Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([O:40][C:41](=[O:45])[CH:42](Br)[F:43])[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:45])[C@@H:42]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][CH:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1)[F:43])[CH3:39]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)C(F)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](F)Oc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Reaction time: 8 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (202 mg, 0.46 mmol) was dissolved in DMF (2 mL) at room temperature. Cs2CO3 (760 mg, 2.33 mmol) was added followed by bromo-fluoro-acetic acid ethyl ester (0.070 mL, 0.583 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (2/1 hexanes/ethyl acetate) to afford the product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([S:34][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[N:9]=[CH:10][C:3]=23)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (1.23 mmol, 250 mg), 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (1.23 mmol, 268 mg) and potassium carbonate (1.4 mmol, 203 mg) were dissolved in DMF (10 mL) and stirred for 60 minutes at room temperature. Its progress was followed by thin layer chromatography and LCMS. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo and purification by column chromatography provided compound A102 as a white solid (264 mg, 66%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.83 (s, 1H); 8.61 (d, 2H); 8.24 (s, 1H); 8.11 (d, 2H); 4.42 (h, 1H); 4.00 (m, 2H); 3.20 (m, 2H); 3.15 (s, 3H); 2.19 (m, 2H); 1.77 (m, 2H); 1.46 (s, 9H). LCMS (ESI), m/z 490.3 (MH+, 100%)
Reaction SMILES: [CH2:1]([N:5]([CH2:49][CH2:50][C:51](O)=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:54][C:55]([CH2:60][OH:61])([CH2:58][OH:59])[CH2:56][OH:57]>>[CH2:1]([N:5]([CH2:49][CH2:50][C:51]([NH:54][C:55]([CH2:60][OH:61])([CH2:58][OH:59])[CH2:56][OH:57])=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCC(=O)O)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: NC(CO)(CO)CO
Product: CCCCN(CCC(=O)NC(CO)(CO)CO)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 17.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 124, 3-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)propanoic acid (Intermediate 158B, 20 mg, 0.026 mmol) and 2-amino-2-(hydroxymethyl) propane-1,3-diol (J. T. Baker, 10 mg, 0.083 mmol) were converted to the title compound (4 mg, 18%). 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 8.73 (br s, 1H), 8.17-7.94 (m, 7H), 7.75-7.65 (m, 3H), 7.23-7.09 (m, 3.5H), 6.96-6.83 (m, 0.5H), 4.61-4.40 (m, 1H), 4.38-3.91 (m, 3H), 3.73-3.66 (m, 3H), 3.66-3.49 (m, 4H), 3.02-2.97 (m, 1H), 2.89-2.79 (m, 2H), 2.75-2.60 (m, 2H), 2.56 (t, J=6.9 Hz, 0.5H), 2.38-2.31 (m, 2H), 2.28-2.23 (m, 1.5H), 1.57-1.18 (m, 4H), 1.14-0.84 (m, 3H), 0.76 (t, J=7.3 Hz, 1H), 0.68 (t, J=7.3 Hz, 1H); MS(ESI+) m/z 859.4 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[N+:30]([O-])=O)=[N:2]1.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:13]1[CH:14]=[C:15]([NH:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: CC(=O)N1CCN(C(=O)Nc2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCN(C(=O)Nc2ccc(/C=C/c3n[nH]c4ccccc34)c(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Compound 86 (150 mg, 0.36 mmol) was dissolved in ethanol (2 mL), and the solution was added with tin (92 mg, 0.77 mmol) and concentrated hydrochloric acid (1.0 mL) under ice-cooling, followed by stirring at 40° C. for 1 hour. To the reaction mixture, 6 mol/L sodium hydroxide was added to neutralize the mixture under ice-cooling. Then, the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate/methanol(4/1) to obtain Compound 87 (110 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(O[N:48]1[N:56]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O.NN>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([NH:48][NH2:56])=[O:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)NN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (Example 78) (120 mg, 0.23 mmol), HATU (95 mg, 0.25 mmol) and N,N-diisopropylethylamine (59 mg, 0.46 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.125 ml, 2.6 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10˜12% of methanol in chloroform to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(4-hydrazino-4-oxobutyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 60 mg, 49%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24][CH3:25])=[CH:15][CH:14]=2)=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)#[N:2].[I:26]NC(=O)CCC(N)=O>>[C:1]([C:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24][CH3:25])=[CH:17][CH:18]=2)=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][C:7]=1[I:26])#[N:2]
Reactant: NC(=O)CCC(=O)NI
Reactant: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(-c2sccc2SC)cc1
Product: CCOC(=O)c1[nH]c(I)c(C#N)c1-c1ccc(-c2sccc2SC)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-237, the title compound is prepared by iodinating ethyl 4-cyano-3-[4-(3 methylthio(2-thienyl))phenyl]pyrrole-2-carboxylate, prepared directly above, with N-iodo-succinamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>CC(O)=O.O=[Pt]=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Cc1cc(N)c2c(c1-c1ccncc1)CCO2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(N)c2c(c1C1CCNCC1)CCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-methyl-4-(pyridin-4-yl)-2,3-dihydrobenzofuran-7-amine (1f) (0.40 g, 1.8 mmol), PtO2 (120 mg, 35%) and TEA (0.24 mL, 3.6 mmol) in HOAc (30 mL) was introduced H2 and stirred at ambient temperature for 24 h (88 psi). The mixture was filtered, concentrated, diluted with EtOAc (50 mL). A solution of ammonium hydroxide was added until pH=10, it was extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated to give the title compound (1g) as a yellow oil. MS-ESI (m/z): 233 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:32][N:31]=[N:30][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 72 h
Yield: 57.9 %

Procedure:
To a solution of ethyl 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carboxylate (730 mg) in dimethylformamide (10 ml) were added sodium azide (1.3 g) and ammonium chloride (1.07 g) and the mixture was stirred at 110°-115° C. for 72 hours. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. To the residue were added 0.5 N-hydrochloric acid (40 ml) and ether (100 ml) for partitioning, and the organic layer was washed with water, dried, and concentrated to dryness. The residue was purified by column chromatography on silica gel to give the desired product as a colorless powder (470 mg, 58%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH:13]=[C:12]([C:14](OCC)=[O:15])[CH:11]=[N:10]1)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([N:9]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[N:10]1)[CH3:8]
Reactant: CCOC(=O)c1cnn(CC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(CO)cn1
Yield: 77.5 %

Procedure:
Lithium aluminum hydride (7.19 g) was suspended in tetrahydrofuran (400 mL). To the obtained mixture were added a solution (100 mL) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate (29.00 g) in tetrahydrofuran on an ice bath with stirring. After stirring the reaction mixture at room temperature for 1.5 hrs, sodium sulfate decahydrate (80 g) was added by small portions on an ice bath with stirring, and the mixture was further stirred at room temperature for 16 hrs. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give (1-ethyl-1H-pyrazol-4-yl)methanol as a colorless oil (16.85 g, yield 78%) from a fraction eluted with ethyl acetate-methanol (1:0 to 49:1, v/v).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22]C#N)[CH2:17][CH2:16]1>>[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:17][CH2:16]1
Reactant: N#CCCN1CCC(O)CC1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC(O)CC3)cc12
Yield: 9.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.6095 g) and 3-(4-hydroxypiperidin-1-yl)propionitrile (2.44 g), 3-[2-(4-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (418.2 mg) was obtained.
Reaction SMILES: C(OCC)(OCC)OCC.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]1([N:24]=[CH:25]OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([NH:11][CH:25]=[N:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CCOC=Nc1ccccc1
Solvent: CCOC(OCC)OCC
Product: C(=Nc1ccccc1)Nc1ccccc1
Yield: 80 %

Procedure:
Thus, a mixture of triethyl orthoformate (1 equ.) and aniline (2 equ.) is heated at reflux for 2 hours. The ethanol evolved during the reaction is then distilled through a fractionating column. The reaction mixture is then allowed to cool, whereupon it solidifies. Recrystallisation of the solid from toluene yields N,N′-diphenyl formamidine in 80% yield. N,N′-diphenyl formamidine (1 equ.) and triethyl orthoformate (2 equ.) are mixed and a catalytic amount of dry aniline hydrochloride is then added. The mixture is heated and ethanol is seen to reflux within a few minutes. The mixture is heated at reflux for 1 hour and then the ethanol is distilled. Following the distillation, anhydrous potassium carbonate is added. The mixture is shaken and then allowed to stand for 2 hours. The reaction mixture is then distilled under reduced pressure. At 93 mmHg, excess triethyl orthoformate is collected at 83-85° C. The pressure is then reduced to 40 mmHg and ethyl N-phenylimdioformate is collected at 117° C. in 95% yield.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([S:32][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Fc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2cccc(F)c2)CC1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol), K2CO3 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol (0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23° C. for 5 min. The reaction mixture was stirred at 80° C. for 17 h, cooled to 23° C. and partitioned between EtOAc and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo gave tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 100%) as a yellow oil. ESI-MS m/z [M+H]+ 255.9.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[O:17][N:16]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:14][C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1cc(CBr)no1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3cc(C)on3)C2=O)nc1C
Yield: 78 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(bromomethyl)-5-methylisoxazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 78% yield: MS (ES+) m/z 351.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16](OCC)[O:17]CC)=O)=[C:4]([O:23][N:24]=C(C)C)[CH:3]=1.Cl.O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]=[O:17])=[N:24][O:23][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1ON=C(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a stirred solution of (4-bromo-2-(propan-2-ylideneaminooxy)phenyl)(2-(diethoxymethyl)phenyl)methanone (Compound 3a) (18 g) in ethanol (50 mL) at 70° C. was added 2M hydrochloric acid (25 mL). The mixture was stirred at 70° C. for 20 min forming a thick suspension. Water (500 mL) was added and the resultant solid filtered off and dried in vacuo at 50° C. to give the title compound (12 g).
Reaction SMILES: N1C=CC=C1.[K].ICCCC.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=[O:17])[NH:15][C:13]1=[O:14].Cl>C(O)C.O1CCCC1>[NH:12]1[C:20](=[O:21])[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: Cl
Agent: [K]
Solvent: CCCCI
Solvent: C1CCOC1
Solvent: c1cc[nH]c1
Product: O=C1CC(=O)NC(=O)N1
Yield: 132.7 %

Procedure:
Potassium pyrrole (3.0 g., 0.03 mole), 1-iodobutane (9.2 g., 0.05 moles) and 10 ml. of tetrahydrofuran were combined and refluxed for 1.5 hours by which time the reaction mixture had become a thick mass. The reaction mixture was diluted with 30 ml. of water and extracted with 35 ml. of ether. The ether was backwashed with water, then added to a solution of anhydrous alloxan (4.8 g., 0.03 mole) obtained by heating in 50 ml. of ethanol. The ether was distilled away, 6N hydrochloric acid (5 ml., 0.03 mole) was added, and the mixture refluxed for 3 minutes, cooled, evaporated to a gum, and triturated with water to afford title product [5.1 g.; m.p. 135 (dec); m/e 265].
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([OH:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[H-].[Na+].I[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:21])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(CC)c2c1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A solution of ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate (2.47 g, 10.5 mmo) in DMF (40 mL) was cooled to 0° C. To this mixture was added 60% NaH (0.42 g, 10.5 mmol) and stirred for 1 hour. To this was added a 0° C. solution of iodomethane (1.50 g, 0.66 mL, 10.5 mmol) in DMF (10 mL). The mixture was kept at 0° C. for several hours before stirring at room temperature overnight. The mixture was diluted with EtOAc, washed with a mixture of saturated aqueous NaHCO3 and saturated aqueous NaCl followed by saturated aqueous NaCl. The organic extract was dried over Na2SO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 3-ethyl-7-methoxy-1H-indazole-5-carboxylate (2.62 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([NH2:17])[C:7]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2].[C:28]1([C:34]2[N:35]([N:45]=[C:46]([CH3:50])[C:47](=O)[CH3:48])[C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([N:17]=[C:47]([CH3:48])[C:46](=[N:45][N:35]2[C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=[C:36]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:50])[C:7]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2]
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(N)c1-c1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)n(N=C(C)C(C)=Nn2c(-c3ccccc3)ccc2-c2ccccc2)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-Amino-2-naphthalen-1-yl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (434 mg, 1.22 mmol) in toluene (7.2 mL) was treated with 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (308 mg, 1.02 mmol) and p-toluene sulfonic acid (8 mg). A Dean Stark trap was attached, and the resulting solution heated to reflux under Ar with the azeotropic removal of water for 18 h, then another portion of p-toluene sulfonic acid (8 mg) was added and the azeotropic removal of water was continued for an additional 75 min. The solution was cooled to rt and concentrated in vacuo. The residue was dissolved in THF/Acetic acid (10/1) and treated with PS-TsNHNH2 resin (Argonaut Technologies, 1.039 g, 2.6 mmol). The suspension was stirred under Ar overnight, then filtered through a polyethylene frit, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 50-100% CH2Cl2/heptane) to afford 1-[2-(2,5-Diphenyl-pyrrol-1-ylimino)-1-methyl-propylideneamino]-2-naphthalen-1-yl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester a66 (240 mg, 37%): 11H NMR (DMSO, chemical shifts relative to TMS, 80° C.): 0.82 (t, 3H, J=7.3 Hz), 1.08 (s, 3H), 1.74 (s, 3H), 3.91 (q, 2H, J=6.9 Hz), 6.42 (s, 2H), 7.03 (s, 1H), 7.11 (d, 4H, J=7.3 Hz), 7.18 (t, 4H, J=7.3 Hz), 7.22-7.25 (m, 2H), 7.32-7.37 (m, 5H), 7.39-7.41 (m, 2H), 7.44-7.47 (m, 2H), 7.53 (d, 1H, J=8.2 Hz), 7.93 (t, 2H, J=8.7 Hz).
Reaction SMILES: [H-].[K+].CN(C)C=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][C:10]=1[OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.O>[CH2:17]([O:16][C:10]1[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][C:9]=1[Br:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)c(O)c1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Oc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. slurry of 1.7 g. (42.5 mmoles) of potassium hydride in 35 ml. of N,N-dimethylformamide was slowly added a solution of 7.22 g. (38.2 mmoles) of 4-bromoresorcinol. The resultant mixture was stirred for 30 minutes and then 4.54 ml. (38.2 mmoles) of benzyl bromide was slowly added. The reaction mixture was stirred 3 hours longer at 0° C. and then added to 200 ml. of cold water and 200 ml. of ether. The ether extract was washed twice with 200 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 400 g. of silica gel eluted with 25% ether-pentane to yield (in order of elution) 2.2 g. (16%) of 2,4-dibenzyloxybromobenzene, 0.21 g. (2%) of 5-benzyloxy-2-bromophenol and 3.52 g. (33%) of 3-benzyloxy-4-bromophenol.