Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C@@H:3]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:4]([OH:6])=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@:22]2([OH:30])[CH2:27][CH2:26][NH:25][CH2:24][C:23]2([CH3:29])[CH3:28])=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@:22]2([OH:30])[CH2:27][CH2:26][N:25]([C:4](=[O:6])[C@H:3]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:2]([CH3:1])[CH3:14])[CH2:24][C:23]2([CH3:28])[CH3:29])=[CH:18][CH:17]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](Nc1cccnc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@@H](Nc1cccnc1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 6.5 %

Procedure:
(R)-3-Methyl-2-(pyridine-3-ylamino)butanoic acid (162 mg, 0.83 mmol), (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (200 mg, 0.83 mmol), EDC (320 mg, 1.67 mmol), HOBT (113 mg, 0.83 mmol), DIPEA (431 mg, 3.34 mmol), and DMF (4 mL) was stirred overnight at rt. Example 607 was isolated as a greenish solid using preparative reverse phase HPLC (22.5 mg, 6.5% yield). M+H=416.18.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.[N:19]1([C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:22]1[CH2:23][CH2:24][N:19]([C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:20][CH2:21]1)=[O:16]
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Reactant: COC(=O)c1ccc2[nH]cc(CCCCCl)c2c1
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
A solution of 3.6 g of 3-(4-chlorobutyl)-5-methoxycarbonylindole [obtainable by reaction of 5-methoxycarbonylindole with 4-chlorobutyryl chloride to give 3-(4-chlorobutyryl)-5-methoxy indole and subsequent reduction with diborane to give 3-(4-chlorobutyl)-5-methoxycarbonylindole] and 3.4 g of 6-piperazino-1,4-benzodioxane ("A") in 200 ml of acetonitrile is stirred at room temperature for 14 hours and worked up in the conventional manner to give 6-[4-(4-(5-methoxycarbonyl indol-3-yl)butyl)piperazino]-1,4-benzodioxane, m.p. 177-179° (dihydrochloride).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:16]([NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1)([CH3:20])[CH2:17][OH:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CC(C)(N)CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CO)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g) in N,N-dimethylformamide (10 mL) was added 2-amino-2-methyl-1-propanol (1.18 g) at 0° C. The mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2-(1,1-dimethyl-2-hydroxyethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.23 g) as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:38])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=3)/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(O)=[O:2].[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH2:39]([NH:46][C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:38])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:2])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1)NCc1ccccc1

Procedure:
A solution of 315 mg (0.6 mmol) of (Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone, 85 mg (0.8 mmol) of benzylamine, 212 mg (0.66 mmol) of TBTU and 1 ml of N-ethyl-N,N-diisopropyl-amine in 5 ml of DMF is stirred for 3 hours at ambient temperature. Then 50 ml of water are added. The yellow precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5])#[N:2].[CH:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([C:3](=[CH:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5])#[N:2]
Reactant: O=CC=Cc1ccccc1
Reactant: C#CCOC(=O)CC#N
Product: C#CCOC(=O)C(C#N)=CC=Cc1ccccc1

Procedure:
Reaction of Propargyl Cyanoacetate with (a) Cinnamaldehyde to form Propargyl 2-cyano-5-phenyl-2,4-pentanedienoate (PCPPD, formula 2a) and with (b) Naphthaldehyde
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:30].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][CH:18]([C:21]([OH:30])([OH:26])[C:22]([F:24])([F:25])[F:23])[CH2:17][CH2:16]3)[C:12]2=[O:27])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)C(F)(F)F)CC3)C2=O)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCC3(CCC(C(O)(O)C(F)(F)F)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 2-(4-tert-butyl-phenyl)-8-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-aza-spiro[4.5]decan-1-one (100 mg, 319 μmol, described in example 360 and 361) in DCM (1 mL) was added to a stirred suspension of Dess-Martin periodinane (501 mg, 1.18 mmol) in DCM (2.5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and poured into a 1:7 mixture of aqueous sat. NaHCO3 and Na2S2O3 and the mixture was stirred for 10 min. The organic phase was separated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by reverse phase prep HPLC to give the title compound as a white solid (94%). MS (m/e): 400.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C1C=C[NH+]=CC=1.[Br:30][Br-]Br>N1C=CC=CC=1>[Br:30][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1C
Reaction time: 16 h
Yield: 76 %

Procedure:
A solution of ethyl 1-methyl-5-(phenylmethoxy)-1H-indole-2-carboxylate (60.9 g, 197 mmol; Monge Vega A, et al., An. Ouim. 1976;72:267) in 550 mL of pyridine is cooled in ice and treated dropwise with a solution of pyridinium bromide perbromide (67.0 g, 209 mmol) in 200 mL of pyridine. The cooling bath is removed, and the mixture is stirred for 16 hours, then added to 4.0 L of cold water. The precipitated solid is filtered, washed with water, and recrystallized from ethyl acetate-hexane to give 58.4 g (76%) of product; mp 125-127° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:16])#[N:2].Cl.CCO.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[O:16]=[C:15]([N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[CH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{[2-cyano-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate (160 mg, 0.4 mmol) in 10 mL of dioxane was added 10 mL of 5 M HCl/EtOH, then the mixture was stirred at room temperature for 3 h. The solvent was removed under reduce pressure. The crude compound was suspension in 20 mL of MeCN and added Na2CO3 (102 mg, 0.96 mmol), then the mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated in vacua to give crude 2-[2-oxo-2-(piperazin-1-yl)ethyl]-5-(1H-tetrazol-1-yl)benzonitrile, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/c1ccc(Cl)nn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
A 500 mL RB flask was charged with 6-chloropyridazin-3-amine (10.0 g, 77.2 mmol) and dimethoxy-N,N-dimethylmethanamine (206 ml, 1544 mmol), equipped with a reflux condenser, then heated to 110° C. for 3 hours then left at room temperature for 16 hours. The precipitate was collected by filtration. The mother liquor was concentrated down to give an yellow solid, which was triturated with EtOAc and collected. The solids were combined to give (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (11.81 g, 82.9% yield) as a white solid
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:15]=3)[CH2:8][CH2:7]2)[CH2:3]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[N+:20]([C:19]1[C:14]([NH:13][CH2:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([N:4]3[CH2:5][CH:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:3]3)[CH2:7][CH2:8]2)=[N:15][C:16]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:34])([F:35])[F:33])=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N4-{[Trans-4-(3-aminoazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (20 mg, 0.04 mmol) was dissolved in CH2Cl2 (1.0 mL). To this solution was added acetic anhydride (0.057 mL, 0.06 mmol) followed by triethylamine (0.084 mL, 0.06 mmol). The reaction was allowed to stir at 25° C. for 18 h. The volatiles were removed and the crude was redissolved in CH2Cl2 and extracted with 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant residue was purified via flash chromatography (SiO2, 10-30% (2:18:80, NH4OH:CH3OH:CH2Cl2)—CH2Cl2) to afford 16 mg (74%) of the target compound, m/z 538.46 (M+1)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]4([CH3:29])OCC[O:25]4)[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[CH3:29])[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
13.10 g (32 mmol) of 9H-fluoren-9-ylmethyl[4-(2-methyl-[1,3]dioxolan-2-yl)cyclohexyl]carbamate (cis/trans mixture) and 1.30 g of p-toluenesulfonic acid are refluxed in 25 mL of water and 500 mL of acetone for 16 hours with stirring. Then the reaction mixture is concentrated by evaporation and the residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropylether and suction filtered. Yield: 7.77 g (89%) of cis compound; NMR: LH201628.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][C:25]=2[O:24]1.C1(C)C(C)=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([C:28]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:31][C:30]=3[CH:29]=2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Brc1cnc(-c2ccc3c(c2)OCO3)cc1Cc1ccccc1
Yield: 38.1 %

Procedure:
A mixture of 400 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate, 410 mg of (3,4-methylenedioxyphenyl)tributyltin, 300 mg of tetrabutylammonium chloride, 20 mg of tetrakis(triphenylphsphine)palladium(0) and 2 ml of xylene was stirred under heating for 3 hours in an oil bath kept at 140° C. in a nitrogen atmosphere. The reaction solution was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 140 mg of the title compound.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[N-]C.[Li+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>CCCCCC>[Cl:14][CH2:13][CH2:12][CH2:11][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: ClCCCBr
Reactant: CC(C)C#N
Agent: C[N-]C
Agent: [Li+]
Solvent: CCCCCC
Product: CC(C)(C#N)CCCCl
Temperature: 25 °C
Yield: 90.9 %

Procedure:
Isobutyronitrile (9.9 g, 0.143 mole) is added dropwise to a suspension of lithium dimethylamide (7.3 g, 0.143 mole) in hexanes. The resultant anion solution is added to a solution of 1-bromo-3-chloropropane (24.8 g, 0.16 mole) in hexane at 5° to 10° C., warmed to room temperature, and quenched with water. The phases are separated and the organic phase is concentrated in vacuo to afford the title product as a yellow oil, 19.0 g(80% pure, 90.9% yield), identified via gas chromatography.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccn1)O2
Yield: 85.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.99 mmol), 370 mg CDI (2.28 mmol) and 324 mg 2-picolylamine (3.0 mmol), produced 579 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-(pyridin-2-ylmethyl)chroman-2-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O)([CH3:45])[CH3:44]>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>[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)([CH3:45])[CH3:44]
Reactant: CC(C)(O)c1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: CC(C)(O)c1ccccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Yield: 40 %

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 50 mg, 0.112 mmol), potassium carbonate (77 mg, 0.561 mmol) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) was added dioxane (561 μl), (2-(2-hydroxypropan-2-yl)phenyl)boronic acid (20.18 mg, 0.112 mmol) and Water (187 μl) and irradiated at 100° C. for 30 min affording conversion to desired product (˜40%) with starting material remaining. To the mixture was added additional boronate (50 ul) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) and irradiated another 30 min at 100° C. affording consumption of starting material and product as the primary species. The organic layer was decanted and the aqueous rinsed once with EtOAc and the organics combined and dried under reduced pressure. To the resulting oil was added DCM (2 ml) and TFA (0.6 ml) and the resulting solution stirred at room temperature. The mixture was dried under reduced pressure and purified with a 25 g HP spherical silica gel (15 μm spherical, Interchim) ramping DCM:MeOH (90:10) in DCM (0-100%) affording product as a yellow film which was lyophilized from MeOH/H2O affording a fluffy yellow solid 1-(2-(2-hydroxypropan-2-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (39 mg, 0.072 mmol, 64.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.92 (br. s., 1H), 8.67-8.55 (m, 2H), 8.27 (br. s., 1H), 7.94 (d, J=8.3 Hz, 1H), 7.77-7.65 (m, 2H), 7.56 (t, J=7.1 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 1.37 (s, 3H), 1.24 (s, 4H). m/z (ESI) 426.0 (M+H)+
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:23][NH2:24]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)=[N:24][NH:23][C:4]1=[O:21]
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of 2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (133.0 g, 450 mmol) in EtOH (1.5 L) was added hydrazine hydrate (45.0 g, 900 mmol, 98%) and the mixture was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was washed with cold EtOH (3×50 mL) to give 4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (80.0 g, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.86 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.99 (q, J=6.4 Hz, 1H), 4.78 (d, J=12.8 Hz, 2H), 1.36 (d, =6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OB(C=C)OCCCC)[CH2:29]CC.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([CH:28]=[CH2:29])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB(OCCCC)OCCCC
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc2cc(OCc3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a microwave vial containing 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 3, step D) (0.21 g, 0.46 mmol), vinylboronic acid dibutyl ester (0.20 mL, 0.92 mmol), and PS-tetrakistriphenylphosphine palladium (0.36 mg, 0.046 mmol) in DME (4 mL) is added Na2CO3 (2.0M, 0.92 mL, 1.83 mmol). This is stirred in the microwave at 110° C. for 10 min, at which time LC/MS reveals complete conversion to the desired product. The resin-bound palladium is removed by filtration and the filtrate is concentrated in vacuo, and purified by reverse-phase Biotage MPLC to afford 5-(3-benzyloxy-7-vinylnaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22][CH3:23])[CH3:21])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:22]([CH:20]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:24])=[CH:4][CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])[CH3:23])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(N(C)C)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(c1nc2ccccc2c(=O)n1-c1ccc(N(C)C)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In a similar manner as described above in Example 7, 3-(4-dimethylamino-phenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Paragraph L, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 519 (MH+).