Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cn3)CC2)c(C)c1
Yield: 49.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 150 and oxazolidin-2-one (96 mg), the title compound (190 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[CH2:9][CH2:10][NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[I:19])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH3:21])[CH2:9][CH2:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[I:19])[C:4]=2[CH:3]=1
Reactant: CN(CCNC(=O)c1ccccc1I)c1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN=C(c2ccccc2I)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
After a mixture of 181 mg of N'-(4-chlorophenyl)-N-(2-iodobenzoyl)-N'-methylethylenediamine, 925 mg of phosphorus pentoxide and 4 ml of phosphorus oxychloride had been stirred at 115° C. to 120° C. for 4 hours, the reaction mixture was allowed to cool and poured into ice water to decompose an excess of the reagents. After having been washed with ether, the aqueous phase was alkalized with sodium carbonate and then extracted with ethyl acetate. After the organic phase had been washed with water, distilling off the solvent therefrom gave 164 mg of 7-chloro-2,3-dihydro-5-(2-iodophenyl)-1-methyl-1H-1,4-benzodiazepine.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2(O)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:6]1>CCO>[NH:16]1[CH2:17][CH2:18][CH:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)[CH2:15]1
Reactant: OC1(c2c[nH]c3ncccc23)CCCNC1
Solvent: CC(=O)Cl
Solvent: CCO
Product: C1=C(c2c[nH]c3ncccc23)CNCC1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
10 ml acetylchloride was slowly added to 200 ml of EtOH (−10° C.). After 15 minutes, this solution was added to compound 4 (5 g, 16.3 mmol) and heated to reflux for 1 hour. The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration over 25 g SCX-2 (MeOH followed by 1 N NH3/MeOH) gave the title compound (1.43 g, 7.18 mmol, 44.1%) as amorphous material. 1H-NMR (400 MHz, CDCl3): δ 11.4-10.8 (bs, 1H), 8.32 (dd, J=5 Hz, 2 Hz, 1H), 8.2 (dd, J=8 Hz, 2 Hz, 1H), 7.15 (dd, J=8 Hz, J=5 Hz, 1H), 6.32-6.27 (m, 1H), 3.76-3.72 (m, 2H), 3.10-3.04 (m, 2H), 2.36-2.29 (m, 2H). (TLC MeOH/triethylamine (97/3 Rf 0.25).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([C:28]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:29])=[CH:26][CH:27]=1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a stirred solution of 185 mg of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride containing 2.0 ml of triethylamine is slowly added a solution of 300 mg of 4-biphenylcarbonyl chloride in 10 ml of methylene chloride at room temperature. The reaction mixture is stirred at room temperature for 16 hours and evaporated in vacuo to give a residue. The residue is extracted with chloroform, washed with water, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 250 mg of the desired product as a solid. Mass spectrum: M+H:366.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:1]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Yield: 84.8 %

Procedure:
Dissolving 15 g (54 mmol) of 4-bromoacetophenone and 5.2 g (55 mmol) of 2-aminopyridine into 100 milliliter of ethanol, adding 7.0 g of sodium hydroxide, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, resultant crystals were separated with filtration, washed with water and ethanol, thereby obtaining 12.5 g of 2-(4-bromo-phenyl)-imidazo [1,2-a] pyridine (yield: 85%).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=2)[CH:9]=1>O>[Na+:2].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH:11]=2)[CH:9]=1.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[C:8]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH:11]=2)[CH:9]=1
Reactant: O=C(O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCc1cc(-c2cc(Cl)ccc2O)on1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Add a solution of NaOH (739 mg, 18.5 mmol) in water (3 mL) to a suspension of 5-[5-(5-chloro-2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid (2.73 g, 9.23 mmol in water (5 mL) and stir at room temperature. Heat to 55° C. for 1 hour, filter hot solution, concentrate, place in 50-60° C. vacuum oven for 2 days. Scrape and crush solids, place in 50-60° C. vacuum oven overnight to afford the title compound (3.14 g, 100%). MS (IS) 296 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][CH:41]([CH3:44])[CH:42]=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:44])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4CC(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide, Example 57, (56 mg, 0.1 mmol) was reacted with 2-methyl-propionaldehyde (0.011 mL, 0.12 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 613 (M+1).
Reaction SMILES: Cl.[CH3:2]O.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:2])=[O:16])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
15 ml of 10% hydrogen chloride-methanol was added to 1.07 g (5.0 mmol) of 4-(4-hydroxyphenyl)benzoic acid and the mixture was refluxed under heating for 5 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto and the solution was extracted twice with a chloroform-methanol mixed solution (10:1 (v/v)). The extract was washed with a sodium hydrogencarbonate aqueous solution and dried (MgSO4). The solvent was distilled off to obtain 0.97 g (4.25 mmol) of methyl 4-(4-hydroxyphenyl)benzoate as a faint yellow powder. Its spectroscopic data are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([CH:26](O)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(O)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(c1ccccc1)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5, and DL-1-phenylethyl alcohol (79.9 μl, 0.661 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). The resulting mixture was heated under reflux for 13 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was separated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate=85:15). The solids thus obtained were each washed with hexane, whereby obtained were the title Isomer 299-A (low-polarity compound) (53 mg, 0.130 mmol, 40%) as a white powder and the title Isomer 299-B (high-polarity compound) (20 mg, 0.0492 mmol, 15%) as colorless columnar crystals.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N[C@H](C1C=CC(F)=CC=1)C[OH:32].CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][OH:32])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 140 °C
Yield: 42 %

Procedure:
2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1; 0.5 g, 1.8 mmol) and (R)-2-amino-2-(4-fluorophenyl)ethanol (0.6 g, 3.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA (0.3 g, 2.3 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hrs, then cooled to 25° C. and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.3 g, 40%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.35 (m, 3H), 7.05-7.00 (m, 2H), 5.99 (s, 1H), 5.20-5.11 (m, 1H), 3.90-3.77 (m, 2H), 1.90-1.86 (m, 1H), 1.05-0.96 (m, 2H), 0.73-0.66 (m, 2H). MS: Calcd.: 396. Found: [M+H]+ 397.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: OCc1ccccc1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 73.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.34 mL, 0.36 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.44 g (74% yield) of the title compound (31a) as a colorless oil. Rf=0.47 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 6H), 2.22-2.29 (m, 2H), 3.18-3.22 (m, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.84 (s, 1H), 3.93 (d, J=9.2 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.35-7.40 (m, 5H) ppm. MS (ESI) m/z 521.16 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]>C1COCC1>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CON(C)C(=O)c1ccc2[nH]ncc2c1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2[nH]ncc2c1
Reaction time: 2 h
Yield: 95 %

Procedure:
EtMgBr (3 M, 2.0 eq, 6.5 mL) was added to a solution of N-methoxy-N-methyl-1H-indazole-5-carboxamide (2 g, 1.0 eq) in dry THF at 0° C. Once addition was complete, the mixture was stirred for 2 h, and extracted by EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (1.8 g, 95%). 1H NMR (400 MHz, CDCl3) δ 11.20 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.08 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: OC1CCCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2CCCC2)cccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and cyclopentanol in 78% yield as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 1.64 (m, 2H), 1.77 (m, 4H), 1.97 (m, 2H), 5.14 (m, 1H), 7.73 (m, 1H), 7.88 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(O)C=CC=CC=1.C1(S([N:22]2[C:30]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=3[CH:24]=[C:23]2[CH2:32][N:33]2[CH2:38][CH2:37][N:36]([S:39]([C:42]3[S:46][C:45]4[CH:47]=[C:48]([Cl:51])[CH:49]=[CH:50][C:44]=4[CH:43]=3)(=[O:41])=[O:40])[CH2:35][C:34]2=[O:52])(=O)=O)C=CC=CC=1>>[NH2:5][C:26]1[C:25]2[CH:24]=[C:23]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([S:39]([C:42]4[S:46][C:45]5[CH:47]=[C:48]([Cl:51])[CH:49]=[CH:50][C:44]=5[CH:43]=4)(=[O:41])=[O:40])[CH2:35][C:34]3=[O:52])[NH:22][C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: Nc1nccc2[nH]c(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)cc12
Temperature: 100 °C

Procedure:
Anhydrous ammonium acetate (0.56 g, 7.2 mmol), phenol (0.45 g, 4.8 mmol) and 1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-2-one (0.31 g, 0.48 mmol, prepared as described previously) are heated to 100° C. for 3.5 days. The mixture is cooled to RT then the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN then the appropriate product fractions are lyophilized to provide the title compound (1.29 g, 2.2 mmol) as a white solid (22.4 mg, 0.038 mmol). 1H NMR (DMSO-d6, 300 MHz) δ12.40 (bs, 1H), 12.00 (bs, 1H), 8.31 (d, 1H), 8.20 (s, 1H), 8.06 (d, 1H), 8.02 (bs, 2H), 7.57 (dd, 1H), 7.48 (m, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.60 (s, 1H), 3.81 (s, 2H), 3.40 (m, 4H). LR-FAB MS, [M+H]+=476, 478.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>O1CCOCC1.O>[CH:36]1[C:35]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]3)=[O:7])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) was added aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reaction mixture was heated at about 60° C. for about 16 h before being allowed to cool to ambient temperature. To the mixture was added NaHCO3 (2.07 g, 24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was acidified to about pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g column) eluting with a gradient of 1-5% MeOH in DCM to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylic acid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) Rt=2.44 min; MS m/z: 366 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([NH:15]C(OCC2C=CC(OC)=CC=2)=O)[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)NC2CC=CCN(S(=O)(=O)c3ccc(OC)cc3)C2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC=CCC(N)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(4-methoxybenzyloxy carbonyl-amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (370 mg, 0.71 mMol) is dissolved in Dichloromethane (15 ml) containing 3% Trifluoroacetic Acid. The reaction is stirred for 1 h at room temperature. The solvents are evaporated and the remaining oil is co-evaporated twice with Toluene. Flash-chromatography Dichloromethane/Methanol (7:1) to afford the free amine: Cal. 546.6 found (M)+=547.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]([CH3:9])=[C:7]([CH3:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)c(Cl)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(OCc2ccccc2)c(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
2-Chloro-3,4-dimethyl-6-nitrophenol (6.44 g, 31.9 mmol) was dissolved in dry DMF (105 mL) and flushed with argon. Benzyl bromide (4.17 mL, 35.1 mmol) and K2CO3 (13.24 g, 95.7 mmol) were added. The reaction mixture was stirred at room temperature for 8 h (protected from light) and filtered. Water (5 mL) was added and the solvent was co-evaporated with xylene (2×150 mL) and CH2Cl2 (100 mL). The residue was mixed with CHCl3 (100 mL), filtered and after evaporation of the solvent 10.8 g of crude product remained. Purification by flash column chromatography (SiO2, CHCl3 -Hexane 1:1) gave the title compound (8.44 g). Mp: 74°-75° C.; 1H NMR (DMSO-d6): δ 7.80 (s, 1H), 7.48-7.37 (m, 5H), 5.06 (s, 2H), 2.37 (s, 3H), 2.34 (s, 3H); 13C NMR (DMSO-d6): δ 145.24, 142.22, 142.08, 135.73, 134.73, 129.61, 128.39, 128.37, 128.35, 123.64, 75.74, 19.74, 17.13; MS (EI, 70 eV): m/z (rel.int.) 293/291 (M+, 0.08/0.37), 187/185 (8/24), 91 (100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)cc1
Yield: 64.6 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-methoxy-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (35 mg, 66%). LC-MS m/e 417.29 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])([O:12][CH3:13])=[O:11]>C(#N)C>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:10]([O:12][CH3:13])=[O:11])(=[O:22])=[O:21])=[O:25])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(N)cc(Cl)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a warmed mixture containing 1.4 g (0.01 mole) 2,4-diamino-6-chloropyrimidine in 50 ml acetonitrile is added 2.4 g (0.01 mole) 2-carbomethoxybenzenesulfonylisocyanate. The reaction mixture was stirred at room temperature for four days. The reaction mixture was filtered and the precipitate washed with ether. The filtered solid was air dried and purified in the following manner. To an aqueous suspension of the reaction mixture was added n-propylamine and the aqueous mixture filtered. The resultant clear solution was carefully acidified with concentrated HCl to pH=1-2. The mixture was filtered, washed with ether and air dried to yield a white solid, m.p. 170°-172° C. The infrared spectrums showed characteristic absorption bands at 1740, 1700 cm-1. The NMR and mass spectral data are consistent for the desired product.