Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(a-5) was synthesized by a dehydrating esterification reaction between stearic acid and N,N-dimethyl-1,3-propanediamine. Specifically, a four-neck flask equipped with a stirrer, a temperature gage and a dewatering pipe was charged with 120 g of N,N-dimethyl-1,3-propanediamine, 284 of stearic acid and 0.12 g of sodium borohydride and the mixture was raised to 180° C. The mixture was heated under stirring at this temperature for about 5 hours while distilling generated water and a part of N,N-dimethyl-1,3-propanediamine to be distilled together with water. The reaction mixture was then cooled to 120° C. and unreacted amine was distilled under reduced pressure (10 torr) to obtain 368 g of the target N-stearoylaminopropyl-N,N-dimethylamine (a-5).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][C:8]1[C:9]([CH2:23][CH3:24])=[N:10][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]=1[CH2:13][CH3:14])(C)(C)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:23]([C:9]1[C:8]([CH2:7][C:6]([OH:5])=[O:25])=[C:12]([CH2:13][CH3:14])[N:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)=[CH:20][CH:21]=2)[N:10]=1)[CH3:24]
Reactant: CCc1nn(Cc2ccc(N)cc2)c(CC)c1CC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(CC)c1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Coupling: To a solution of [1-(4-amino-benzyl)-3,5-diethyl-1H-pyrazol-4-yl]-acetic acid tert-butyl ester (intermediate 2.1.2, 99 mg, 0.29 mmol) in dimethylformamide (1.5 mL) was added 4-(trifluoromethyl)benzoic acid (67 mg, 0.34 mmol), diisopropylethylamine (90 μL, 0.53 mmol) and TBTU (82 mg, 0.25 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was treated with aqueous K2CO3 solution (2 M, 0.15 mL) and filtered over Alox B, eluting with 10% methanol in dichloromethane. Cleavage of tert-butyl ester: The volatiles were removed under reduced pressure and the residue was treated with trifluoroacetic acid (2 mL). After 42 h, the mixture was concentrated under reduced pressure and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:10])[F:9])#[N:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C.C1COCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:9])[F:10])#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(C(F)(F)F)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(C(F)(F)F)n1C

Procedure:
In a manner analogous to the procedure set forth in Scheme II, step A, hydrogenate ethyl 4-cyano-1-methyl-3-[4-(phenylmethoxy)phenyl]-5-(trifluoromethyl)pyrrole-2-carboxylate, (intermediate prepared in example A-237) using Pearlman's catalyst and 60 psi of hydrogen gas in 1:1 ethanol/THF for 11 hours. Filter the reaction through diatomaceous earth and concentrate in vacuo. Purify the residue via radial chromatography eluting with ethyl acetate and hexane to provide the title compound. MS (m/e): 337.0 (M−1) 1H NMR: 7.20 (d, 2H, J=8.3 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.85 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 4.05 (s, 3H), 1.07 (t, 3H, J=7.0 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[C:26]([Cl:28])[CH:27]=2)[O:21][CH:22]=1>>[Cl:28][C:26]1[CH:27]=[C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[S:24][CH:25]=1
Reactant: ClCc1coc(-c2cc(Cl)cs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Clc1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4-chloro-2-thienyl)oxazole to give 2-(4-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 80%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 69-70° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15]C2)[N:7]=1)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Br
Reactant: Nc1cncnc1
Agent: [Pd]
Product: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1

Procedure:
Palladium catalysed arylation of 3-Bromo-6-cyclopropyl-pyridine-2-carboxylic acid ethyl ester with 5-Aminopyrimidine according to the general procedure described in example 78 step 3 yielded the title compound as a white solid, MS (ISP): m/e=273.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:16][CH2:17][NH2:18]>CC(O)C>[NH:15]1[CH:11]=[C:12]([CH2:16][CH2:17][NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:13]=[CH:14]1
Reactant: NCCc1cnc[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]cn2)nc1

Procedure:
2.22 g (14 mmol) of 2-chloro-5-nitropyridine and an equimolar equivalent of histamine base (1.56 g) in 10 ml of 2-propanol are brought to reflux for 48 h. The reaction mixture is concentrated to dryness and the solid residue is taken up in water, heated to boiling, cooled and filtered. The filtrate is concentrated to dryness and chromatographed on a column of silica gel which is eluted with a mixture of chloroform and methanol (5, 10 and 20%). The combined pure fractions are evaporated to dryness and the solid residue is crystallized from absolute ethanol to provide the product. M.p.: 162°-163° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[F:17][C:18]([F:26])([CH:23]([F:25])[F:24])[C:19](OC)=[O:20].[Cl-].[NH4+].Cl>C1COCC1>[F:17][C:18]([F:26])([CH:23]([F:25])[F:24])[C:19](=[O:20])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC(=O)C(F)(F)C(F)F
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(F)(F)C(F)F
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Lithium hexamethyldisilazide (250 ml of a 1M solution in THF, 0.25 mol) was cooled in an argon atmosphere to −78° C. and ethyl acetate (23 ml, 0.26 mol) was added dropwise with stirring. Stirring was continued for one hour at −78° C., then methyl 2,2,3,3-tetrafluoropropionate (22 g, 0.137 mol) was added dropwise with stirring. Stirring was continued for three hours at −78° C., then a saturated solution of ammonium chloride (175 ml) was added dropwise. The mixture was allowed to reach room temperature overnight. The mixture was acidified with 1M HCl, the phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed two times with 1M HCl, brine, dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by vacuum distillation to yield 25.7 g (0.119 mmol, 87%) of a colourless liquid that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C@H:16]3[C@H:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)[CH:6]=[N:7][CH:8]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C@H:16]3[C@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cncc(N2C[C@H]3CCNC[C@H]32)c1
Yield: 91.2 %

Procedure:
The product of Example 88A (0.540 g, 1.70 mmol) and trifluoroacetic acid were processed according to the procedure described in Example 64C to provide the title compound (0.340 g, 1.55 mmol, 91% yield).
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:28]([OH:30])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].C1CCC([N:47]=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:28]([NH2:47])=[O:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(C)c2c1OC(C)(C)CC2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(N)=O)c(C)c2c1OC(C)(C)CC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A] Z-Arg(Pmc)-OH (2.87 g, 5 mmoles) was dissolved in 15 ml of DMF, then added with 0.837 g (5.5 mmoles) of HOBT ammonium salt, and the reaction mixture was cooled to 0° C. After the addition of 1.135 g (5.5 mmoles) of DCC, the reaction mixture was brought to room temperature and kept under stirring for 300 minutes. After filtering dicyclohexylurea off, the solvent was evaporated under vacuum and the residue taken up in 25 ml of ethyl acetate and washed with an aqueous solution of 5% sodium hydrocarbonate, then with water till neutrality. The organic phase was anhydrified, the solvent evaporated under vacuum and the residue crystallized from ethyl ether/n-hexane. There were obtained 2.8 g of Z-Arg(Pmc)-NH2 [HPLC (gradient from 20 to 60% of B in A for 20 minutes): R.t. 15.7 min.; purity 98%].
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1cccc(OC)c1
Yield: 86.7 %

Procedure:
Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (anti isomer) (1.6 g.) and a 2 N aqueous solution of sodium hydroxide (4 ml.) were treated according to a similar manner to that of Preparation (5-3)(c) to give colorless prisms of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (anti isomer) (1.3 g.), mp 97° to 98° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH2:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:34].[H-].[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH2:20][CH3:21])=[C:18]([O:34][C:25]3[CH:26]=[CH:27][C:28]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:29][C:24]=3[F:23])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 27.7 %

Procedure:
4-(6-Chloro-5-ethyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (50 mg, 0.152 mmol), 2-fluoro-4-methanesulfonyl-phenol (43.5 mg, 0.228 mmol) and sodium hydride (60% dispersion in mineral oil, 7.28 mg, 0.182 mmol) were dissolved in DMSO (2 mL) and the mixture was heated under microwave irradiation for 1 h at 150° C. The crude was quenched with water and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by HPLC to afford Compound C6 (20.3 mg, 27.6%) as a white powder. 1H NMR (CDCl3, 400 MHz) δ 1.13 (t, J=7.33 Hz, 3H), 1.18 (d, J=6.32 Hz, 6H), 1.72-1.76 (m, 2H), 1.89-1.94 (d, 2H), 2.64 (q, J=7.33 Hz, 2H), 3.02 (s, 3H), 3.35-3.41 (m, 2H), 3.63-3.66 (m, 2H), 4.85-4.88 (m, 1H), 5.25-5.32 (m, 1H), 7.35-7.37 (m, 1H), 7.69-7.74 (m, 2H), 8.13 (s, 1H). Exact mass calculated for C22H28FN3O6S 481.17, found 482.4 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][C:23](=[O:29])[NH:24]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:20]([C:17]([OH:19])=[O:18])=[CH:28][CH:27]=[CH:26][C:25]=2[NH:24][C:23]1=[O:29])([CH3:3])[CH3:2]
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cccc(C(=O)O)c32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 4-carboxy-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[CH:38]=[C:37]([NH:39][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:36]=[N:35]2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cn2)CC1

Procedure:
4-{4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-pyrazol-1-yl}-piperidin-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.48 mmol) and 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.168 g, 0.63 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as a tan solid (0.134 g, 51%). MP=Softened at 161-166° C. then melted at 207-209° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.78 (d, J=6.52 Hz, 1H), 8.42 (d, J=8.00 Hz, 2H), 8.06 (d, J=7.89 Hz, 2H), 7.94 (d, J=7.45 Hz, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 7.12 (t, J=6.89 Hz, 1H), 4.32 (s, 1H), 4.04 (d, J=11.40 Hz, 2H), 3.28 (s, 3H), 2.91 (s, 2H), 2.005 (d, J=11.77 Hz, 2H), 1.76 (q, J=12.21 Hz, 2H), 1.42 (s, 9H). MS=538 (MH)+.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:18][C:19]([O:21]CC)=[O:20])[CH:2]=[CH2:3].Cl>[OH-].[Na+]>[C:19]([CH2:18][N:9]1[C:10]2[C:5](=[C:4]([CH2:1][CH:2]=[CH2:3])[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:24])([OH:21])=[O:20]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
2 Grams of 5,7-diallyl-3,4-dihydro-1-(ethoxy-carbonylmethyl)-6-hydroxy-2(1H)-quinolinone obtained in Example 57 was dissolved in 100 ml of 1N-sodium hydroxide aqueous solution, and the solution was stirred at 60° C. for 4 hours. Under ice-cooling condition, the reaction mixture was acidified with hydrochloric acid, the crystals thus precipitated were collected by filtration, washed with water and dried. There was obtained 0.8 g (53%) of 1-(carboxymethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CCOCC>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(CN)OC
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CCOCC
Product: COC(CNCC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of aminoacetaldehyde dimethyl acetal (2.2 ml, 0.04 mole) in ether (10 ml) was cooled to 0° C. Benzyl bromoacetate (1.6 ml, 0.02 mole) was added. After stirring at ambient temperature overnight, the solid aminoacetaldehyde dimethyl acetal hydrobromide was filtered and the solution was concentrated to an oil. Flash chromatography on silica (LPS-1) (40:60 ethyl acetate:hexane eluant) gave 2.2 gms of the purified title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:41])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:35][CH2:34]4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].[O:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57](O)=[O:58])[CH2:52][CH2:51]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[Si:43]([O:42][C@H:3]1[C@H:2]([NH:1][C:57](=[O:58])[CH2:56][N:53]2[CH2:54][CH2:55][O:50][CH2:51][CH2:52]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:34][CH2:35]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[C:9]=2[Cl:41])[CH2:4]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CN5CCOCC5)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.6 %

Procedure:
A mixture of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171E, 40 mg, 0.057 mmol), 2-morpholinoacetic acid (9.96 mg, 0.069 mmol) and HATU (26.1 mg, 0.069 mmol) in DMF (1 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with dichloromethane and was filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-50% ethyl acetate/hexanes). (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-morpholinoacetamide (46 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4C)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-methylphenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.44 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.26-7.21 (m, 4H), 6.81-6.74 (m, 4H), 4.20 (t, J=6.6 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.50 (s, 6H), 1.25 (t, J=7.2 Hz, 3H); MS (EI) 500.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl

Procedure:
13.7 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)acetate are heated under reflux with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride for 2 hours. The mixture is then concentrated in vacuo up to a bath temperature of 140° C. and 15.7 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are obtained as an oil, nD25 : 1.5302.