Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:8]2=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17]1[O:18][CH:44]=[N:46][N:47]=1)[C:8]2=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC

Procedure:
5-(t-Butyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione was prepared as described for Example 8 from 3-[5-(tert-butyl)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (0.81 g, 5.0 mmol), formic hydrazide (0.35 g, 5.8 mmol), and phosphorus oxychloride (1.0 mL, 10.7 mmol) in acetonitrile (20 mL). The product was isolated as a white solid (800 mg, 38% yield): mp, 136.0-138.5° C.; 1H NMR (CDCl3) δ 1.35 (s, 9H, CH3), 1.44 (t, J=6.9 Hz, 3H, CH3), 3.79 (dd, J=5.9, 16.1 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 4.38 (dd, J=10.3, 15.8 Hz, 1H, CHH), 5.80 (dd, J=5.9, 10.4 Hz, 1H, NCH), 6.82 (d, J=8.2 Hz, 1H, Ar), 7.11-7.17(m, 2H, Ar), 7.70 (br s, 2H, Ar), 7.82 (br s, 1H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDC3) δ 14.71, 27.73, 31.08, 35.72, 51.78, 55.92, 64.44, 111.36, 112.58, 120.31, 120.63, 123.26, 128.94, 130.33, 131.14, 131.84, 148.41, 149.42, 153.02, 158.82, 164.07, 168.25, 168.39; Anal Calcd for C25H27N3O5+0.11 H2O: C, 66.51; H, 6.08; N, 9.31; H2O, 0.43. Found: C, 66.42; H, 5.83; N, 9,18; H2O, 0.43.
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH2:22][O:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])=[N:19]2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH2:22][O:23][C:24]3[CH:25]=[C:26]([NH:27][C:7](=[O:9])[CH2:8][C:3]([CH2:1][CH3:2])([CH3:10])[C:4]([OH:6])=[O:5])[CH:28]=[CH:29][CH:30]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Reactant: CCC1(C)CC(=O)OC1=O
Product: CCC(C)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2-ethyl-2-methylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 179°-180°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][NH:26]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][N:26]2[CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 401.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][C:8]2=[O:18]
Reactant: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccc(Cl)c2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 82 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23 g, 68 mmol) was dissolved in H2O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered. The solid was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1H-NMR (CDCl3): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([OH:24])[CH2:9][O:10][CH2:11][C:12]([F:23])([F:22])[C:13]([F:21])([F:20])[C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27]>>[C:26]([O:24][CH:8]([CH2:9][O:10][CH2:11][C:12]([F:22])([F:23])[C:13]([F:21])([F:20])[C:14]([F:18])([F:19])[CH:15]([F:16])[F:17])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:27])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Product: CC(=O)OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 273.1 %

Procedure:
To 37.5 g of 1-morpholino-3-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2-propanol was added 11.2 g of acetic anhyride. The mixture was stirred at 50° C. for 10 hours, followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 39.6 g of 2-morpholino-1-{(2,2,3,3,4,4,5,5-octafluoropentyloxy)-methyl}ethyl acetate (yield 95%).
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:12][C@H:13]([C:15]([C:17]1([NH2:38])[C:23](=[O:24])[N:22]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:18]1=[O:37])=[O:16])[CH3:14]>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:12][C@H:13]([C:15]([C:17]2([NH2:38])[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:18]2=[O:37])=[O:16])[CH3:14])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by L.C. 2000 eluting with CH2Cl2/EtOAc (1:1 gradient to 1:2) then flash chromatography eluting with 2:1 EtOAc/CH2Cl2. Rf=0.47 and 0.37 (CH2Cl2/EtOAc, 1:2).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:7]([NH:8][C@@H](C2C=CC=CC=2)C)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>[Pd].C(O)C>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:2]1([CH3:24])[CH3:1]
Reactant: [H][H]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)CC1(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A pressure bottle was charged with palladium on carbon (0.192 g, 0.180 mmol) and (R)-tert-butyl 3,3-dimethyl-4-((R)-1-phenylethylamino)piperidine-1-carboxylate (3.00 g, 9.02 mmol) in ethanol (60 mL) and the resulting mixture was shaken under 50 psi of hydrogen on a Parr apparatus. After 5 h, the catalyst was removed by filtration, rinsed with methanol, and the filtrate was concentrated in vacuo to afford the title compound as a clear oil (2.0 g, 8.76 mmol, 97%). Material was not further purified and was used directly in next transformation. 1H NMR (500 MHz, METHANOL-d4) δ 4.07 (d, J=13.0 Hz, 1H), 3.78-3.62 (m, 1H), 3.01-2.62 (m, 2H), 2.56 (dd, J=11.1, 4.2 Hz, 1H), 1.74-1.63 (m, 1H), 1.51 (s, 9H), 1.49-1.43 (m, 1H), 1.00 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][C:28]=3[S:37]([N:40]3[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]3)(=[O:39])=[O:38])=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2S(=O)(=O)N2CCNC(=O)C2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 4-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C22H16F4N6O3S, 520.09; m/z found, 520.8 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.29 (d, J=1.9, 1H), 8.26 (s, 1H), 8.19 (dd, J=8.2, 1.9, 1H), 8.07-8.01 (m, 1H), 7.77 (d, J=7.9, 1H), 7.70-7.64 (m, 1H), 7.49 (dd, J=10.8, 1.7, 1H), 7.44-7.36 (m, 3H), 3.39 (s, 2H), 3.07-2.96 (m, 4H).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(Cl)(=O)C>N1C=CC=CC=1>[CH3:19][O:18][C:16]1[N:17]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=2)[CH:13]=[C:14]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:15]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: COc1ccc(CCNc2cc(-c3cccc(NC(C)=O)c3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine acetate [156 mg, 0.38 mmol, Example 2] in pyridine (1.3 mL) is added acetyl chloride (32 μL, 0.45 mmol). The reaction mixture is stirred for 3 hours at ambient temperature, quenched with the addition of water (20 mL), and extracted three times with EtOAc (20 mL). The combined extracts are washed four times with aqueous copper sulfate solution (10 mL), with water (10 mL), with brine (10 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica gel (4.5 g) eluting with 3% MeOH in DCM to afford N-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetamide [51 mg, 34%, Example 6(b)]. LCMS: RT=2.3 minutes, MS: 393 (M+H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH:23]([CH3:25])[CH3:24])[C:14]=2[CH:26]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl>[Br:2][C:1]([Br:5])=[CH:26][C:14]1[C:15]([CH:23]([CH3:25])[CH3:24])=[N:16][C:17]2[C:22]([C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (12.620 gm, 38.0 mmol) in CH2 Cl2 (20 ml) was added over a 10 minute period to a cold (-10° C.) solution of 4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (7.394 gm, 25.2 mmol) and triphenylphosphine (19.86 gm, 75.7 mmol) in CH2 Cl2 (140 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to 50 ml. The residue was triturated with Et2O and the precipitated triphenylphosphine oxide was removed by filtration. The filtrate was stripped and the residue was chromatographed (flash, Merck SiO2, 10% EtOAc in hexane) to give 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline as a light yellow foamy oil (11.556 gm, 102% theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][O:8][P:9](=[O:12])([OH:11])[OH:10].[OH-].[Na+].C(=O)(O)[O-].[Na+].O=C1CCC(=O)N1[O:42][C:43](=O)[CH:44]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC(C)=O>[CH3:62][O:61][C:59](=[O:60])[NH:58][CH:44]([C:43](=[O:42])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:7][O:8][P:9]([OH:10])([OH:11])=[O:12])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)CN(C(CCCCN)COP(=O)(O)O)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)NC(C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)NC(C(=O)NCCCCC(COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 66 %

Procedure:
57 mL (or approximately 26 mmol) of the aqueous solution of phosphoric acid mono-{6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl}ester (XIX) was neutralized with 40 mL of 1N sodium hydroxide. The pH of the solution (pH˜4-5) was then adjusted to pH=8 by adding 150 mL solution of saturated of sodium bicarbonate. To this well stirred solution was added a freshly prepared solution, in 130 mL of acetone, of methoxycarbonylamino-3,3-diphenyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (13.34 g, 34 mmol) prepared according to Anderson et al J. Am. Chem. Soc. 1964, 1839. The resulting clear solution was stirred for 12 h. The reaction mixture was concentrated and the remaining aqueous phase extracted twice with ethyl acetate. The aqueous phase was then acidified with 1N hydrochloric acid and the resulting suspension extracted with ethyl acetate. The organic phase was washed with water then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The solid residue was again suspended in ethyl acetate and acidified with HCl (g). The resulting beige precipitate was collected by filtration to give 12.5 g (66%) of the title product. Purity was determined by LC_MS and is greater than 97%.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15]C(=O)N)([CH2:3][CH3:4])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[OH:15])([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)c1cccc(C(C)CC)c1OC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(C)c1cccc(C(C)CC)c1O
Yield: 100.3 %

Procedure:
R-(+)-1-Phenyl-ethyl)-carbamic acid (−) 2,6-di-sec-butylphenyl ester (1b) (4.1 g, 11.6 mmol) was dissolved in a 100 ml 1:1 mixture of dioxane: 1M NaOH aq. The reaction mixture was stirred at 70° C. for 15 min. Volatiles were removed at reduced pressure to a volume of ˜50-70 ml. The pH was adjusted to 3-4 with 1M HCl. The phenol was extracted with ether (3×50 ml), washed with 1 M HCl, brine and dried over anhydrous MgSO4. Evaporation yielded crude yellow oil (2.4 g, ˜100%). Vacuum distillation was performed (120-125° C./˜5 mm) (2.1 g, 89%). Optical rotation: α20D=−14.11° (c=2, pentane).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:27]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][N:35]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)[CH2:36][CH2:37]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:46]([O:50][C:51](=[O:60])[NH:52][C:53]([CH3:59])([CH2:56][CH2:57][CH3:58])[CH2:54][NH2:55])([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:46]([O:50][C:51](=[O:60])[NH:52][C:53]([CH3:59])([CH2:56][CH2:57][CH3:58])[CH2:54][NH:55][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:22][CH:21]=[CH:20][C:19]=3[F:23])=[CH:7][CH:8]=[CH:9][C:10]=12)=[O:17])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1nn2c(OCc3c(F)cccc3F)cccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 100 mg (0.19 mmol, 61% pure) of 7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 130A in 4 ml of tetrahydrofuran was admixed with 39.1 mg (0.287 mmol) of 1-hydroxybenzotriazole and 74.3 mg (0.287 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The resulting solution was stirred at room temperature for 15 min, and then 62.2 mg (0.287 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.1 ml (0.575 mmol) of N,N-diisopropylethylamine After the addition, the mixture was stirred at room temperature for a further 15 h. The solvent was drawn off under reduced pressure and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried with a phase separation cartridge and concentrated under reduced pressure, which gave 45 mg (24% of theory, 53% pure) of the target compound.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][N:12]=[C:13]=[S:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>C(OCC)(=O)C>[F:17][C:2]([F:1])([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][NH:12][C:13]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[S:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)c1ccc(CN=C=S)cc1
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Product: FC(F)(F)CNC(=S)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
2.1 g of 4-pentafluoroethylbenzyl isothiocyanate and 0.78 g of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetate, and the solution was left to stand at room temperature for 24 hours. Ethyl acetate was evaporated under reduced pressure. The resulting white crystals were recrystallized from hexane to give 2.6 g of the captioned compound.
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>Br>[OH:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(OC)cc3)nc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(O)cc3)nc12
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
60% w/w Hydrobromic acid (20 ml) was added to 5-(4-methoxybenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (630 mg) and the mixture stirred at 130° C. for 90 minutes. On cooling, the reaction was neutralized with saturated aqueous sodium carbonate solution and partitioned between dichloromethane (40 ml) and water (40 ml). The aqueous layer was further extracted with dichloromethane (100 ml), the combined organic layers dried (MgSO4), filtered and evaporated under reduced pressure. Crystallisation from ethyl acetate gave the title compound (75 mg), m.p.260° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CBr)cc1
Yield: 67.5 %

Procedure:
(a) A mixture of 20 g of ethyl 2-(p-tolyloxy)-2-methylpropionate, 17.7 g of N-bromosuccinimide, 0.2 g of benzoyl peroxide and 140 ml of anhydrous carbon tetrachloride is refluxed under heating for 4 hours. After the reaction, the reaction mixture is left to stand for cooling and washed with water. The carbon tetrachloride layer is dried and then concentrated. The resulting oily product (28 g) is distilled under reduced pressure to give 18.3 g of ethyl 2-(4-bromomethylphenoxy)-2-methylpropionate, bp 146° to 148° C./1-2 mmHg.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH2:29][CH2:30][CH3:31])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 10.96 g (50 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 mL of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 12.0 g of 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([N+:15]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([NH2:15])[CH:5]=1
Reactant: COCCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCNc1ccc(C(=O)OC)cc1N
Yield: 94.5 %

Procedure:
3-Amino-4-(2-methoxy-ethylamino)-benzoic acid methyl ester (800.0 mg) was prepared by following General Procedure B starting from 4-(2-methoxy-ethylamino)-3-nitro-benzoic acid methyl ester (960.0 mg) and Pd/C (20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.