Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[CH3:4][C:5]1([CH3:19])[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18]>C(#N)C>[I-:3].[CH3:4][C:5]1([CH3:19])[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[N+:7]([CH2:1][CH3:2])=[C:6]1[CH3:18]
Reactant: CCI
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Solvent: CC#N
Product: CC[N+]1=C(C)C(C)(C)c2c1ccc1ccccc21
Product: [I-]
Yield: 91.3 %

Procedure:
Ethyl iodide (1.1 g, 7.2 mmol) was added to an acetonitrile solution (40 ml) of 1,1,2-trimethylbenz[e]indole (1) (1.0 g, 4.8 mmol, Daiichi Pure Chemicals Co., Ltd.), and then the mixture was heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure, and ether (80 ml) was added to the residue. The resulting solid was repeatedly washed with ether to obtain the title compound (2) as a dark violet solid (1.6 g, 91%). mp. 213-218° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:18][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ncc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of ethyl [[2-(4-bromophenyl)-2-oxoethyl]amino]oxoacetate (35 g, 0.11 mole) and phosphorus oxychloride (150 ml) was maintained at reflux for 10.5 hours and cooled to room temperature. The solution was poured into a mixture of ice and water (3 liter) and stirred for 1.0 hour. The resulting solid was collected by filtration and air-dried. Recrystallization from methylcyclohexane gave 22.3 g (0.075 mole) of product (yield, 68%), m.p. 119.5°-122°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccncc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccncc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 4-hydroxypyridine were reacted as starting materials at 150° C. for 22 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (201.6 mg, 85.2%). Melting point: 186.8-188.8° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][CH:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH:16]([CH3:18])[CH2:17][CH:12]([CH3:11])[CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC1CNCC(C)C1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CC(C)CN(c2ccc(Cl)cc2C#N)C1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 5-chloro-2-fluoro-benzonitrile (0.700 g, 4.499 mmol) in anhydrous DMF (8.0 mL) was added 3,5-dimethylpiperdine (0.713 g, 6.299 mmol) and cesium carbonate (4.30 g, 13.497 mmol). The reaction mixture was heated at 80 C for 2 h. Upon cooling to rt, water and ethylacetate was added. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. To the combined organic layer was added ether and the organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to give 1.15 g (96%) of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile as solid. LCMS 249(M+1)+. The compound was >98% purity and was hence used directly for the next step
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=O)[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4].[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:19].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:25]3[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:32][CH2:31]1)=[O:18])[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc2cc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)ccc2c1
Yield: 64.6 %

Procedure:
Using 6-butoxy-2-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.7 g), triethylamine (0.85 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (0.5 ml), an amidation as that described in Example 6 is carried out. The reaction mixture is purified by silica gel column chromatography (hexane:acetone=3:2). The product is converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to afford 1-(6-butoxy-2-naphthoyl)-4(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.7 g) as colorless prisms, m.p. 185°-190° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][CH:4]3[CH:3]=[C:2]([CH3:1])[C:11]4[C:6]([N:5]3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccnc2ccccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=CC2OC(c3ccc(Cl)cc3)c3ccccc3N2c2ccccc21
Yield: 50 %

Procedure:
Following the general procedure, treatment of 4-methylquinoline (0.073 g, 66 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=50/50) of the crude reaction mixture afforded 5-(4-chlorophenyl)-8-methyl-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.090 g, 50% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:1).
Reaction SMILES: CC1(C)C[O:36][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:40]>O1CCOCC1.O>[O:36]=[C:5]1[CH2:6][CH2:7][C@H:8]([CH2:10][C@H:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:12]([OH:40])=[O:13])[CH2:9]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](C[C@H]1CCC2(C1)OCC(C)(C)CO2)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Temperature: 110 °C
Yield: 73 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-trifluoromethyl-phenyl)-propionamide (250 mg, 0.47 mmol) in dioxane (2.5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (50 mL) and extracted with a chloroform/methanol solution (3:2, 2×25 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (102 mg, 73%) as a pale yellow oil: [α]22589=−86.1° (c=0.18, methanol); ES-HRMS m/e calcd for C15H15O3F3 (M+Na)+ 323.0865, observed 323.0865; 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.73 (t, J=7.8 Hz, 1H, ArCHCO), 7.47-7.61 (m, 4H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH2:10][S:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CCOCC.O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH2:10][S:11][C:12]([CH3:16])([CH3:17])[C:13]([O:15][CH3:19])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(SCC(=O)c1cc(F)cc(F)c1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(C)SCC(=O)c1cc(F)cc(F)c1

Procedure:
To a solution of 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoic acid from Step A (400. mg, 1.46 mmol) in MeOH (3 mL), was added trimethylsilyldiazomethane (2 M in hexanes) until yellow color persists. The reaction mixture was stirred for an additional twenty minutes. The reaction mixture was diluted with ether (30 mL) and water (10 mL). The organics were washed with 5% sodium bicarbonate and then with saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:Hexanes—40:60 to 90:10, to give the title compound. MS: m/z=229 (M−CO2Me).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2)([O-:3])=[O:2].C[C:17]([O:19][C:20](C)=O)=O.CN(C)C=O.C(OC)(OC)OC>CCOCC>[CH3:17][O:19]/[CH:20]=[C:7]1/[C:8](=[O:15])[NH:9][C:10](=[O:14])[C:11]2[C:6]/1=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Solvent: COC(OC)OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc([N+](=O)[O-])cc21

Procedure:
To a stirred mixture of 0.41 g (2.0 mmol) of 6-nitroisoquinoline-1,3(2H,4H)-dione, 3.2 ml (34 mmol) of Ac2O, and 0.80 ml of N,N-dimethylformamide is added 0.44 ml (4.0 mmol) of trimethyl orthoformate. The mixture is heated to 125° and maintained for 30 m, cooled, diluted with ether, and stirred for 10 m. The resulting brown solid is filtered, washed with ether, and dried to give 372 mg (74%); 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.19 (dd J=2.0, 8.6 Hz, 1H), 4.33 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:3][N:2]=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>CN(C=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:23]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][NH:7][C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)[CH2:14][CH2:13]2)=[O:22])=[CH:31][CH:30]=1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Reactant: c1cc(NCC2CCNCC2)cnn1
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ccnnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol, from EXAMPLE 66, Step 1) in DMF (3 mL) was added carbonic acid-4-fluoro-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.28 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-[(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S. (M+1): 345.29
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (0.100 g) in dichloromethane (2 mL) is added Et3N (0.25 mL) followed by methanesulfonyl chloride (0.075 mL). The reaction mixture is stirred at room temperature for 2 h. The reaction is diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give the title compound (101 mg). 1H NMR (400 MHz, CDCl3): δ 7.40-7.60 (m, 3H), 5.10 (s, 2H), 3.20-3.30 (m, 1H), 2.85 (s, 3H), and 1.40-1.50 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:13])[C:11]#[N:12].[CH3:14]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12]
Reactant: COc1ccc(C(C)C#N)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19 g, 0.097 mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL) was flushed with argon for 2 min and cooled to 0° C. Sodium hydride (60% oil susp., 4.4 g, 0.11 mol) was added in small portions. The thick suspension was stirred for another 18 h at 25° C. and then poured into water (300 mL) and extracted with Et2O (3×100 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving a yellow oil which was distilled. Bp: 103-106° C./0.06 mbar, clear oil that solidifies on standing. Yield: 17.5 g (83%). GCMS: >99%
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1>>[Br:1][CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CSc1ccc(Cl)cc1
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Yield: 98.7 %

Procedure:
64 g (0.4 mol) of bromine were slowly added to 97 g (0.4 mol) of 1-(4-chlorophenylmercapto)-2,2-dimethylbutan-3-one at room temperature. The reaction mixture was worked up in a manner corresponding to that in Example 1. 127 g (99% of theory) of 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a viscous oil. ##STR771##
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:26]([O-])(=[O:28])C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([CH:26]=[O:28])=[CH:10][CH:9]=1
Reactant: CCCCOC(=O)CCCCCN(C)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)CCCCCN(C)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Phosphorus oxychloride (18.4 g, 0.12 mol) was added dropwise with stirring, at 5° C., under nitrogen, to N,N-dimethylformamide (DMF, 50 mL). The resulting orange solution was stirred for 2 hours, then 27.6 g (0.81 mol) of butyl 6-(N-methyl-N-phenylamino)hexanoate was dropwise. The reaction mixture was stirred at 5° C. for 1 hour and then was heated in a water bath to 90° C., for 4 hours. After cooling the hot solution was poured over 200 g of crushed ice and naturalized to pH 6 by a slow addition of solid sodium acetate with vigorous stirring. The mixture was extracted with three portions of 200 mL dichloromethane. The combined organic extracts were washed three times with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled in vacuo yielding 23.4 g (76.8%) of pale yellow oil bp 151°-153° C. (3×10-4 mm).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[C:22](Cl)[N:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:11]([CH3:29])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]1[O:38][C:37]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=2[O:31]1>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:35]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:38][C:37]=5[CH:36]=4)[N:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:11]([CH3:29])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Cl)nccc12
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CC1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(-c3ccc4c(c3)OCO4)nccc12

Procedure:
Example 5, was prepared according to the general method described above from 1-benzoyl-3-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine and 3,4-methylenedioxyphenyl boronic acid, Precursor 14a-13, to provide 1-benzoyl-3-methyl-4-[(7-(3,4-methylenedioxyphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)+ Calc'd for C28H25N4O5: 497.18; found 497.03. HPLC retention time: 1.41 minutes (column B).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cn2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A suspension of 5-bromo-2-bromomethyl-pyridine (1.34 g, 5.34 mmol), thiomorpholine 1,1-dioxide (0.860 g, 6.36 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in acetone (15.0 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature and the volatiles were evaporated. The residue was partitioned between EtOAc (100 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 4-(5-bromo-pyridin-2-ylmethyl)-thiomorpholine 1,1-dioxide as a white solid (1.37 g, 84%). m.p.=129-131° C.; LCMS (m/e) 305 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.64 (d, 1H, J=2.3 Hz), 8.82 (dd, 1H, J=2.3 and 8.3 Hz), 7.29 (d, 1H, J=8.3 Hz), 3.78 (s, 2H), 3.13-3.02 (m, 8H).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[O:22].C(O)(=O)C.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[N:37]1([NH:23][C:21](=[O:22])[O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7]3)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNCC1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NN3CCCCC3)ccc21
Reaction time: 24 h
Yield: 125 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 60 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.83 g) and this mixture was stirred for 24 hours. Then 4.5 ml of glacial acetic acid was added to the reaction mixture followed by piperidine (0.95 g) in 10 ml of tetrahydrofuran. This mixture was then stirred for 24 hours, quenched with water and basified with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (4.6 g), which was eluted with 5% methanol in dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil (3.65 g).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12](S(C2C=CC=CC=2)(=O)=O)[O:11]1)(=[O:7])[CH3:6].[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>ClCCl>[C:5]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:27][CH:26]=[CH2:25])[O:11]1)(=[O:7])[CH3:6]
Reactant: C=CC[Si](C)(C)C
Reactant: CC(=O)OC[C@H]1CCC[C@H](S(=O)(=O)c2ccccc2)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC[C@H]1CCC[C@H](COC(C)=O)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Aluminium trichloride (1 g) was cooled to -78° C. under a nitrogen atmosphere and dichloromethane (15 ml) was added. A solution of trans-6-(benzenesulfonyl)tetrahydro-2H-pyran-2-methanol acetate (S. V. Ley et al., Tetrahedron (1989), 45 (13), 4293) (1 g) and allyl trimethylsilane (835 mg) in dichloromethane (10 ml) was then added dropwise. The reaction was stirred at -78° C. for 2 h, then -35° C. for 1 h. After quenching with 1N HCl and extracting with dichloromethane the crude product was purified by flash chromatography (40% EtOAc/hexane) to give the title compound of (414 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)benzoate (46 mg, 0.10 mmol) and lithium hydroxide monohydrate (21 mg, 0.51 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give 4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoic acid. MS (ESI+) m/z 436.22 [M+H]+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]1([C@H:21]([NH:20][C@H:17]2[CH2:18][CH2:19][C@@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH2:16]2)[CH3:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1)c1cccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
Under a nitrogen stream, (1S,3R)-3-[4-(benzyloxy)phenyl]-N-[(1R)-1-(naphthalen-1-yl)ethyl]cyclopentanamine (740 mg, 1.8 mmol) was dissolved in methanol (10 mL). After adding 10% palladium/carbon (70 mg) to the mixture, the atmosphere was replaced with hydrogen, and then the mixture was stirred for 16 hours at room temperature. The catalyst was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue obtained was purified by column chromatography (methanol/methylene chloride: 0/100-10/90) to give the title compound (427 mg, 73%).