Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[CH:2].[CH3:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>CN(C)C=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>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([C:13]3[N:14]=[C:15]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]4)[S:16][CH:17]=3)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=2)=[CH:34][CH:33]=1)(=[O:31])[CH3:29]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C#Cc1cc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#Cc4ccc(C(C)=O)cc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
In the same manner as in Example 98c, to a solution (3 mL) of the compound (200 mg, 0.49 mmol) obtained in Example 98b, 4-bromoacetophenone (150 mg, 0.74 mmol), triethylamine (0.14 mL, 0.98 mmol) and copper iodide(I) (19 mg, 0.10 mmol) in N,N-dimethylformamide was added tetrakistriphenylphosphinepalladium (58 mg, 0.050 mmol), and the mixture was stirred at 90° C. overnight. The palladium catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (97 mg, 38%) as a pale-yellow solid.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)[C:3]([NH2:5])=[NH:4].[SH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>CCO.O>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: COC(=O)CCS
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCSCc1csc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To 2-guanidino-4-chloromethylthiazole hydrochloride (3.86 g.) and methyl 3-mercaptopropionate (3.0 g.) in EtOH (45 ml.) at 0° was added sodium hydroxide (1.6 g.) in water (15 ml.) over 15 minutes. The reaction mixture was allowed to attain room temperature and to stand for 18 hours. The solution was poured into water and extracted with EtOAc. The extract was washed with aqueous sodium hydroxide solution, water, dried and evaporated to give methyl 3-(2-guanidinothiazol-4-yl-methylthio)propionate as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC([S:24]([Cl:27])(=[O:26])=[O:25])=CC=1.N1C=CC=CC=1>ClCCl>[CH3:1][CH2:2][CH2:3][CH:4]([S:24]([Cl:27])(=[O:26])=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCC(O)CCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(CCC)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hexadecanol (12.29 g 0.051 mol) and p-Toluenesulfonyl chloride (12 g 0.063 mol) were dissolved Pyridine (100 ml) and stirred overnight at room temperature. Dichloromethane (400 ml) was added. Dichloromethane solution was then washed well with water, H2SO4 (3%), water, NaHCO3 (3%) and water, dried with anhydrous magnesium sulphate (10 g). After evaporation of the solvent 20 g of crude 4-Hexadecanesulfonyl chloride was obtained.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:30][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:25][C:24]=1[O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)c(OCc2ccccc2)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-benzyloxy-4-fluorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17FN4O, 385. Found, 385.
Reaction SMILES: [S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([O-:20])=O)(=[O:3])=[O:2].[NH2:21]O.Cl>CN(C=O)C>[S:1](=[C:4]1[N:9]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][NH:6][C@@H:5]1[C:18]([NH2:21])=[O:20])(=[O:2])=[O:3]
Reactant: O=C([O-])[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1NCCN(C(=O)N2CCOCC2)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Step 5—Formation of N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carbox-amide Methyl 1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxylate (1.11 g, 2.2 mmol) was dissolved in DMF (17 mls) to which was added 50% aqueous NH2OH (20 mls) and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into cold 1.0N HCl (100-120 mls) and extracted with EtOAc (4×). The combined EtOAc extractions were washed with 10% aqueous LiCl (4×), saturated NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc) and the resulting pure oil was dissolved in 1:1 acetonitrile:water and lyophilized to give N-hydroxy-1-[4-(4-fluorophenoxy)phenyl)]sulfonyl-4-(4-morpholinylcarbonyl)piperazine-2-(R)-carboxamide as a white solid (659 mg, 59%). LC/MS Calcd for [M+H]+ 509.1, found 509.1. 1HNMR (400 MHz, CD3OD): δ 7.69 (d, 2H, J=9.2 Hz), 7.04 (m, 4H), 6.95 (d, 2H, J=9.2 Hz), 4.30 (m, 1H), 3.76 (m, 1H), 3.50 (m, 7H), 3.10 (m, 4H), 2.90 (dd, 1H, J=13.2, 4.4 Hz), 2.72 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)[CH3:3].CCN(CC)CC.[C:22](Cl)([CH3:24])=[O:23]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:22](=[O:23])[CH3:24])[CH2:11][CH2:12]1)[CH3:3]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(trans-4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (10.0 g, 45 mmol, intermediate B) was dissolved in CH2Cl2 (150 ml) and Et3N and AcCl (3.89 g, 50 mmol) were added. The reaction mixture was stirred 3 h at room temperature before washing it with H2O and brine. After drying (Na2SO4) the solvent was evaporated to yield 8.42 g (82%, 37 mmol) of a white solid. MS (m/z): 228.3 ([M+H]+).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C(Cl)CCc1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Yield: 50.9 %

Procedure:
To a solution of (Z)-methyl 3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.30 g, 16.4 mmol) in DCM (25 mL) was added a solution of 3-(3-fluorophenyl)propanoyl chloride (2.77 g, 14.8 mmol) in DCM (5 mL) dropwise with stirring. At the end of addition, the mixture was stirred further at rt for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (2.00 g, 51%).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[C:13](OC(=O)C)(=[O:15])C>C(O)=O>[CH:13]([NH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4])=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)(C(=O)O)c1ccccc1
Solvent: O=CO
Product: CC(NC=O)(C(=O)O)c1ccccc1

Procedure:
(RS)-2-amino-2-phenylpropanoic acid (20 g, 0.12 mol) in 88% formic acid (220 mL) was reacted with acetic anhydride (100 mL) at such rate as to keep the internal temperature at 60-65° C. After the final addition, the reaction was stirred until the internal temperature dropped to 35° C., and then concentrated. The solid residue was dried by azeotroping with toluene. The solid residue was dissolved in hot ethanol (70 mL), treated with active charcoal (0.5 g), and filtered. Hot water (210 mL) was added with stirring to the hot filtrate. The mixture was cooled in the refrigerator for 3 days. The resulting crystals was collected by filtration, washed with cold EtOH/water (1:3), and dried at 60° C. for 4 hours to give the title compound as colorless crystal. (17.8 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=2.CCN(C(C)C)C(C)C.[C:28]1([C:34]2[N:39]=[N:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([NH:41][NH:40][C:37]1[N:38]=[N:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[O:16])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(C(C)(C)C(=O)O)cc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc2ccc(C(C)(C)C(=O)NNc3ccc(-c4ccccc4)nn3)cc2c1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid (92 mg, 375 μmol), DIEA (66 μl, 375 μmol), and o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uronium hexafluorophosphate (143 mg, 375 μmol) in DMF was stirred for 2 h at 23° C. To the solution was added 1-(6-phenylpyridazin-3-yl)hydrazine (70 mg, 375 μmol) and stirred for 72 h at 23° C. Reaction partitioned between 9:1 CHCl3/IPA (25 mL) and 1M NaOH (5 mL). Organic dried over MgSO4 the concentrated to a solid from toluene under reduced pressure. Solid triturated with ACN (2 mL) and collected by filtration. 2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide isolated as a white solid. MS (ESI pos. ion) m/z: 414 (MH+). Calc'd exact mass for C24H23N5O2: 413.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 46.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 650 mg, 4.45 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 831 mg, 4.36 mmol), copper(II) acetate (807 mg, 4.45 mmol) and triethylamine (623 μL, 4.45 mmol) in 1,2-dichloroethane (4.5 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (592 mg, 46%) as a yellow oil that solidified on standing.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][C@@H:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: Clc1ccc2[nH]c3c(O[C@@H]4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1 H), 8.14-8.11 (m, 2H), 7.44 (dd, J=8.4, 0.6 Hz, 2 H), 7.31 (dd, J=8.4, 2.2 Hz, 2 H), 5.41 (t, J=4.6 Hz, 1 H), 3.91-3.72 (m, 2 H), 3.56-3.45 (m, 2 H), 2.48-2.40 (m, 1 H), 1.28-1.16 (m, 1 H); MS (ESI) m/z 408.2 (M−H)−; MS (ESI) m/z 410.1 (M+H)+
Reaction SMILES: C(Cl)Cl.[NH3:4].[CH:5]1[CH:10]=[C:9]2C(C(O)(O)[C:14](=[O:15])[C:8]2=[CH:7][CH:6]=1)=O>CO>[C:14]([NH2:4])(=[O:15])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccccc1

Procedure:
RF 0.8 in 100:30:5/CH2Cl2:MeOH: 880 Ammonia, visualised with ninhydrin.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:29][N:30]([CH3:31])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CNC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (40 mg, 0.10 mmol, prepared as described in Example 18) in DMSO (1 ml) was added dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) and DIPEA (0.09 ml). The mixture was heated under microwave irradiation firstly at 140° C. for 1 h, then at 160° C. for 1 h and then at 180° C. for 1 h. Further dimethylamine (2M in THF, 0.052 ml, 0.10 mmol) was added and the mixture was heated under microwave irradiation at 160° C. for 2 h. The product was then purified by Mass Directed Automated Preparative HPLC (Method B), then further purified by chromatography using an SCX cartridge (1 g), which was eluted with MeOH (2 column volumes) and then ammonia in MeOH (2M, 1 column volume). The product-containing fractions were combined and blown down under a stream of nitrogen. Purification using an aminopropyl cartridge (1 g), which was eluted with MeOH (1 column volume), afforded the title compound (9.8 mg) as a pale orange gum.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@:13]12[C:19]([CH3:21])([CH3:20])[C@@:16]([CH3:22])([CH2:17][CH2:18]1)[C:15](=[O:23])[O:14]2)=[O:12])[CH2:2][CH2:3][CH3:4].[OH-:28].[K+].Cl>C(O)C.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([OH:28])[CH2:18][CH2:17][C@@:16]([CH3:22])([C:15]([OH:14])=[O:23])[C:19]1([CH3:20])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(O)CC[C@@](C)(C(=O)O)C1(C)C
Temperature: 60 °C
Yield: 75.2 %

Procedure:
A mixture of the product from Example 102 (50.0 mg, 0.127 mmol) and potassium hydroxide (71.5 mg, 1.27 mmol) in ethanol (1 mL) and water (0.2 mL) was heated to 60° C. for 24 hours. After cooling to ambient temperature, 1N HCl (aq) was added to adjust the pH to −1. The mixture was extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated by rotary evaporator to give a white solid. Recrystallization of the solid from ethyl acetate afforded 39.2 mg (75%) of the title compound. 1H NMR (DMSO-d6) δ 0.79 (s, 3H), 0.92 (t, J=7.2 Hz, 3H), 1.07 (br s, 3H), 1.18 (br s, 3H), 1.27-1.40 (m, 3H), 1.50-1.63 (m, 3H), 1.68 (s, 9H), 1.85 (br s, 1H), 2.51-2.59 (m, 2H), 2.91 (br s, 2H), 9.07 (br s, 1H), 12.10 (br s, 1H). MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][S:12]2(=[O:18])=[O:17])[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[O:17]=[S:12]1(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH2:10][CH:9]1[N:4]2[C:1](=[O:3])[CH:2]=[C:28]([OH:34])[C:29]([OH:30])=[C:5]2[C:6](=[O:27])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:8]1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(O)cc(=O)n2C(CN2CCCCS2(=O)=O)CN1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-5-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one (75 mg, 0.19 mmol) and diethyl oxalate (29 μL, 0.21 mmol) in DMF (3 mL) under an atmosphere of nitrogen, a solution of sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 30 min. Then additional sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 1 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:13](=[O:31])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:25][CH2:24][N:23]([CH3:1])[C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:12][C:13]2=[O:31])=[CH:22][CH:21]=1)[CH3:28]
Reactant: C=O
Reactant: CCN(CC)CCNc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCN(C)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
Aqueous 37% formalin solution (100 μL) and 0.3 mol Zn[B(CN)H3]2/methanol solution (1.0 mL, 0.3 mmol, prepared from ZnCl2 and NaB(CN)H3) were added to a methanol solution (1 mL) of the compound obtained in Example 15 (7 mg, 0.018 mmol), and stirred at room temperature for 45 minutes. Aqueous 1 N sodium hydroxide solution was added to the reaction liquid, extracted with chloroform, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain the entitled compound (2.8 mg, 39%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)C(C)(C)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=501(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])[CH3:9])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccccc1S
Reactant: CC(Cl)c1ccc(Cl)cc1
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc(Cl)cc1
Yield: 78 %

Procedure:
The intermediate 2(-1-[4-chlorophenyl]ethylthio)pyridine N-oxide was prepared from 1-(4-chlorophenyl)ethylchloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 106° - 108°C. Structure confirmed by IR and NMR.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13].[CH3:34][CH2:35][C:36](=[O:39])[CH2:37][CH3:38]>O1CCCC1>[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:36]([CH2:37][CH3:38])([OH:39])[CH2:35][CH3:34])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(=O)CC
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)CC
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A 2.5 M solution of n-butyllithium in hexane (14.7 mL, 36.73 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 4.28 g, 14.69 mmol) in tetrahydrofuran (92 mL) at −78° C. Pentan-3-one (4.85 mL, 44.07 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for three hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=6/1) to give the title compound (3.66 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.C([O-])([O-])=O.[Ca+2].I[Cl:20]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([Cl:20])[C:11]=1[I:12]
Reactant: ClI
Agent: COC(=O)c1cc(I)c(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n. To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.