Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][CH3:32])=[C:18]([C:20]([CH3:30])([CH3:29])[CH2:21][C:22]2([C:25]([F:28])([F:27])[F:26])[CH2:24][O:23]2)[CH:19]=1.[O-]CC.[Na+]>C(O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][CH3:32])=[C:18]([C:20]([CH3:29])([CH3:30])[CH2:21][C:22]([OH:23])([C:25]([F:28])([F:27])[F:26])[CH2:24][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[C:2]([CH3:1])=[CH:3]2)[CH:19]=1
Reactant: Cc1c[nH]c2ccccc2c1=O
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(C)c(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
A mixture of 3-methyl-1H-quinolin-4-one (0.76 g), 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (0.089 g) and sodium ethoxide in ethanol (0.18 mL of a 21 wt. % solution) in 2 mL of anhydrous ethanol was heated at 85° C. for 12 hours, cooled to room temperature, and most of the volatiles removed in vacuo. The residue was diluted with diethyl ether and methanol and washed with water and brine, and dried over magnesium sulfate. The residue was purified by flash silica gel chromatography using ethyl acetate as the eluent. The product-rich fractions were concentrated in vacuo and dried to afford 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H-quinolin-4-one, m.p. >225° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=O)[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:33]([O:50][NH2:51])[C:34]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:26]=[CH:27][C:28]=1[O:29][C:30](=[O:32])[CH3:31])(=[O:21])[CH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:51]/[O:50][CH:33]([C:34]([O:36][CH:37]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C:25]2[CH:26]=[CH:27][C:28]([O:29][C:30](=[O:32])[CH3:31])=[C:23]([O:22][C:19](=[O:21])[CH3:20])[CH:24]=2)/[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)ns1
Reactant: CC(=O)Oc1ccc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Solvent: CO
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2nsc(NC(=O)OC(C)(C)C)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reaction time: 3 h
Yield: 100 %

Procedure:
2-(5-Tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1.49 g) was dissolved in methanol (60 ml), and to this solution a solution of diphenylmethyl (3,4-diacetoxyphenyl)-2-aminooxyacetate (2.45 g) in methanol (25 ml) was added dropwise. The mixture was stirred for 3 hrs. at the room temperature, and the solvent was evaporated to obtain (Z)-2-(5-tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-[[(diphenylmethyloxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetic acid (3.84 g).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.O>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:2]=[O:3])[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, 263 g of methoxymethyl triphenylphosphonium chloride was suspended in THF (800 mL), and 90 g of potassium-tert-butoxide was added the resultant suspension at an inside temperature of 0° C. or less, followed by stirring at an inside temperature of 0° C. for 20 minutes. Then, a solution of 4-(3,5-difluorophenyl)cyclohexanone (119 g) in THF (300 mL) was added at an inside temperature of 5° C. or less, followed by stirring at an inside temperature of −5 to 8° C. for 30 minutes. After water (10 mL) was added, the solvent was distilled off under reduced pressure, and water (400 mL), methanol (400 mL), hexane (500 mL), and 7.3 g of a 70% aqueous tert-butyl hydroperoxide solution were added to the residue, followed by stirring at room temperature for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a 50% aqueous methanol solution and water two times in that order, and the solvent was distilled off under reduced pressure. Then, 10% hydrochloric acid (400 mL) and THF (400 mL) were added to the resultant residue, followed by heating under reflux for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with ethyl acetate. The ethyl acetate extract was combined with the organic layer and washed with saturated brine two times. The solvent was distilled off under reduced pressure, and methanol (300 mL) and a 10% aqueous sodium hydroxide solution (20 mL) were added to the resultant residue, followed by stirring at 5° C. to −15° C. for 1 hour. The mixture was neutralized with 10% hydrochloric acid, and then water (300 mL), THF (200 mL), and ethyl acetate (400 mL) were added to the mixture. An organic layer was washed with saturated brine two times and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield 112 g of trans-4-(3,5-difluorophenyl)cyclohexane carbaldehyde as a light yellow oil.
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1

Procedure:
100 mg of 6-[[2-(piperidin-1-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 47 mg was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].[C:38](Cl)(=[O:46])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[C:40]1([O:39][C:38]([N:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:8](=[O:9])[C:7]5[C:6]([F:24])=[CH:5][CH:4]=[C:3]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:2]=5[F:1])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)[CH:23]=[N:22]2)=[O:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cn[nH]c4)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C(=O)Oc5ccccc5)c4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
In a reaction vial, propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (23, 7 mg, 0.02 mmol) is dissolved in 0.05 mL of acetonitrile and potassium carbonate (4 mg, 0.03 mmol) and carbonochloridic acid, phenyl ester (24, 0.0025 mL, 0.02 mmol) are added and the reaction is stirred at room temperature overnight. The reaction is concentrated under vacuum and the resulting material is purified by reverse phase HPLC to provide the desired compound (P-1016, 0.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([CH3:15])[C:11]=3[CH:16]=2)=[C:4]([CH2:19]Cl)[CH:3]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([CH3:15])[C:11]=3[CH:16]=2)=[C:4]([CH2:19][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Cn1nnc2ccc(Cc3ccc(Cl)cc3CCl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1nnc2ccc(Cc3ccc(Cl)cc3Cn3cncn3)cc21
Yield: 51.8 %

Procedure:
A suspension of 6-[4-chloro-2-(chloromethyl)benzyl]-1-methyl-1H-benzotriazole (0.11 g) from Example 78, 1H-1,2,4-triazole (37 mg) and cesium carbonate (0.18 g) in acetonitrile (2 ml) was refluxed for 30 minutes. After removal of the solvent, the resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1), to give the title compound (63mg; 52%). The purity of the compound was 96.7% by HPLC.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2C[CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:33]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(C(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:33])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(F)(F)F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: FC(F)(F)c1cccc(NCC2CCCC2)c1
Product: CN(C(=O)N(c1cccc(C(F)(F)F)c1)C1CCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Br>COCCOC>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][CH:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:7]=2[N:6]2[C:2]([CH3:1])=[N:3][N:4]=[C:5]12
Reactant: CN(C)CCBr
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2CCN(C)C
Reaction time: 18 h

Procedure:
37.0 g of 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 7.8 g of a 50 percent sodium hydride mineral oil dispersion in 400 ml of dry 1,2-dimethoxyethane are stirred for 2 hours. A solution of 13.7 g of 2-dimethylaminoethyl bromide in 40 ml of dry 1,2-dimethoxyethane is added and the whole is stirred for 18 hours. The solvent is evaporated and the residue is partitioned between methylene chloride and water. The organic phase is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:23])[CH3:24])=[O:27])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)cc3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 4-fluorobenzyl amine (47 mg, 0.32 mmol). The crude material was purified by chromatography on silica gel (0→45% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[C:15](OC(=O)C)(=O)C.C(Cl)(=O)C>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCc1ccccc1C(=O)O
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CCc1ccccc1C(=O)O

Procedure:
2-carboxybenzenepropanoic acid (9.7 g., 0.05 mole), acetic anhydride (15.5 g., 0.15 mole) and acetyl chloride (0.5 g) in dichloromethane (200 ml) was boiled at reflux under nitrogen for 16 hr. The solvents were removed at high vacuum and the residual cyclic anhydride was heated at reflux with methanol (250 ml) for 2 hrs. Evaporation of solvent gave the sub-title compound as an oil which crystallised with petroleum ether (b.p.60°-80°) to a solid (6.3 g) mp 76°-79°. This was further purified by continuous extraction of the crude product with boiling petroleum (b.p.40°-60°) in a Soxhlet apparatus. The pure compound, mp 79°-81° separated from the extracts on cooling.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>O>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=O)N(C)Cc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.12 gms. (0.02 mole) of 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) in 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature of the reaction mixture at circa 0° C. Stirring is continued for 30 minutes and then the reaction mixture is allowed to stand at room temperature overnight. Solvent is stripped and the residue suspended in water. Upon removal of the water there is obtained 1-(p-acetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:15][O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([OH:40])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH2:15][C@H:13]([OH:14])[CH2:12][N:30]([CH2:31][CH3:32])[CH2:29][CH3:28])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O

Procedure:
After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (308 mg, 1.35 mmol), potassium carbonate (149 mg, 1.08 mmol) and dimethylformamide (9 ml) to 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (372.0 mg, 0.90 mmol),
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([NH:38][C@H:39]([C:41](O)=[O:42])[CH3:40])(OC(C)(C)C)=O>>[NH2:38][C@@H:39]([CH3:40])[C:41]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:42]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: C[C@H](N)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-alanine via General Procedure B followed by Boc removal with TFA to generate 30.9 mg of 104 after purification. MS (Q1) 484.3 (M)+.
Reaction SMILES: CO[C:3](=[O:27])[C:4]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CCCCCC>[N+](C1C=CC=CC=1)([O-])=O>[CH3:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[CH3:24])[C:17]([C:4]1[C:3](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[NH:6][CH:5]=1)=[O:26]
Reactant: COC(=O)C(=CNc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(C)c(C)c1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2c[nH]c3ccc(C(F)(F)F)cc3c2=O)cc1C
Yield: 83.3 %

Procedure:
2-(3,4-dimethyl-benzoyl)-3-(4-trifluoromethyl-phenylamino)-acrylic acid methyl ester 2c (151 mg, 0.40 mmol) was refluxed in 5 mL of nitrobenzene for 3 h, then cooled down and to it was added 10 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was washed with hexane to give 115 mg of 3-(3,4-dimethyl-benzoyl)-6-trifluoromethyl-1H-quinolin-4-one as off-white crystals 3b: LC-MSD, m/z for C19H14F3NO2, [M+H]+=346.4,; HPLC retention time: 2.3 min.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[NH2:26][CH2:25][CH2:24][NH:27][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: NCCN
Agent: [H-]
Agent: [Na+]
Product: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (1.58 g, 4.0 mmol) in ethylenediamine (Aldrich, 70 mL) was added NaH (Aldrich, 95%, 1.0 g, 40 mmol) in small portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 1.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were successively washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a brown solid. (Yield 1.1 g, 88.7%).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:13]C(OCC1C=CC=CC=1)=O)[CH3:3].CO.[H][H]>[Pd].O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH2:13])[CH3:3]
Reactant: [H][H]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium on carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:35])([F:34])[CH:26]([C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:28]Br.O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:28][CH2:27][CH:26]([C:25]([F:24])([F:34])[F:35])[C:30]([F:31])([F:33])[F:32])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: FC(F)(F)C(CCBr)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.89 g (8.07 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A were initially charged in 60 ml of DMF, 7.89 g (24.2 mmol) of caesium carbonate and 2.30 g (8.88 mmol) of 4,4,4-trifluoro-3-(trifluoromethyl)butyl bromide were added and the reaction mixture was stirred at RT for 90 min. 60 ml of water were then added, the precipitated solid was filtered off and the filter residue was washed with 100 ml of water and twice with 20 ml of tert-butyl methyl ether. The precipitate obtained from the filtrate was filtered off and washed with mother liquor. Both filter residues were taken up in 50 ml of ethyl acetate. The solution was concentrated on a rotary evaporator and the residue was dried under reduced pressure overnight. This gave 2.25 g of the target compound (95% pure, 64% of theory).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[I-].[C:18]([Si:22]([CH3:39])([CH3:38])[O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30](N2C=C[N+](C)=C2)=[O:31])[CH2:26][CH2:25]1)([CH3:21])([CH3:20])[CH3:19].N12CCN(CC1)CC2>CN(C)C=O>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:38])[CH3:39])[CH2:25][CH2:26]2)=[O:31])=[N:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[n+]1ccn(C(=O)N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccc1
Agent: C1CN2CCN1CC2
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Temperature: 40 °C
Yield: 79.9 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (214 mg, 1.00 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (451 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in dimethylformamide (10 mL) was stirred for 18 hours at room temperature followed by heating for 3 days at 40° C. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60), yielding the title compound (364 mg, 77% yield)
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.CCOCC>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 1 h

Procedure:
A solution of 15% w/w n-butyl lithium in hexane (51 ml.) ca. 0.12 m) was added portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand at room temperature for 1 hour to form 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline. The solution was then added dropwise to a cooled, stirred solution of methylchloroformate (9.45 g., 0.1 m) in ether (100 ml.). The mixture was further treated as described in Example 25 of copending U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.