Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([C:28]4[CH:29]=[CH:30][C:31]5[C:35]([CH:36]=4)=[N:34][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=5)[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([N:33]1[CH:32]=[C:31]2[C:35]([CH:36]=[C:28]([C:20]3[CH:19]=[C:18]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][CH2:17][NH:8][CH2:9]5)=[CH:14][CH:13]=4)[N:26]4[C:21]=3[C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)[CH:29]=[CH:30]2)=[N:34]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(-c3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-[4-amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.7 g, 4.7 mmol) in DCM (17 mL) was added TFA (8.6 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and ethyl acetate was added. Saturated, aqueous NaHCO3 was added until the pH was basic. Yellow gum formed in the wall of glass, it was dried in vacuum oven overnight and the title product was obtained as light yellow solid, 2.2 g (98%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.1 (m, 2 H), 3.2 (m, 2 H), 2.80 (m, 2 H); ES-MS m/z 472.29 [M+H]+, HPLC RT (min) 2.22.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C[O-].[Na+].CO>C(OCC)C>[O:23]=[C:17]([CH2:15][C:14](=[O:16])[C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)c1cnc(Oc2ccccc2)nc1

Procedure:
A mixture consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Example 38, Step B, 214 mg, 1.00 mmol) and diethyl oxalate (0.14 mL, 150 mg, 1.0 mmol) in diethyl ether (10 mL) under a nitrogen atmosphere at room temperature was stirred for ten minutes. Sodium methoxide (65 mg, 1.2 mmol) was subsequently added followed by methanol (1.0 mL). The solution was stirred overnight at room temperature. The off-white precipitate which had formed was collected by filtration and washed with diethyl ether. The solid was dissolved in water and the pH adjusted to 3 using acetic acid. The solid precipitate which formed was filtered and washed with water. The solid was air dried to afford a mixture comprising both the ethyl and methyl esters.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25](=[S:27])[NH:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3].IC.[CH:31](N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25]([S:27][CH3:31])=[N:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2ccc3ncc(S(C)(=O)=O)c(-c4ccccc4)c3c2)S1

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 61j), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one. LC-MS m/e 441 (MH+).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1ccc(-c2ccc([C@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Ethylaminomethyl -pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.05 g, 0.112 mmol) in CH2Cl2 (0.2 mL) is added trifluoroacetic acid (0.2 mL) at 0° C. Reaction mixture allowed to warm to room temperature and stirred for 2 hours. The volatiles were removed under reduced pressure to obtain crude material purified by column chromatography eluting in 10% methanol in CH2Cl2 to afford crude title compound (0.04 g, crude). LC-MS (m/z): [M+H]=304.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14].[H-].[Na+].I[CH2:27][CH2:28][CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([N:19]([CH2:27][CH2:28][CH3:29])[C:20](=[O:23])[CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: CCCI
Reactant: CCC(=O)Nc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)CC)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(3-(2,4-Dichlorophenyl)-2,6-dimethylpyrazolo[5,1-b]oxazol-7-yl) propionamide (634 mg, 1.800 mmol) is suspended in dry DMF (20 ml) and treated with NaH (60% in oil) (86 mg, 2.160 mmol) under N2 at RT. The mixture is stirred at RT for 10 minutes before cooling to 0° C. in an ice bath. 1-Iodopropane (0.263 ml, 2.70 mmol) is added dropwise and the reaction mixture is stirred at 0° C. for 1 hr. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc and washed with 1M NaOH, 1M HCl, H2O, brine, dried (MgSO4) and evaporated down to give a brown oil. Purification by chromatography on silica eluting with 0% to 50% EtOAc/iso-hexane affords the title compound as a clear oil; MS: m/z 394.1 [M+H]+
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]([CH:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:17])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:18]([N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[CH3:17])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
N,N-Dimethylformamide and benzyl bromide (2.3 ml, 19 mmol) were added sequentially to ethyl 3-[N-(t-butoxy carbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionate (5.10 g, 16 mmol) obtained from Example 16a and potassium carbonate (3.27 g, 24 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford the desired compound (5.57 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:16])[C:13](=[O:15])[CH3:14])=[CH:8][C:6]=2[N:7]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1B(O)O>>[NH:23]1[C:31]2[C:26](=[C:27]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:16])[C:13](=[O:15])[CH3:14])=[CH:8][C:6]=4[N:7]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(=O)N(C)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OB(O)c1cc2ccccc2[nH]1
Product: CC(=O)N(C)Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 193. NMR: 400MHz; CDCl3 2.10, 2.18 (3H,s,2 rotamers); 3.00 (3H,s); 3.84 (4H,m); 4.00 (4H,m); 4.73, 4.77 (2H,s,2 rotamers); 7.26 (2H,m); 7.33 (1H,s); 7.42 (1H,m); 7.48 (1H,s); 8.13 (1H,m); 8.21 (1H,br s). MS: (ESI+):M+H(422)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=1.[Br:14]Br.Cl>C(=O)([O-])[O-].[K+].[K+]>[F:13][C:2]([F:1])([F:12])[C:3]1[NH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[C:6]([Br:14])[N:7]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cnc(C(F)(F)F)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1nc(Br)c(C(F)(F)F)[nH]1
Yield: 64 %

Procedure:
2,5-bistrifluoromethylimidazole is dissolved in an aqueous solution of potassium carbonate. Bromine 1.1 equivalents is added and heated until color dissipates. Solution is acidified with dilute hydrochloric acid and extracted with ether. The ether layer is washed once with brine solution, dried over sodium sulfate and stripped to give product in 64% yield.
Reaction SMILES: CC(S([NH:7][C:8]1([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][O:10][CH2:9]1)=O)(C)C.[ClH:18].C(OCC)C>CO>[ClH:18].[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[C:8]1([NH2:7])[CH2:11][O:10][CH2:9]1
Reactant: CC(C)(C)S(=O)NC1(c2ncccn2)COC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1(c2ncccn2)COC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a yellow solution of 2-methyl-N-(3-(pyrimidin-2-yl)oxetan-3-yl)propane-2-sulfinamide (0.025 g, 0.098 mmol) in MeOH (1 ml) in a 10 ml round-bottomed flask was added a solution of HCl in diethyl ether (0.098 ml, 0.392 mmol, 4N). The reaction mixture was stirred at 0° C. for 10 min., and then concentrated at 25° C. The residue was washed with n-hexane and dried to give the titled product as a white solid (0.017 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.15 (bs, 2H), 9.01 (d, J=4.8 Hz, 2H), 7.64 (t, J=5.0 Hz, 1H), 5.00 (d, J=7.2 Hz, 2H), 4.87 (d, J=7.2 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]12[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]1[CH2:17][O:16][NH:15]2>ClCCl>[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]12[CH2:21][NH:20][CH2:19][CH:18]1[CH2:17][O:16][NH:15]2
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2cnccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(C23CNCC2CON3)cn1
Reaction time: 1 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (40 mL) is added to a stirred solution of tert-butyl 6a-pyrazin-2-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5.14 g, 17.58 mmol) in dichloromethane (200 mL) at room temperature. The mixture is stirred for 1 hour and the solvents are evaporated under reduced pressure. The resulting residue is dissolved in methanol (100 mL) and loaded onto an ion exchange column (50 g) and the column is first eluted with methanol (110 mL) followed by 7 M ammonia/methanol solution (150 mL). This basic fraction is concentrated under reduced pressure to give a crude product which is further purified by silica gel column chromatography using a 0-10% gradient of 0.14 M ammonia/methanol in dichloromethane to give the title compound (2.4 g, 71%). ES/MS (m/e): 193 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH:29]([CH3:33])[NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH:29]([CH3:33])[N:28]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]4)[CH2:11][CH3:12])[C:27]=3[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: CC1CCc2c(cnn2-c2ccc(F)cc2)N1
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)cc1C
Product: CCC(C(=O)N1c2cnn(-c3ccc(F)cc3)c2CCC1C)n1nc(C(F)(F)F)cc1C
Yield: 46 %

Procedure:
The title compound was prepared from 2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 13 mg (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.47 (m, 2H), 7.16 (m, 2H), 6.35 (s, 1H), 5.37 (dd, J=6.7, 8.6 Hz, 1H), 4.63 (m, 1H), 2.86 (m, 1H), 2.73 (ddd, J=1.9, 5.1, 11.3 Hz, 1H), 2.37 (s, 3H), 2.27 (m, 2H), 1.92-1.97 (m, 2H), 0.93 (t, J=6.5 Hz, 3H), 0.57 (t, J=6.7 Hz, 3H); MS: (ES) m/z calculated for C22H24F4N5O [M+H]+ 450.2, found 450.2.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31](ON2C3C=CC=CC=3N=N2)=[N:30][CH:29]=1>CS(C)=O>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: c1ccc2c(c1)nnn2Oc1ccncn1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.3 mL of DMSO was added sodium hydride (60% suspension in mineral oil, 13 mg, 0.32 mmol) at room temperature. The reaction mixture was stirred for 5 minutes, and was treated with 1-(pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole (Example 110, Step A) (170 mg, 0.80 mmol). The reaction mixture was stirred at 110° C. for 13 hours. The reaction mixture was cooled to room temperature, quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 45% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:25]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]([C:23]#[N:24])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[N:18][CH:19]=3)[N:14]=2)=[CH:8][CH:7]=1.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH2:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[C:22]([C:23]#[N:24])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[N:18][CH:19]=3)[N:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Nc2nc3ccncc3cc2C#N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(Nc2nc3ccncc3cc2C#N)cc1
Yield: 96 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-[4-(3-cyano[1,6]naphthyridin-2-ylamino)phenyl]propionic acid methyl ester (0.12 g) was disolved in dioxane (2 ml) and treated with saturated solution of hydrogen chloride in dioxane (2 ml) for 2 h at room temperature. The solvent was removed under reduced pressure to yield the title compound (0.1 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.Cl.O1CCOC[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Yield: 91.4 %

Procedure:
A suspension of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoic acid (preparation 38, 0.47 g, 1.5 mmol) and a 4M solution of hydrochloric acid in dioxane (2.00 mL, 8.0 mmol) in methanol (2 mL) was heated in a sealed tube at 80° C. with stirring. After stirring overnight the mixture was cooled and ethyl acetate and saturated aqueous potassium carbonate solution were added. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The resultant oil was taken up in a small amount of ethyl acetate and the suspension was filtered. The filtrate was evaporated to give the title compound (0.46 g, 86%) as a foam.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:10]=1)(=O)=O.O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:20][C:19]([F:22])([F:21])[S:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][O:6][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(OCCc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 0.85 g (2.11 mmole) of 4-(trifluoromethylsulfonyloxy)phenethyl trifluoromethansulfonate, 0.27 g (2.2 mmole) p-hydroxybenzaldehyde and 0.72 g (2.2 mmole) cesium carbonate in acetonitrile was stirred at room temperature over night. The salts were filtered off and the solvent evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent gave 0.6 g (yield 75%) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[CH2:38][C:39]1[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=1>CS(C)=O>[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[N:26]([CH2:38][C:39]4[N:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][CH:40]=4)[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cesium carbonate (1.63 g) was added to a stirred solution of the product of step (iv) (1.5 g) in dimethylsulphoxide (20 ml). After 15 minutes triethylamine (0.71 ml) was added followed by the product from step (ii) (1.11 g). The mixture was stirred at room temperature for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% methanol in chloroform. Yield 1.86 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14]N(C)CCCN=C=NCC.CCOCC>CC#N.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C([O-])Cc1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-(S-[4-tert-butoxycarbonyl)-4-(tert -butoxycarbonylamino)]butanoyl)indoline-5-acetate 7. Crude 3 (327 mg, 1.9 mmol) was prepared as described above (see compound 4), dissolved in dry MeCN (30 mL) and treated with DMAP (611 mg, 5 mmol) and N-tert-BOC-L-glutamic acid α-tert-butyl ester (607 mg, 2 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (422 mg, 2.2 mmol). The mixture was stirred at rt for 18 h, then evaporated and the residue was dissolved in EtOAc and washed successively with 0.5 M aq. HCl, saturated aq. NaHCO3 and brine, dried and evaporated to give a viscous oil. Flash chromatography [EtOAc-hexanes (55:45)] and trituration with ether gave. 6 as white crystals (626 mg, 69%), mp 80-81° C. (EtOAc-hexanes); IR: νmax/cm−1; 3340, 1730, 1680, 1655, 1625; 1H NMR: δH (400 MHz) 8.15 (d, J=8 Hz, 1H), 7.07-7.11 (m, 2H), 5.23 (d, J=6.9 Hz, 1H), 4.22 (m, 1H), 4.03 (2×t, J=8.5 Hz, 2H; rotamers), 3.68 (s, 3H), 3.57 (s, 2H), 3.17 (t, J=8.5 Hz, 2H), 2.43-2.59 (m, 2H), 2.18-2.31 (m, 1H), 1.98-2.07 (m, 1H), 1.47 (s, 9H) and 1.41 (s, 9H). Anal. Calcd for C25H36N2O7: C, 63.01; H, 7.61; N, 5.88. Found: C, 63.08; H, 7.81; N, 5.64.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:44]=[CH:43][C:11]([CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:42])=[C:24]([C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]3)[CH3:21])=[O:19])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:42][C:23]1[C:22]([N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:11]2[CH:43]=[CH:44][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][CH:10]=2)=[CH:40][CH:39]=[C:38]([Cl:41])[C:24]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCCBr)cc4)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCCC5=O)cc4)c3Cl)c2n1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a stirred solution of 8-[3-[N-[4-(bromobutyramido)cinnamoylglycyl]-N-methylamino]-2,6dichlorobenzyloxy]-2-methylquinoline (50 mg) in N,N-dimethylformamide was added potassium carbonate (30 mg) at ambient temperature and the resulting mixture was stirred at the same temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (methanol-ethyl acetate=1:12, V/V) to afford 8-[2,6-dichloro-3-[N-methyl-N-[4-(2-oxo-1-pyrrolidinyl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (33.4 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[CH3:5][C:6]1[C:11]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:21][C:22]([OH:24])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:4][O:3][N:2]([CH3:1])[C:22](=[O:24])[CH2:21][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:6]=1[CH3:5]
Reactant: CNOC
Reactant: Cc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1C

Procedure:
1 ml of N,O-dimethylhydroxylamine was added progressively to a mixture of 2.88 g of 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid and 2.06 g. of dicyclohexylcarbodiimide in 50 ml of chloroform and the mixture was stirred for 4 hours at room temperature. The precipitate was filtered off and the filtrate was evaporated to dryness to obtain N-methoxy-N,2-dimethyl-3-(p-chlorobenzoyl)-phenylacetamide.