Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:18])[C:15](O)=[O:16])=[CH:9][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH3:28]>ClCCl.CN(C)C=O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:18])[C:15]([NH2:28])=[O:16])=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
305 mg (1.07 mmol) of 3-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-acrylic acid is dissolved in 8 ml of dichloromethane and one drop of dimethylformamide is added. The solution is cooled to 0° C. and treated dropwise with 676 mg (5.33 mmol) oxalyl chloride. The resulting solution is stirred at 0° C. for additional 30 minutes, then 2 hours at RT. Evaporation of the solvent leaves the crude acid chloride which is dissolved in 5 ml THF. This solution is slowly added under stirring to 10 ml of concentrated ammonia. The precipitate is filtered off and recrystallised from methanol to yield 199 mg (65%) of a colorless solid. MS: m/e=286.2 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][NH:18][CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH:33]1([CH2:36][N:18]2[CH2:17][CH2:16][C@:15]3([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:10]=4)[C@@H:20]([CH2:21][C:22]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]5)=[N:25][C:23]=4[CH2:24]3)[CH2:19]2)[CH2:35][CH2:34]1
Reactant: O=CC1CC1
Reactant: c1ccc(COc2cccc([C@@]34CCNC[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(COc2cccc([C@@]34CCN(CC5CC5)C[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
(4aR, 12aR)-4a-(3-benzyloxyphenyl)-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (84 mg), and cyclopropanecarboaldehyde (0.0305 ml, 0.40 mmol) were dissolved in dry THF (4 ml), and triacetoxysodium borohydride (84. 8 mg, 0.40 mmol) and acetic acid (0.0126 ml, 0.22 mmol) were added to the resultant solution, followed by stirring at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution (30 ml) and water (30 ml) were then added to the solution, and the resultant mixture was extracted with chloroform (100 ml, twice). The organic layers were dried over sodium sulfate, and then concentrated. The residue was purified by using a silica gel column to obtain (4aR, 12aR)-2-cyclopropylmethyl-4a-(3-benzyloxyphenyl)-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (78 mg, 82% in two steps).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:19])[F:17])[CH2:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Yield: 77 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid ethyl ester (Example I5) (2.8 g) in ethanol (40 ml) was added a solution of sodium hydroxide (0.51 g) in water (15 ml). The reaction mixture was stirred at reflux for 1 hour. After cooling to ambient temperature aqueous hydrochloric acid (1M) (20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallised from diisopropyl ether to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 13.07 (s, 1H), 7.91-7.58 (m, 6H), 4.85 (d, 1H), 4.44 (d, 1H), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH3:19][NH2:20]>CO>[OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:20][CH3:19])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: O=Cc1c2ccccc2c(CO)c2ccccc12
Reactant: CN
Solvent: CO
Product: CN=Cc1c2ccccc2c(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10-(hydroxymethyl)-9-anthraldehyde (3.00 g, 12.7 mmol) was added to 50 mL of a saturated solution of methylamine in methanol and stirred at room temperature for 2 h. The solvent and excess methylamine was removed under reduced pressure to afford the imine as a bright yellow powder (quant); 1H NMR (300.13 MHz, DMSO-d6) δ 3.35 (s, 3H), 5.51 (s, 2H), 7.61 (m, 4H), 8.55 (m, 4H), 9.48 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6])=[O:4].P([O-])([O-])([O-])=[O:18].[K+].[K+].[K+]>C(O)C>[OH:18][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:15]=1)[CH:12]([CH3:13])[CH3:14]
Reactant: O=P([O-])([O-])[O-]
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [K+]
Solvent: CCO
Product: COC(=O)C(C)c1ccc(C(O)C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Experimental description: 150 mg ibuprofen methyl ester was dissolved in 1.4 mL ethanol and added to 150 mL potassium phosphate buffer pH 8.0. P450BM3 was added to the mixture at a final concentration of 10 μM. The mixture was split in 4 mL-aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL 10 mM NADPH in KPi buffer was added to each vial and stirred for 2 minutes. 500 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 48 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5-40% ethyl acetate/hexane) afforded the activated product (methyl 2-(4′-(1″-hydroxy-2″-methylpropyl)phenyl)propanoate, 73 mg). 15 mg (0.06 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 11 μL DAST (0.72 mmol) was added. The reaction was stirred in dry ice for 16 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, methyl 2-(4′-(1″-fluoro-2″-methylpropyl)phenyl)propanoate (10 mg, 65% yield, colorless oil). 1H-NMR (300 MHz, CDCl3): δ 0.84 (d, J=6.9 Hz, 3H, CH3), δ 1.01 (d, J=6.9 Hz, 3H, —CH3), δ 1.49 (d, J=8.7 Hz, 3H, CH3), δ 2.05-2.08 (m, 1H), δ 3.66 (s, 3H, OCH3), δ 3.73 (q, J=7.5 Hz, 1H), δ 5.07 (dd, J=40.0, J=6.9 Hz, 1H, CHF), δ 7.25 (m, 4H); 13C-NMR (75 MHz, CDCl3): δ 15.5, 17.82 (d), 18.54 (d), 34.48 (d, J: 85.7 Hz), 45.37, 52.31, 99.3 (d, J=174 Hz), 175.6; 19F-NMR (282 MHz, CDCl3): δ −179.8 (m). HRMS (EI+): exact mass calculated for C14H19FO2 requires m/z 238.1369, found 238.1367.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-Hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.0575 g, 0.000236 mol) was dissolved in tetrahydrofuran (3.00 mL, 0.0370 mol) in a capped 40 mL reaction vial equipped with a magnetic stir bar. trans 4-tert-Butyl-cyclohexanol (0.0443 g, 0.000284 mol) was added, followed by triphenylphosphine (0.0992 g, 0.000378 mol) and the mixture was heated to reflux. diisopropyl azodicarboxylate (0.0745 mL, 0.000378 mol) was then added and the reaction mixture was heated at reflux overnight. TLC analysis showed that the reaction was complete. The stir bar was removed and the mixture was concentrated via Genevac. The resulting product was purified by flash chromatography (20-30% EtOAc in methylene chloride) to give 0.0446 g of the title compound (49% yield).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[N:30]=[CH:31][C:24]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([O:21][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:39])[N:30]=[CH:31][C:24]=23)[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (127 mg, 3.17 mmol) was added to (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (765 mg, 2.64 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (871 mg, 2.91 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was neutralised with 1M citric acid and the reaction mixture diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (445 mg, 30.5%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([C:3]1[C:4]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of Example 236D (400 mg, 0.680 mmol) in 5 mL methanol and 5 mL tetrahydrofuran was added 1N aqueous sodium hydroxide (3398 μL, 3.40 mmol) and the mixture was stirred at room temperature overnight and at 70° C. for 1 hour. The mixture was diluted with water, neutralized to pH 5-6 and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (AnaLogix IntelliFlash 280) eluting with 0-3% methanol in dichloromethane to afford the title compound. MS (ESI+) m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[C:4]([CH3:18])=[N:3]1.[CH3:19][NH:20][CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:19][N:20]([CH3:21])[CH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CNC
Reactant: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2

Procedure:
(Method 2): 6-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-one (1.1 mmol) was dissolved in MeOH. Dimethyl-amine (24.5 mmol), acetic acid (0.11 mmol) and sodium cyanoborohydride (2.2 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (79%). MS [MH]+=270.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[C:13](Cl)(=[O:17])[C:14](Cl)=O.CN(C=O)C.[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl.CC#N>[CH:32]([C:29]1[CH:30]=[CH:31][C:26]([N:25]([CH3:24])[C:13](=[O:17])[CH2:14][N:9]2[C:10]3[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]=3[N:7]=[CH:8]2)=[CH:27][CH:28]=1)([CH3:34])[CH3:33]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)[nH]c2nc[nH]c2c1=O
Reactant: CNc1ccc(C(C)C)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(N(C)C(=O)Cn2cnc3[nH]c(=O)n(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of acid 120 (0.25 g, 1.11 mmol) in CHCl3 (20 mL) and CH3CN (20 mL) at 0° C. was added oxalyl chloride (0.84 g, 6.69 mmol) and a catalytic amount of DMF. The resulting solution was stirred for 2 h at rt and concentrated in vacuo. The residue was re-dissolved in CHCl3 and the resulting solution cooled to 0° C. To this mixture was added N-methyl-4-isopropyl aniline (0.29 g, 2 mmol) and the reaction was stirred overnight warming to rt. The reaction was then diluted with CHCl3 (30 mL) and washed with 1 N HCl (50 mL). The combined organic layers were washed with water (75 mL), dried over Na2SO4 and concentrated in vacuo and the product was purified by chromatography on silica gel eluting with EtOAc/hexanes and EtOAc/MeOH to yield 392 (0.2 g, 51%) as a light brown solid. mp: 271-273° C. MS (APCI): m/z 356.2 [M+H]+ Anal. Calcd. For C18H21N5O3. 0.35H2O: C, 59.77; H, 6.05; N, 19.36. Found C, 59.77; H, 6.07; N, 19.29.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1C#N.C[CH2:22][N:23](CC)CC.[C:28]12[C:42](=[O:43])[O:41][S:38](=[O:40])(=[O:39])[C:29]=1[C:30]([Br:37])=[C:31]([Br:36])[C:32]([Br:35])=[C:33]2[Br:34].Cl>C1COCC1>[Br:37][C:30]1[C:31]([Br:36])=[C:32]([Br:35])[C:33]([Br:34])=[C:28]([C:42]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=2[NH:12][C:13]2[CH:20]=[CH:19][C:18]([C:22]#[N:23])=[CH:17][CH:14]=2)=[O:43])[C:29]=1[S:38]([OH:41])(=[O:40])=[O:39]
Reactant: CCN(CC)CC
Reactant: O=C1OS(=O)(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: N#Cc1ccccc1Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2c(Br)c(Br)c(Br)c(Br)c2S(=O)(=O)O)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Into a mL are placed -{[2-amino-4-(trifluoromethyl)phenyl]amino}benzonitrile (100 mg, 0.361 mmol), Et3N (0.15 mL, 1.08 mmol), tetrabromo-2-sulfobenzoic acid cyclic anhydride (270 mg, 0.541 mmol), and THF (5 mL). The mixture is heated with efficient shaking at 40° C. for 16 h. The solution is cooled and 1M HCl is added and the organic phase is extracted with EtOAc (3×). The organic fractions are combined, washed with brine, and concentrated. The crude product is dissolved in MeOH (20 mL) and then Dowex (10 eq) is added. The mixture is efficiently shaken at rt for 16 h. The resin is then filtered and the solution concentrated. The yield is 108 mg of 2,3,4,5-tetrabromo-6-({[2-[(4-cyanophenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)benzenesulfonic acid, 46%. 1H NMR (400 MHz, DMSO-d6): □ 10.06 (s, 1 H), 8.89 (s, 1 H), 7.70-7.68 (m, 2 H), 7.65-7.61 (m, 2 H), 7.56-7.54 (m, 1 H), 7.32-7.30 (m, 2 H). ESI+ for C21H10Br4F3N3O4S m/z 778 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.I[C:23]1[CH:28]=C[C:26]([OH:29])=[CH:25][CH:24]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)#[C:31][CH3:32].O1CC=C(B2OC(C)(C)C(C)(C)O2)CC1>>[O:29]1[CH2:28][CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:35]5[CH:36]=[N:37][CH:38]=[C:33]([C:30]#[C:31][CH3:32])[CH:34]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:25][CH2:26]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: Oc1ccc(I)cc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(C4=CCOCC4)cnc2O3)c1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (prepared using the same procedures as described in Method CC6 but using 4-iodophenol), 5-(prop-1-ynyl)pyridin-3-ylboronic acid, and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].NC1[S:15]C=CN=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[C:30]([CH2:35][N:36]([CH2:43][C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:37]2CCNC[CH2:38]2)=[N:31][CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.CN(C=O)C>[S:15]1[CH:12]=[CH:11][N:10]=[C:9]1[NH:8][C:1]([N:3]1[CH2:4][CH2:38][CH:37]([N:36]([CH2:43][C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:35][C:30]2[C:29]([CH3:28])=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:6][CH2:7]1)=[O:2]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: Nc1nccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2nccs2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 12.9 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (79.6 mg, 0.491 mmol), 2-aminothiazole (48.2 mg, 0.481 mmol), and DIPEA (0.17 mL, 0.97 mmol) in CH2Cl2 (5 mL) and DMF (2 mL) was stirred at room temperature for 4 h. The mixture was concentrated to a minimum volume, diluted with DMF (3 mL), and COMPOUND 249 (150 mg, 0.482 mmol) was added and stirred at 60° C. for 20 hours. The solution was concentrated to dryness, treated with saturated aqueous NaHCO3 (30 mL) and H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) followed by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) provided COMPOUND 289 (27 mg, 13%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.82 (m, 4H), 1.97 (d, 2H, J=11.7 Hz), 2.08 (s, 6H), 2.64-2.84 (m, 3H), 3.81 (s, 4H), 4.20 (d, 2H, J=12.9 Hz), 6.85 (d, 1H, J=3.6 Hz), 7.09 (dd, 2H, J=7.2, 5.1 Hz), 7.31 (d, 1H, J=3.6 Hz), 7.37 (d, 2H, J=7.5 Hz), 8.34 (d, 2H, J=4.5 Hz), 9.47 (br s, 1H); 13C NMR (CDCl3) 18.37, 27.47, 44.83, 54.97, 57.59, 113.16, 122.87, 133.78, 137.00, 138.47, 146.35, 153.46, 157.43, 161.07; ES-MS m/z 459 (M+Na). Anal. Calcd. for C23H28N6OS.0.3H2O.0.2 CH2Cl2: C, 60.71; H, 6.37; N, 18.31. Found: C, 61.05; H, 6.61; N, 17.94.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS([C:24]1[N:29]=[C:28]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[CH:31]2)[CH:27]=[CH:26][N:25]=1)(=O)=O>CN(C=O)C>[NH3:1].[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:24]2[N:29]=[C:28]([N:30]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[CH:31]3)[CH:27]=[CH:26][N:25]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc(N)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(N)c1
Product: N
Temperature: 100 °C
Yield: 97.1 %

Procedure:
(S)-1-(3-aminophenyl)-1-aminoethane (23.7 mg) was dissolved in DMF (1 mL), diisopropylethylamine (90 μL) was added followed by 2-methylsulfonyl-4-[benzimidazol-1-yl]pyrimidine (43.2 mg). The resulting mixture was left heating at 100° C. for 65 h then cooled, concentrated in vacuo then the residue purified on silica gel twice (3% then 2% (2M NH3 in MeOH)/CH2Cl2) to yield 27.9 mg of the title compound (98%). 1H NMR (500 MHz, CDCl3, partial): δ 8.52 (br s, 1H); 8.39 (d, J=5.3 Hz, 1H); 7.83 (m, 1H); 7.36 (m, 2H); 7.18 (t, J=7.8 Hz, 1H); 6.84 (d, J=7.8 Hz, 1H); 6.77 (m, 2H); 6.61 (m, 1H); 1.61 (d, J=7.1 Hz, 3H).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[Cl:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: COc1ccc(C#N)cc1Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-chloro-4-methoxybenzonitrile (0.757 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 84% yield) as a solid after drying. MS: MS m/z 316.1 (M++1).