Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[C:10]([S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:11]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), 3-chloro-benzyl bromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.55 g, 1.1 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]C)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCC(C(=O)O)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylate (160 mg, 0.38 mmol) in 10 mL of methanol was added a solution of sodium hydroxide (154 mg, 3.8 mmol) in 2 mL of water at room temperature. Then the reaction mixture was stirred at this temperature for 24 hours. Then solvent was evaporated at 40° C. at reduced pressure and the residue was suspended in 30 mL of THF, then treated with 2N HCl to pH=2. The solvent was evaporated and the residue was dissolved in 50 mL of THF, then filtered and the filtrate was evaporated to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (95 mg, 61.4%) as a yellow solid. LC-MS: 402.1 [M+H]+, tR=1.33 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:14])[NH:12][NH2:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:15][O:16][C:17]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:17]=2[O:16][CH3:15])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: COc1c(C=O)cccc1-c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Product: COc1c(C=NNC(=S)Nc2ccc(C(=O)O)cc2)cccc1-c1ccc(C)cc1
Reaction time: 24 h
Yield: 14.3 %

Procedure:
A solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (11 mg, 0.05 mmol) and 2-methoxy-3-(4-methylphenyl)benzaldehyde (14 mg, 0.06 mmol) in dimethylformamide (1 mL) was shaken with 4 Å molecular sieves for 40 h. PS-TsNHNH2 resin (17 mg, 0.05 mmol) was added and shaking continued for 24 h, then the resin was filtered off. The solvent was removed under vacuum and the residue chromatographed by reverse phase HPLC (CombiPrep ODS-A, 10–90% acetonitrile/water+0.1% trifluoroacetic acid) to give the title compound (3 mg, 14%) as a solid. MS (ES−) m/e 418 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4C(O)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu]=O.C(OCC)(=O)C>[O:38]1[C:34]([C@H:31]2[CH2:32][CH2:33][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][N:27]=[C:19]34)[CH2:29][CH2:30]2)=[CH:35][N:36]=[CH:37]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)O)CC2)c2ncnn12
Agent: O=[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of 5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylic acid (0.94 g), copper(II) oxide (0.005 g) and quinoline (5 mL) was stirred at 180° C. for 16 hr. 1 N Hydrochloric acid and ethyl acetate were added to the reaction mixture, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.65 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH:14]([C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([NH:1][CH2:14][C:16]3[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=3)[C:19]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[CH:3]=[C:4]2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: O=Cc1cccc(C(=O)Nc2cccnc2)c1
Reactant: CC(=O)c1cc2cc(N)cnc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)c1cc2cc(NCc3cccc(C(=O)Nc4cccnc4)c3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanone (1 eq) and 3-Formyl-N-pyridin-3-yl-benzamide (1.1 eq) were stirred in a mixture of MeOH/AcOH (10/1; 0.06M) for 2 h. Then NaBH3CN (1.2 eq) was slowly added and the mixture was stirred under argon at RT overnight. The reaction was quenched by addition of saturated NaHCO3 solution until neutrality. MeOH and acetic acid were evaporated. The crude was filtered and washed with water and Et2O before being purified on reverse phase (H2O 1% TFA/MeCN 1% TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H2O and basified with saturated NaHCO3 solution until pH=8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated to give the expected product.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[O:39]([Si](C)(C)C)[K]>C1COCC1.CO>[C:2]([O:7][C:6]1[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:24][CH:25]=2)=[CH:11][C:5]=1[CH2:4][OH:3])(=[O:39])[CH3:1]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(F)c5)cc4)C(=O)O3)ccc2O1
Reactant: C[Si](C)(C)O[K]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc([C@@H](O)CNCCc2ccc(OCCOCc3cccc(F)c3)cc2)cc1CO
Temperature: 75 °C

Procedure:
(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-(2-[(3-fluorobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one (125 mg) in THF (1 mL) was treated with KOSiMe3 and the resulting solution was heated at 75° C. for 2 h. The solution was then diluted in MeOH, passed down an SCX-2 cartridge (10 g) and then concentrated in vacuo. The residue was purified by chromatography (SPE, 5 g) eluting with CH2Cl2-MeOH-2M NH3 in MeOH (98:1:1) and then CH2Cl2-MeOH-2M NH3 in MeOH (95:4:1) to give the free base of the title compound. This was converted to the acetate salt using acetic acid to give the title compound (38 mg). LCMS RT=2.56 min. ES+ve 456 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([O:26]C)=[O:25])=[C:7]([C:11]([C:13]3[N:14]=[CH:15][C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([OH:26])=[O:25])=[C:7]([C:11]([C:13]3[N:14]=[CH:15][C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Yield: 60.7 %

Procedure:
To a mixture of methyl [6-chloro-2-[(5,6,7,8-tetrahydroisoquinolin-3-yl)carbonyl]-1H-indol-3-yl]acetate (Example 1) in MeOH (20 ml)-THF (20 ml) was added 2N aqueous NaOH (0.6 ml, 1.2 mmol) at room temperature and the resulting mixture was heated at reflux temperature for 8 h. The mixture was cooled and concentrated. The residue was dissolved in water (20 ml) and washed with diethyl ether (20 ml×3). The aqueous layer was acidified with 2N aqueous HCl and extracted with ethyl acetate (40 ml×3). The combined organic layers were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to afford 23.3 mg (60.7%) of the title compound as yellow solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=[C:17]3I)[CH:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([Cu])#[N:41]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=[C:17]3[C:40]#[N:41])[CH:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-(1-benzenesulfonyl-3-iodo-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 0.4 mmol), CuCN (0.13 g, 1.4 mmol), Pd2(dibenzylideneacetone)3 (0.017 g, 0.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.040 g, 0.07 mmol) was taken up in 5 mL 1,4 dioxane and warmed to reflux for one hour. The mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. Purification via flash chromatography (gradient: 15 to 25% EtOAc in hexanes) afforded 4-(1-benzenesulfonyl-3-cyano-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 97%) as a white foam; MS (M+H)=557.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH:16]1[CH:21]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:17]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CC(O)C>C1COCC1>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[CH3:17])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of phenol 4 (1 g, 3.29 mmol) and PPh3 (1.8 g, 6.58 mmol) in THF (25 mL) was added DIAD (1.3 mL, 6.58 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. 2-Propanol (0.4 mL, 4.94 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 20 hours. The mixture was extracted with EtOAc/H2O (50 mL/50 mL) and was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the desired product 6 (913 mg, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH:8]=2)=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:8][CH:9]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3ccncc3)CC1CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1ccncc1)C2
Yield: 99.3 %

Procedure:
In a high-pressure reactor, under nitrogen, 0.17 g of 5% palladium-on-charcoal is added to 0.46 g of tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate solubilized in 20 ml of methanol. The reaction mixture is placed under a hydrogen pressure of 3 atmospheres at 25° C., and mechanically stirred for two and a half hours. The palladium is filtered off on Whatman paper and washed with methanol. The solvent is evaporated off and 0.46 g of tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane-8-carboxylate is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][C:26]([CH3:32])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O>O.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.O1CCOCC1>[F:22][C:23]1[C:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:27][C:26]([CH3:32])=[CH:25][N:24]=1
Reactant: Cc1cnc(F)c(B(O)O)c1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
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: OBO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
To a microwave vial charged with 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG; 3.00 g, 9.35 mmol), 2-fluoro-5-picoline-3-boronic acid (1.469 ml, 12.16 mmol), potassium carbonate (6.46 g, 46.8 mmol) and Pd(Ph3P)4 (1.081 g, 0.935 mmol) was added Dioxane (46.8 ml) and Water (15.59 ml) and heated thermally to 120° C. After 3 hrs LC-MS indicated about 40% conversion with starting material present. Additional boronic acid was added (1 g) and heating continued at 120° C. for 4 hrs affording ˜75% conversion. The mixture was allowed to stir at room temperature over the 3 days under nitrogen afford little to no further conversion. Additional boronic acid (500 mg) and Pd(PPh3)4 (500 mg) was added and the mixture heated back to 120° C. for 3 hr affording near complete conversion according to LC-MS. The mixture was cooled to room temperature, transferred to a seperatory funnel, diluted with water and extracted with EtOAc but the material stayed in the aqueous phase, although this wash did remove many impurities (including PPh3O). The aqueous was washed with DCM, but again the material stuck in the aqueous phase. The aqueous was acidified to ˜pH 2 affording a precipitate which was collected as a brown solid, fairly clean product by LC-MS (300 mg). The aqueous was dried to near dryness affording a precipitate which was collected but was mostly salts with some product. The solid and filtrate were combined and silica gel added and the mixture dried under reduced pressure. The material was purified with a 100 g ultra snap column ramping MeOH in DCM (0-50%) affording product (only 400 mg) as a light yellow solid. Much of the material had remained on the dry pack. The dry packed slurry was purified 2× (split into two parts) by loading directly onto a KP-C18-HS 60 g Biotage column using the reverse phase MPLC ramping IPA in H2O (with 1% NH4OH) (0-100%) affording 1 g of product as a brown solid, in total (1.4 g, 38%). m/z (ESI) 396.2 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(S(C)(=O)=O)C3)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), methanesulfonyl chloride (0.032 mL, 0.413 mmol) was added. The mixture was stirred at room temperature for 18 h. It was then purified by HPLC to give the titled compound (6 mg). MS 462.4 (M+H); UV 204.7, 248.6 nm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9]OS(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:16]([CH3:17])[CH3:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(CN(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 222 mg of 1-methanesulfonyloxymethyl-cyclopropane carboxylic acid ethyl ester in 5 mL of tetrahydrofuran was added 3 mL of 2M dimethyl amine in tetrahydrofuran, and stirred at room temperature for 3 days. The solvent was distilled off, and the residue was added with 2 mL of 1N hydrochloric acid, and washed with diethyl ether. The aqueous layer was added with 10% potassium carbonate aqueous solution, and extracted with ethyl acetate. The extracted layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 56 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][C:19]1[S:20][C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:22]([CH3:24])[N:23]=1>O1CCCC1>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[S:25]([C:21]2[S:20][C:19]([CH3:18])=[N:23][C:22]=2[CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N(C)S(=O)(=O)c2sc(C)nc2C)cc1
Temperature: 0 °C
Yield: 16.7 %

Procedure:
Under nitrogen in a flame-dried round-bottomed flask fitted with a dropping funnel, stir bar and condensor, was added N-methyl-p-anisidine (1.0 grams, 7.29 mmol) in 30 mL of anhydrous tetrahydrofuran (THF). To this was added triethylamine (1.01 mL, 7.29 mmol) and the flask was cooled to 0° C. with an ice bath. Next, 2,4-dimethyl-5-thiazolesulfonyl chloride (1.54 grams, 7.29 mmol, Maybridge Chem. Co.) in 20 mL of THF was added dropwise and the reaction allowed to stir at 25° C. overnight. The reaction was quenched by pouring it slowly into 200 mL of saturated aqueous sodium bicarbonate and extracting the crude product with dichloromethane (CH2Cl2). After drying the organic extracts over magnesium sulfate (MgSO4), the solvent was removed in vacuo to a dark brown oil. Chromatography on silica gel, eluting with hexanes:ethyl acetate (EtOAc) (4:1), gave 380 mg of pale brown oil.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16].[Br:18]Br>C(O)(=O)C>[Br:18][C:13]1[C:14]2[CH:1]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2c(ccc3ccccc32)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)c(Br)cc1ccccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Phenanthrene-2-carboxylic acid (1, 0.116 g, 0.5 mmol) was dissolved in acetic acid at 70° C. and then bromine (0.027 ml, 0.5 mmol) was added. The mixture was stirred at 70° C. overnight. The following day, bromine (0.027 ml, 0.5 mmol) was added and the mixture was refluxed for 6 h and then allowed to cool. The resulting precipitate was collected by filtration. 1H NMR (270 MHz, DMSO):—7.8 (m, 2H), 8.1 (d, 1H), 8.25 (d, 1H), 8.45 (s, 1H), 8.9 (s, 1H), 8.95 (m, 1H) and 9.05 (d, 1H).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[CH2:13]([C:15](CO)(C)[C:16]([O:18][CH2:19][CH3:20])=[O:17])O.N1C=CC=CC=1.C(=O)=O.CC(C)=O.[NH4+].[Cl-].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O.O>[CH3:13][C:15]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)(CO)CO
Agent: Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1(C)COC(=O)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
A solution of triphosgene (19.5 g, 0.065 mol) in CH2Cl2 (200 mL) was added stepwise to a CH2Cl2 solution (150 mL) of ethyl 2,2-bis(methylol)propionate (EtMPA) (21.1 g, 0.131 mol) and pyridine (64 mL, 0.786 mol) over 30 min at −75° C. with dry ice/acetone. The reaction mixture was kept stirring for another 2 hours under chilled condition and then allowed to heat to room temperature. Saturated NH4Cl aqueous solution (200 mL) was added to the reaction mixture to decompose excess triphosgene. The organic phase was then treated with 1 N HCl aq (200 mL), followed by saturated NaHCO3 (200 mL), brine (200 mL), and water (200 mL). After the CH2Cl2 solution was dried over MgSO4 and evaporated, the residue was recrystallized from ethyl acetate to give white crystals (13.8 g, 56%). 1H NMR: delta 4.68 (d, 2H, CH2OCOO), 4.25 (q, 1H, OCH2CH3), 4.19 (d, 2H, CH2OCOO), 1.32 (s, 3H, CH3), 1.29 (t, 3H, CH3CH2O). 13C NMR: delta 171.0, 147.5, 72.9, 62.1, 39.9, 17.3, 13.8. HR-ESI-MS: m/z calcd for C8H12O5; Na, 211.0582; found, 221.0578.