Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].CO.[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:2][C@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])=[CH:18][CH:17]=1
Reactant: C[C@@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
In a 250 mL, 4 necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, D-alaninamide hydrochloride (6.1 g) and methanol (80 mL) are charged and stirred for 15 min at 20° C. Triethylamine (5 g) is added at such a rate that the temperature remains below 30° C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (10 g, Example 10b) is added portion wise in about 30 min. After stirring for 3 hours at 20° C., the mixture is cooled to 5° C. After stirring for 3 hours at this temperature, the solid is filtered and washed with small amount of pre-cooled methanol. The wet solid is dried under vacuum for 12 hours a 25° C., yielding 6.4 g of title compound as white solid, with 46.4% yield; m.p 111.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:39][OH:40])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:37]=[CH:36][C:35](Cl)=[CH:34][N:33]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:70][N:71](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:39][OH:40])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:70]#[N:71])=[CH:34][N:33]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C#N)cn5)n4)c3CO)ncc2c1
Temperature: 150 °C
Yield: 91 %

Procedure:
Take up 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide (prepared in example 23, above) (31 mg, 55.2 μmol), zinc cyanide (51.8 mg, 441 μmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6 mg, 14.6 μmol) in 1.5 ml of dry dimethylformamide in a small capacity microwave tube and thoroughly degas with argon. Add tris(dibenzylideneacetone)dipalladium(0) (7 mg, 7.6 μmol) and degas again. The mixture was heated in a microwave reactor at 150° C. for 60 minutes. The solvent was stripped (rotary evaporator/pump) and the remainder was taken up in ethyl acetate (25 ml) and water (25 mL) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×20 ml). The organic phase was combined, dried from magnesium sulfate, filtered and stripped. The crude was purified by preparative thin layer chromatography (1 plate, eluting with 9.5% methanol in dichloromethane). The product band was collected, providing semi-pure desired product (21 mg, 91% pure). For greater purity the material was again loaded onto 1 preparative thin layer chromatography plate and eluted with 7% methanol in dichloromethane. Re-develop the plate with 7% and then 8.5% and finally 9% methanol in dichloromethane, at which point a more polar impurity was separated. The less polar product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-cyano-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide as an off-white solid (17 mg, 56%). LC/MS calc'd for C29H25FN8O3 (m/e) 552.57, obs'd 553 (M+H, ES+).
Reaction SMILES: BrC1C=CC=CC=1S.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([C:37]2[CH:42]=[C:41](F)[CH:40]=[CH:39][C:38]=2[SH:44])([OH:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][C:33]([OH:36])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[SH:44])[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Sc1ccccc1Br
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2S)CC1

Procedure:
This intermediate was prepared from 2-bromo-benzenethiol and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in a similar way as described for 4-(5-fluoro-2-mercapto-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12]
Reactant: C1=COCCC1
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Yield: 82 %

Procedure:
A suspension of methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) (1.35 g, 5.29 mmol), pyridinium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4 dihydro-2H-pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20 mL) was refluxed 5 h under argon. The suspension was turned into the clear solution. The solution was cooled and the excess solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with dilute NaHCO3 solution (satd. NaHCO3 soln/H2O: 1:9). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (100% hexanes→5:95 EtOAc:hexanes) to get methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) as a white solid (1.47 g, 4.34 mmol, 82% yield). 1H NMR (DMSO-d6) δ ppm 8.22 (d, J=1.4 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.68 (dd, J=7.2, 1.6 Hz, 1H),), 6.02 (dd, J=8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79 (m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.73 (m, 1H). 1.60-1.58 (m, 2H); ESIMS found for C14H15BrN2O3 m/z 340.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1.[CH2:29](C([Sn])=C(CCCC)CCCC)[CH2:30]CC.CCOC(C)=O>C1(C)C=CC=CC=1>[CH:29]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1)=[CH2:30]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nccc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Aryl bromide from Step 1 was dissolved in toluene (about 0.15 mM solution) and treated with tributylvinyltin (1.5 eq) and [Ph3P]4Pd(0) (0.05 eq). The reaction mixture was stirred at 100° C. under N2 atmosphere for 2 h. After cooling to RT, the reaction mixture was poured into EtOAc and washed with brine. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE/EtOAc 8/2 v/v as eluent) to give the title compound as a viscous oil. MS (ES+) C22H26N2O5 requires 398. Found: 399 (M+H+).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]#[N:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)(O)[O-].[Na+]>CO>[Si:1]([O:18][CH2:19][CH2:20]/[C:21](=[N:24]/[OH:25])/[NH2:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](OCC/C(N)=N/O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}propanenitrile (4.4 g, 14.2 mmol) in methanol (40 ml) was added hydroxylamine hydrochloride (8.9 g, 128 mmol) and sodium bicarbonate (11.9 g, 142 mmol). The mixture was heated at reflux for 48 hours. The mixture was then cooled to room temperature, the solvent was evaporated, ice water was added, and the resulting solution was extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (50-100% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[O-]CC.[Na+].[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([C:24]([CH3:34])([CH3:33])[CH2:25][C:26]2([C:29]([F:32])([F:31])[F:30])[CH2:28][O:27]2)[CH:23]=1>CCO>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:28][C:26]([OH:27])([C:29]([F:30])([F:32])[F:31])[CH2:25][C:24]([C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=2[O:35][CH3:36])([CH3:33])[CH3:34])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(C(F)(F)F)cc(Cl)c1=O)C(F)(F)F
Temperature: 85 °C

Procedure:
A mixture of 3-chloro-5-trifluoromethylpyridin-2-ol (135 mg, 0.68 mmol) in 1 mL of EtOH was added to 0.13 mL of a 1M sodium ethoxide solution in ethanol and was heated to 85° C. for 5 minutes in a sealed vial. The mixture was cooled to room temperature, 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane was added, and the mixture heated to 85° C. overnight in a sealed vial. The volatiles were removed in vacuo and the residue diluted with water and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified on PLC plate (hexanes-EtOAc (8:2)) to give 125 mg of 3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-5-trifluoromethyl-1H-pyridin-2-one as a solid.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[Cl-].[Na+:22]>O>[CH2:2]([N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[Na+:22].[Na+:22]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Crude MTC product (MW 373.90, 10.0 g, ˜26.7 mmol) was fully dissolved in H2O (270 cm3). Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate (MW 372.24, 1 g, 2.68 mmol, 0.1 equivalents) was added. The mixture was stirred at 65° C. for approximately 1 hour. The mixture was filtered by vacuum filtration. The filtrate was collected. Sodium chloride (NaCl, MW 57.96, 16 g, 0.276 mol, 10 equivalents) was added to the filtrate while stirring. The resulting precipitate was collected by vacuum filtration.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([Cl:1])[N:17]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1N
Temperature: 40 °C
Yield: 67.4 %

Procedure:
A solution of N-chlorosuccinimide (556 mg, 4.2 mmol) in DMF (10 ml) was added to a solution of 1b (960 mg, 4.0 mmol) in DMF (15 ml) at rt. The reaction was heated at 40° C. for 30 min. The reaction mixture was cooled to rt and the reaction was quenched with saturated aqueous sodium thiosulfate (Na2S2O3) solution (100 mL). The mixture was extracted with ethyl acetate (3×20 ml) and the organic layers were washed with aqueous sodium thiosulfate solution, brine and were dried over sodium sulfate. The solvents were removed under reduced pressure and the dark red oil was purified by chromatography on silica (continuous gradient 0 to 40% Hexane/EtOAc) to give 125a as an off-white solid (746 mg, 68% yield). [M+H]+=277.11. 1H NMR (500 MHz, CDCl3): 7.41 (d, 1H, J=7.4 Hz), 7.20 (t 1H, J=7.4 Hz), 7.11 (t, 1H, J=7.4 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.85 (d, 1H, J=8.1 Hz), 3.91 (s, 1H), 1.39 (s, 9H).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[C:26]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:27][CH:28]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[C:26]([N:34]3[CH2:35][CH2:36][N:37]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:38][CH2:39]3)=[N:27][CH:28]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[CH:30]=2)[CH2:23][CH2:24]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 78.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (427 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=3[O:42][CH3:43])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Reactant: COc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncnc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.040 g, 0.084 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.021 g, 0.126 mmol), tetrakis(triphenylphosphine)palladium(0) (9.69 mg, 8.39 μmol), and potassium carbonate (0.058 g, 0.419 mmol). Dioxane (0.419 mL) and water (0.140 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (12 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated and purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:DCM) to afford 4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.01 (br. s., 1H), 9.45 (s, 1H), 8.38 (br. s., 1H), 8.06-7.76 (m, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.31 (d, J=4.1 Hz, 1H), 7.21 (d, J=11.2 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.90 (d, J=4.3 Hz, 1H), 3.70 (br. s., 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16]O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([O:34][C:35]([NH:37][S:38]([NH:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:30]([O:34][C:35]([N:37]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1)[S:38]([NH:41][CH2:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)(=[O:40])=[O:39])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCC1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)S(=O)(=O)NCC1CCCCC1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of the product from step d (764 mg, 2.00 mmol), the product from step e (642 mg, 2.20 mmol) and triphenylphosphine 576 mg, 2.20 mmol) in dry tetrahydrofuran (20 ml), under an atmosphere of argon, was added over 10 min a solution of diethylazodicarboxylate (383 mg, 2.20 mmol) in dry tetrahydrofuran (5 ml). The mixture was stirred for 2 h, the solvent evaporated and the residue purified by flash column chromatography (silica; 30% ethyl acetate/dichloromethane). Thus, the product was isolated as a colourless foam (800 mg, 60%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].CCOCC.[F:13][C:14]1[C:19](I)=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:13][C:14]1[C:19]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: Fc1ccc(I)c(F)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)Cc1ccc(F)nc1F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a 500 mL RBF was added neopentylmagnesium chloride, 111.0M in ether (28.0 ml, 28 mmol) and an ice bath. After cooling, zinc(II) chloride, 0.5M in THF (56.0 ml, 28 mmol) was added dropwise. The cooling bath was removed and after stirring for 45 minutes, Reactant 1 (0.26 g, 0.32 mmol) was added followed by 2,6-difluoro-3-iodopyridine (2.74 g, 8.0 mmol) in THF (10 mL), which was added dropwise. The yellow solution was then heated to 60° C. After stirring overnight the reaction was allowed to cool and sat'd. NH4Cl was added cautiously. The reaction mixture was partitioned between EtOAc/Water. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers washed with brine and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 1% EtOAc in hexane, to provide 2,6-difluoro-3-neopentylpyridine as a colorless oil. MS m/z: 186 (M+1).
Reaction SMILES: C(N=C=O)(C)(C)C.[C:8]([NH:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38]C)=[C:33]([O:40][CH2:41]C)[CH:32]=3)[C@@H:28]3[C@@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22]2=[O:43])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([NH:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:40][CH3:41])[CH:32]=3)[C@@H:28]3[C@@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22]2=[O:43])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: CC(C)(C)N=C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and t-butylisocyanate as described for compound 6. Crystallisation from ether. M. p. 164-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=O)=[CH:6][NH:7]2.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[C:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18])=[CH:6][NH:7]2
Reactant: COc1cccc2[nH]cc(C=O)c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cccc2[nH]cc(C=C3C(=O)OC(C)(C)OC3=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
4-MethoxyIndole-3-carboxaldehyde (5.0 g) and Meldrum's acid (2,2-Dimethyl-[1,3]dioxane-4,6-dione, 4.11 g) were mixed in toluene (200 ml). To this mixture was added 0.6 ml each of piperidine and acetic acid. The reaction mixture was stirred at room temperature for four hours. The precipitate was filtered and washed with toluene to afford 4.25 g of crude 5-(4-methoxy-1H-indol-3-ylmethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as an orange solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (153.4 mg, 0.33 mmol, 1.00 equiv) and sodium hydroxide (66 mg, 1.65 mmol, 5.00 equiv) in tetrahydrofuran/MeOH (1:1) (12 mL) was placed in a 50-mL round bottom flask and stirred for 5 h at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid, then concentrated under vacuum. The resulting solid was washed with methanol affording 47 mg (31%) of 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.