Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CS(N)(=O)=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(C)(=O)=O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (50 mg, 0.075 mmol) and methane sulfonamide (9.3 mg, 0.098 mmol) as described in the general procedure above to give [18-(isoquinolin-1-yloxy)-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (300 MHz, CD3Cl3) δ 1.18 (s, 9H), 1.25–1.96 (m, 11H), 2.26 (m, 1H), 2.54 (m, 1H), 2.71 (m, 2H), 3.18 (s, 3H), 4.08 (m, 1H), 4.26 (m, 1H), 4.64 (m, 2H), 5.00 (m, 2H), 5.73 (m, 1H), 6.01 (s, 1H), 6.73 (s, 1H), 7.28 (d, J=5.5 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.65–7.76 (m, 2H), 7.98 (d, J=5.9 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 10.28 (s, 1H). LC-MS (Method A, retention time: 3.57 min), MS m/z 670 (M++1).
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>>[Cl:26][CH2:27][C:28]([N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:12]=[C:7]([O:6][CH2:2][CH:3]([CH3:5])[CH3:4])[N:8]=[CH:9][N:10]=2)[CH2:14][CH2:15]1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)COc1cc(N2CCN(C(=O)CCl)CC2)ncn1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a mixture of 4-isobutoxy-6-(piperazin-1-yl)pyrimidine hydrochloride (300 mg, 0.97 mmol) and triethylamine (0.68 mL, 4.9 mmol) was added chloroacetyl chloride (121 mg, 1.07 mmol) at 0° C. After being stirred at the same temperature for 30 min, the mixture was poured onto water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (1.5:1-1:1) to give the title compound (262 mg, 86%) as a colorless oil.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:5]([O:19][CH2:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1>CO>[Cl:3][C:4]1[CH:9]=[C:8]([OH:1])[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23]
Reactant: CC1(C)OB(c2cnc(OCC(F)(F)C(F)F)c(Cl)c2)OC1(C)C
Reactant: OO
Solvent: CO
Product: Oc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
Hydrogen peroxide solution (30% aq. solution, 30.2 mL, 0.26 mol) was added to a solution of 3-chloro-2-(2,2,3,3-tetrafluoropropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 49, 81.0 g, 0.22 mol) in methanol (500 mL) at 0° C. and the reaction was allowed to warm up to room temperature for 4 hours. The reaction mixture was quenched with aqueous sodium thiosulphate (10%, 100 mL) and the methanol removed in vacuo. The resulting mixture was extracted with EtOAc (2×250 mL). The combined organics swere dried over magnesium sulfate, filtered and evaporated to yield a yellow oil, which was purified by silica gel chromatogrpahy eluting with 10% EtOAc in heptane to afford the title compound as a viscous colourless oil (46.7 g, 82%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1C(O)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 67.5 g. (0.5 mole) N-methyl benzamide and 1200 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 688 ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwise over about 1 hour maintaining temperature below 8° C. The resulting dilithio salt is stirred at 5° C. for an additional hour and then a solution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml. tetrahydrofuran is added dropwise in about 1 hour maintaining the temperature between -10° to +10° C. The resulting mixture is stirred at 5° C. for 1 hour longer and 300 ml. of saturated ammonium chloride is added maintaining the temperature at about 10° C. The layers are separated and the organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give α-hydroxy-N-methyl-α-phenyl-o-toluamide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1COCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:29])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (2.0 g, 8.7 mmol) and 4-nitrophenyl isocyanate (1.5 g, 8.8 mmol) in 150 mL of THF was heated to reflux for 2 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 100 mL of ethyl acetate and tritutrated to provide a precipitate which was collected filtration to provide the title compound (3.1 g, 91%). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.45 (m, 4H), 2.86 (d, J=6.44, 2H), 4.48 (d, J=6.44, 2H), 7.37 (m, 1H), 7.63 (m, 1H), 7.70 (m, 2H), 7.90 (m, 1H), 7.99 (s, 1H), 8.19 (m, 2H), 8.89 (s, 1H), 9.43 (s, 1H); MS (DCI/NH3) m/z 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[NH:18][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ccc(-c2nc3ccccc3[nH]2)cn1
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 6-chloronicotinic acid (0.785 g, 5.000 mmol) and o-phenylenediamine (0.540 g, 5.000 mmol) was added to pre-heated (150° C.) polyphosphoric acid (5 g) with stirring. The stirring was continued at 150° C. overnight. Water was added to the reaction mixture, and the resulting solution was neutralized with NaHCO3, and extracted with ethyl acetate. The organic phase was dried and evaporated to afford 2-(6-chloropyridin-3-yl)-1H-benzoimidazole in 40% yield (0.468 g, 2.04 mmol).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl.Cl.[CH2:15]([NH:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[CH2:15]([N:22]1[N:23]=[CH:2][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNCc1ccccc1
Reactant: O=C(O)c1ccccc1C(Br)Br
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1c2ccccc2cnn1Cc1ccccc1
Yield: 51.2 %

Procedure:
α,α-dibromo-o-toluic acid (29.4 g), benzylhydrazine dihydrochloride (19.5 g) and triethylamine (60 g) were allowed to react as in Example 4. There was obtained 12.1 g (yield: 51%) of 2-benzyl-1-phthalazinone having a melting point of 104°-105° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([O:34]CC)=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([OH:34])=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@@H](C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.5 mL, 2 M, 1.0 mmol) was added to a solution of ethyl (3R)-1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-3-carboxylate (255 mg, 0.52 mmol) in a 1:1 mixture of MeOH:H2O (10 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (50 mL). The solvent was concentrated to 50 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 236 mg (98%); MS (ESI) (M+H)+=464.1.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[CH3:11][O:12][C:13](=[O:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]2[S:15][C:14]([C:13]([O:12][CH3:11])=[O:16])=[CH:8][C:7]=12
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(F)cncc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a cooled (0° C.) solution of 3,5-difluoro-4-formylpyridine (1.00 g, 6.99 mmol) in THF (12.3 mL) was added mercaptoacetic acid methyl ester (625 μL, 6.99 mmol). The reaction stirred 1 h at 0° C. and 1 h at room temperature, and then cesium carbonate (2.28 g, 6.99 mmol) was added. The reaction then stirred a further 18 h at room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and brine (50 mL). The layers were separated and the organic fraction was washed with water (1×50 mL) and brine (1×25 mL), then dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (20 to 40% ethyl acetate:hexanes) afforded 942 mg (64%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.23-9.29 (m, 1 H), 8.56 (dd, J=2.0, 0.5 Hz, 1 H), 8.25 (d, J=0.8 Hz, 1 H), 3.94 (s, 3 H); MS (ESI): 212.09 [M+H]+; HPLC tR=3.17 min (ZQ3, polar—4 min).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:29]([OH:30])=[CH:28][C:21]4[N:22]([CH3:27])[C:23](=[O:26])[CH2:24][O:25][C:20]=4[CH:19]=3)(O)[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:29]([OH:30])=[CH:28][C:21]4[N:22]([CH3:27])[C:23](=[O:26])[CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a solution of 7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (4.0 g, 8.1 mmol) in trifluoroacetic acid (1.8 mL, 24.4 mmol) was added triethylsilane (3.9 mL, 24.4 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography with ethyl acetate in hexanes (10 to 100% gradient) to afford 7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (2.66 g, 71%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ9.53 (s, 1H), 7.44-7.28 (m, 10H), 6.99-6.95 (m, 3H), 6.89-6.84 (m, 2H), 6.54 (s, 1H), 6.40 (m, 1H), 4.90 (s, 1H), 4.57 (s, 2H), 3.21 (s, 3H); MS (ES+) m/z 477.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:12]([CH:14]=[CH2:15])=O.Cl.[OH-].[Na+]>CCOC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=1)[N:5]=[CH:15][CH:14]=[CH:12]2
Reactant: C=CC=O
Reactant: COc1ccc(N)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2ncccc2c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
2,4-Dimethoxyaniline (20.0 g, 131 mmol), 8.70 mL (7.30 g, 131 mmol) acrolein and 500 mL 1 N HCl are refluxed for 30 min. The reaction mixture is cooled to 23° C., poured into 200 mL of vigorously stirring EtOAc, and neutralized with 10N NaOH. The resulting bi-phasic solution is stirred for 30 min and filtered through celite. The layers are separated, and the aqueous layer is extracted with 3×300 mL EtOAc. The combined organics are washed with 1×400 mL H2O, 1×400 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2, eluting with 4/1 EtOAc/hexanes containing 10% MeOH, gives 6.40 g (33.8 mmol, a 26% yield) of the title compound as an off-white solid. MS (ES) m/z 190 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[N:6]=[C:5]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:34]#[C:33][CH2:32][OH:35])[CH:3]=2)[N:8]=1
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Yield: 42.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol) was added to a solution of (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (prepared as described in Synthesis 32-A, 0.250 g, 0.515 mmol), propargyl alcohol (0.043 g, 0.773 mmol) and triethylamine (0.108 mL, 0.773 mmol) in THF (2.5 mL) and the solution heated to reflux for 16 hours. The mixture was cooled then purified by ion exchange chromatography on SCX-2 Isolute acidic resin (5 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by column chromatography, eluting with 5% methanol in dichloromethane, gave the title compound as a solid (0.100 g, 42%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[C:25](F)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1>CN(C=O)C>[F:18][C:19]1[C:25]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2cccc3cnccc23)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
5-Isoquinolinethiol 1.00 g (6.2 mmol) was dissolved in DMF 25 ml, potassium carbonate 1.60 g (11.6 mmol) and 4,5-difluoro-2-nitroaniline 1.00 g (5.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and the resulting precipitates were collected and washed with water to give 4-fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 1.95 g (quantitative).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Br:16])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Br:16])=[C:8]([C:12]([F:14])([F:13])[F:15])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.40 g, 4.68 mmol) was suspended in MeOH (15 mL); Sodium hydroxide (2.0 M aqueous solution) (14.04 mL, 28.1 mmol) was added and the suspension was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in water (100 mL) and then acidified by the addition of 5.0M HCl(aq). The product was extracted into ethyl acetate (2×75 mL) and the combined organic extracts were washed with water (50 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as a yellow solid. 1H-NMR: [400 MHz, DMSO-d6] δ 13.24 (1H, br s, CO2H), 7.74 (1H, s, ArH), 7.17 92H, br s ArNH2). m/z 285.1, 287.1 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH2:11][CH2:10]2)=[O:5])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:12]1[C:13]2[C:9](=[C:8]([CH3:24])[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]([CH3:16])[C:14]=2[NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:10][CH2:11]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
N-(5-Ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in DMF (15 ml), and 1-iodooctane (5.0 g) and K2CO3 (2.9 g) were added, which was followed by stirring under a nitrogen atmosphere at 50° C. for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0 -50/1) to give 3.5 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([OH:10])[CH2:7][C:8]#[N:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.B.O1CCCC1.B.[ClH:22]>CO>[ClH:22].[NH2:9][CH2:8][CH2:7][CH:6]([C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][CH:5]=1)[OH:10]
Reactant: N#CCC(O)c1csc2ccccc12
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCC(O)c1csc2ccccc12
Temperature: 75 °C
Yield: 58 %

Procedure:
3-Benzo[b]thiophen-3-yl-3-hydroxy-propionitrile (1.2 g, 5.90 mmol) was slowly treated with a solution of borane-tetrahydrofuran complex (13 mL, 12.98 mmol, 1M in tetrahydrofuran) at 0° C. After bubbling ceased, the reaction mixture was heated to 75° C. for 2 hours and 6.0 eq of additional borane was added to drive the reaction to completion. The reaction mixture was concentrated. The white solid obtained was treated with methanol (14 mL), followed by hydrogen chloride (2M in diethyl ether, 43 mL). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. To the residue was added aqueous hydrochloric acid (10 mL, 1 N) followed by diethyl ether (20 mL). The aqueous layers were separated and concentrated at reduced pressure to give the product as a yellow solid (840 mg, 58%).
Reaction SMILES: C1(CNC([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=O)C=CC=CC=1.C(O)C.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([O-:35])=O>[Pd].ClCCl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=[O:35]
Reactant: NC(=O)CC(NC(=O)NCc1ccccc1)C(N)=O
Reactant: O=C([O-])c1ccc2ccccc2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)CC(NC(=O)c1ccc2ccccc2n1)C(N)=O

Procedure:
A solution of [S-[1R*(R*),2S*]]-N1[3-[[[(1,1-dimethylethyl)amino]carbonyl]n-butyl)amino]-2-hydroxy-1-(phenylmethy)propyl]-2-[(phenylmethylcarbamoyl)amino]butanediamide (1.03 g, 1.77 mmol) in 40 mL of abs. ethanol was then deprotected by hydrogenolysis in the presence of 10% palladium on carbon catalyst to give, after filtration and concentration, the free amine (428 mg) which was coupled with N-hydroxysuccinimide ester of 2-quinoline carboxylate (270 mg, 1.0 mmol) in dichloromethane for 16 h to give 380 mg, 63% of [1S-[1R*(R*),2S*]]-N1[3-[[[1,1-dimethylethyl)amino]carbonyl](n-butyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide, mp 102.1°-103° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine