:9][CH:8]=1)([CH3:12])[CH3:11]
Reactant: Cc1cc(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c1
Solvent: CO
Product: Cc1cc(C)c2c(c1)OCC2c1ccc(C(C)C)cc1
Yield: 85 %

Procedure:
Using 2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5-dimethylphenol synthesized in Reference Example 10, the title compound was synthesized in the same manner as in Reference Example 13. Yield 85%. Melting point: 46-47° C. (methanol).
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)#[N:9]>>[ClH:1].[C:8]([C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)#[N:9]
Reactant: CCOC(=O)CCc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccccc1C1(C#N)CCNCC1
Reaction time: 2 h
Yield: 99 %

Procedure:
4 M HCl/dioxane (905 μL, 3.62 mmol) was added to neat tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate at 23° C. and was stirred for 2 h. The solution was concentrated to yield ethyl 3-(2-(4-cyanopiperidin-4-yl)phenyl)propanoate hydrochloride (22, 230 mg, 99% yield over 2 steps).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O=C1C=CC=CN1CC1C=CC(OC(=O)N(C)C2C=CC=CC=2)=CC=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Agent: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCOc2ccccn2)cc1)c1ccccc1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 29% of the isomeric methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester was isolated, see characterization above. 1H NMR (400 MHz; CDCl3): δ 3.08 (t, 2H), 3.41 (br s, 3H), 4.49 (s, 2H), 6.73 (d, 1H), 6.88 (dd, 1H), 7.05 (br d, 2H), 7.22–7.42 (m, 7H), 7.61 (dt, 1H), 8.18 (dd, 1H); HPLC-MS: m/z=349.2 (M+1); Rt=3.97 min.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.O>[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=C1N=c2c(OC(F)(F)F)cccc2=C2OCCC12
Reactant: Cc1ccccc1N
Solvent: O
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Temperature: 250 °C
Yield: 82.7 %

Procedure:
4-Oxo-6-trifluormethoxy-2,3-dihydrofuro[3,2-c] quinoline (272 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol and 2-methylaniline (267 μl 1.0 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 298 mg of desired compound as solid in 83% of yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](O)=[O:42])=[N:39][CH:40]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C)C=O.O>[C:25]([NH:24][C:10]1[S:11][CH2:12][CH:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:41]([C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)=[O:42])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)c(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: O=C(O)c1ccc(F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (302 mg, 647 μmol) and 5-fluoropyridine-2-carboxylic acid (110 mg, 777 μmol) are combined in dichloromethane (3 mL) and dimethylformamide (0.5 mL). 1-Hydroxybenzotriazole (116 mg, 842 μmol) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg, 842 μmol) are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with water and the pH adjusted with 1 N NaOH to ˜12 and then extracted with ethyl acetate (3×). The organic layers are combined and filtered to collect the insoluble material. The solids are washed with water and ethyl acetate and dried under vacuum to give the title compound. The organic layer from the filtrate is dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue is purified over silica gel with a 20 minute 5% to 100% ethyl acetate in hexanes gradient to give additional title compound with a combined yield (275 mg, 72%). ES/MS (m/e): 590 (M+H).