Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21]([N:2]2[C@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:22])[N:20]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.87 min; [M+H]+=425.1.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([SiH2:10][O:11][C:12]([CH3:29])([CH3:28])[C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.[CH:38](N1CCCCC1)=[O:39].Cl>C(OCC)C>[C:6]([SiH2:10][O:11][C:12]([CH3:29])([CH3:28])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:26]=1[S:25][C:24]1[C:23]([CH2:38][OH:39])=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]2[CH3:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN1c2ccccc2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN1c2cccc(CO)c2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
36.4 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon at -78° to a solution of 14.0 g (39.2 mmol) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazine and 6.39 ml of N,N,N',N'-tetramethylethylenediamine in 120 ml of diethyl ether. The reaction mixture was stirred at -78° for 30 minutes, brought slowly to room temperature, stirred for 3 hours, thereupon treated with 5.66 ml (51.0 mmol) of N-formylpiperidine, stirred at 0° for 40 minutes and then poured into 50 g of ice, 50 ml of 0.1N aqueous hydrochloric acid solution and 250 ml of diethyl ether. The aqueous phase was extracted several times with diethyl ether. The combined organic phases were dried over magnesium sulphate and concentrated. The crude 6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazine-4-carbaldehyde (about 14 g) remaining as the residue was dried in a high vacuum, dissolved in 120 ml of tetrahydrofuran and treated at 0° with 50 ml of lithium borohydride solution (1N in tetrahydrofuran). The reaction mixture was stirred at room temperature for 1 hour and then poured into 100 ml of 0.1N aqueous hydrochloric acid solution, 100 g of ice and 150 ml of diethyl ether. The aqueous phase was extracted with diethyl ether and the combined organic fractions were dried over magnesium sulphate and concentrated. The residue was chromatographed on 1.3 kg of silica gel with ethyl acetate/hexane (1:4), whereupon, after drying in a high vacuum, 4.57 g (30.0%) of [6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazin-4-yl]-methanol were obtained as a colourless oil. MS: 387 (M+ ; 100), 238(91), 224(24), 75(97).
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O=S(Cl)[Cl:16].O>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][Cl:16])[C:3]=1[O:12][CH3:13]
Reactant: COc1cc(Br)c(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c(OC)c(CCl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 52 (7.5 g, 30 mmol) and ZnCl2 (1 g) in THF (100 ml) was added SOCl2 (5.31 g, 45 mmol) dropwise. After 1 hr at rt, the reaction was poured into water and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography on silica gel (10% EtOAc/hex) to give 53 as an oil (5.5 g, 75%): 1H NMR(DMSO-d6) δ 7.21(d, 1 H, J=3.0 Hz), 7.08 (d, 1 H, J=3.0 Hz), 4.73 (s, 2 H), 3.78 (s, 3 H), 3.75 (s, 3 H)
Reaction SMILES: S(=O)(=O)(O)O.C([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)(=O)C.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23].OO>O.C(O)=O>[C:22]([O:25][C:9]1[CH:21]=[CH:20][C:19]2[C:14]3[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: O=CO
Product: CC(=O)Oc1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Sulfuric acid (40 mL) was added to a mixture of 2-acetylfluorene (165 g), formic acid (320 g), acetic anhydride (120 g) and dicholoromethane (1 L), and then aqueous hydrogen peroxide (120 mL) was dropwise added thereto. The solution was stirred for 30 minutes at a room temperature, and it was heated up to 40° C. and further stirred for 5 hours. Water (1 L) was added to the reaction mixture, and the dichloromethane layer was separated. The dichloromethane layer was washed in order with a saturated sodium carbonate aqueous solution, a sodium hydrogensulfite aqueous solution and water, and then it was dried on anhydrous magnesium sulfate and concentrated to obtain a solid matter. This was recrystallized from a mixed solvent of heptane-ethyl acetate (1:1) to obtain 2-acetoxyfluorene (149 g) of colorless needle crystal. The melting point was 130 C.
Reaction SMILES: N1([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])C2C=CC=CC=2N=N1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.CCN(CC)CC>C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])([CH3:13])[NH:24]2)=[N:21][CH:22]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(C)=CC(=O)n1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
(400 mg, 2.0 mmol) 1-Benzotriazol-1-yl-3-methyl-but-2-en-1-one (Example 1, step 1), (5-bromo-pyridin-2-yl)-hydrazine (410 mg, 2.2 mmol, 1.1 equiv.) and Et3N (1.95 ml, 14.0 mmol, 7 equiv.) were dissolved together in THF (2 ml) and stirred for 90 minutes at reflux temperature. The reaction mixture was cooled and extracted with saturated Na2CO3 solution and two times with ethyl acetate. The organic extracts were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 2-(5-bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (230 mg, 43% yield) was obtained as a yellow oil, MS: m/e=270.2/272.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:35])=O.ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:35])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A mixture of 7-(2-dimethylamino-benzooxazol-5-yloxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (364 mg, 0.83 mmol), phosphorus oxychloride (92 μL, 1.00 mmol) and dichloroethane (4.5 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was then stirred with saturated sodium bicarbonate for fifteen minutes at ambient temperature. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (220 mg): MS: (+) m/z 456.32 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].S(Cl)([Cl:16])(=O)=O>C(OCC)C>[Cl:16][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc(O)c(O)c1
Solvent: CCOCC
Product: COC(=O)c1cc(O)c(O)c(Cl)c1
Temperature: 0 °C

Procedure:
To a suspension of methyl 3,4-dihydroxybenzoate (5.0 g) in diethyl ether (300 mL) stirred at 0° C. was added sulfuryl chloride (3.7 mL) dropwise. The reaction mixture was stirred at 0° C. for 16 h. The solvent was removed in vacuo. The residue was washed with hot chloroform (2×150 mL) to afford methyl 3-chloro-4,5-dihydroxybenzoate (D68) (1.9 g) as a white solid. δH (DMSO-d6, 400 MHz): 3.78 (3H, s), 7.33 (1H, d), 7.37 (1H, d), 10.11 (2H, br s). MS (ES): C8H7ClO4 requires 202. found 203.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 64.8 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (360 mg) was reacted with 4-chlorophenol (178.3 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(4-chlorophenoxy) propanamide (248 mg).
Reaction SMILES: [C@@H:1]12[CH2:7][CH2:6][C@@H:5]1[CH2:4][N:3]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:2]2.[OH-].[Na+].Cl>CO>[C@@H:5]12[CH2:6][CH2:7][C@@H:1]1[CH2:2][N:3]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH2:4]2
Reactant: COC(=O)c1ccc(OCCCN2C[C@H]3CC[C@H]3C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCN2C[C@H]3CC[C@H]3C2)cc1

Procedure:
A mixture of 3.5 g of the compound of Step 1, of 12.7 ml of 2N sodium hydroxide solution and 8 ml of methanol is heated at reflux for one hour. To the reaction mixture, cooled in an ice bath, there are added 12.7 ml of 2N HCl. The precipitate is washed with water and dried in vacuo.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 58 mg (yield 95%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[OH:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[N:5][N:4]2[CH2:3][C@@H:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:14])=[CH:8][CH:9]=1
Reactant: C[C@H](N)Cn1ncc2ccc(O)cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Yield: 543 %

Procedure:
To a suspension of 1-((S)-2-aminopropyl)-1H-indazol-6-ol (2.00 g, 10.5 mmol) in THF (20 mL) was added saturated aqueous sodium bicarbonate (10 mL) and benzyl chloroformate (1.50 mL, 1.5 mmol). The mixture was stirred until all of the solid starting amine dissolved. After stirring at ambient temperature for 45 minutes saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were dried (MgSO4) and evaporated to give a tan foam (2.65 g, 78%): LC/MS (+APCI) m/z 326 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[F:16][CH:17]([F:34])[C:18]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:34][CH:17]([F:16])[C:18]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])=[CH:23][C:19]=1[C:20]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:21]
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)C)cnc3C(F)F)cccc12
Yield: 4.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 100 mg, 0.50 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 161 mg, 0.60 mmol), oxalyl chloride (113 mg, 0.90 mmol), DMF (1 drop) and DIPEA (192 mg, 1.49 mmol) in CH2Cl2 (2 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.64 (m, 1H), 8.48 (m, 2H), 8.08 (m, 3H), 7.53 (m, 1H), 7.23 (t, J=54 Hz, 1H), 4.44 (m, 1H), 4.41 (d, 2H), 2.50 (m, 1H), 1.27 (d, J=6.9 Hz, 6H), 1.04 (d, J=7.5 Hz, 6H); MS [M+H]+: 457.47.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)propanoate (42 mg, 0.092 mmol) was dissolved in THF (0.738 mL) and water (0.184 mL) before lithium hydroxide monohydrate (2.56 μL, 0.092 mmol) was added and stirred at ambient temperature for 2 h. The reaction mixture was concentrated, acidified with 1 N HCl, filtered, washed with water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 441.2; Observed: 442.2 (M++H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl.CCO>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:10]1[N:34]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(F)cc1Nc1ccncc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a suspension of (S)-Boc-alaninamide (385 mg, 2.05 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (389 mg, 2.05 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was left to stir at RT for 1 h. The volatiles were removed under reduced pressure and to the resulting residue was added 4-fluoro-N2-pyridin-4-yl-benzene-1,2-diamine (208 mg, 1.02 mmol) in absolute EtOH (5 mL) and the mixture was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound as a pale yellow oil (210 mg, 58%). LCMS (Method C): RT 2.84 min [M+H]+ 357.15
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.[F:40][C:41]1[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][C:44](B(O)O)=[C:43]([O:53][CH3:54])[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3[C:44]3[CH:45]=[C:46]([CH:47]([CH3:49])[CH3:48])[C:41]([F:40])=[CH:42][C:43]=3[O:53][CH3:54])[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc([N+](=O)[O-])cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 90 °C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (3.877 g, 7.35 mmol) in a toluene (24 mL): ethanol (12 mL): water (6 mL) mixture was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (2.337 g, 11.03 mmol), tetrakis (triphenylphosphine) palladium(0) (425 mg, 5 mol %) and sodium carbonate (1.56 g, 14.72 mmol). The resulting mixture was bubbled with nitrogen and then heated in a 90° C. oil bath for 10 h. An aliquot showed complete consumption of the starting material. The reaction was quenched with brine. The resulting mixture was extracted with EtOAc and dried over Na2SO4. The resulting glassy mixture was purified by SiO2 (Biotage 40S cartridge, EtOAc/hexane, gradient). The titled compound was obtained as a crystalline solid. LC-MS: 615.26 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 8.31 (s, 1 H), 8.20-8.26 (m, 1 H), 7.86 (s, 1 H), 7.70 (s, 2 H), 7.39-7.43 (m, 1 H), 6.96-7.01 (m, 1H), 6.67-6.72 (m, 1H), 5.64 (d, J=8.0 Hz, 0.5H), 5.48 (d, J=8.0 Hz, 0.5H), 4.90 (d, J=16.3 Hz, 0.5H), 4.86 (d, J=16.3 Hz, 0.5 H), 4.10-4.16 (m, 0.5 H), 3.84-3.94 (m, 1.5 H), 3.77 (s, 1.5H), 3.75 (s, 1.5H), 3.15-3.26 (m, 1H), 1.15-1.29 (m, 6 H), 0.57 (d, J=6.6 Hz, 1.5 H), 0.40 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][CH:19]=2)[N:14]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][CH:19]=2)[N:14]=1
Reactant: COc1ccc2cc(C(=O)O)c(NCCCNC(=O)OC(C)(C)C)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2cc(C(=O)O)c(NCCCN)nc2c1

Procedure:
A suspension of 2-(3-tert-Butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid (30 mg, 0.08 mmol) in dry 4N HCl/1,4-Dioxane (1 ml) solution was heated at reflux for 5 days. After evaporating the solvent, the residue was recrystallized from methanol and diethyl ether to give 2-(3-Amino-propylamino)-7-methoxy-quinoline-3-carboxylic acid as the white crystal; 19.3 mg (88%). 1H NMR (400 MHz, DMSO-d6) ppm 1.91 (m, 2H), 2.90 (t, 2H, J=7.3 Hz), 3.56 (m, 2H), 3.83 (s, 3H), 6.74 (dd, 1H, J=2.4, 8.6 Hz), 6.88 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=8.6 Hz), 8.24 (br, 1H), 8.37 (s, 1H), 10.38 (br, 1H). LC/MS: m/z 276 (M+1)+, 274 (M−1)−.