Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH2:31]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:31][CH2:30][CH:21]2[O:20][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH2:22]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1COc2ccccc2O1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCC2COc3ccccc3O2)=C(c2ccccc2)S1(=O)=O
Temperature: 100 °C
Yield: 64.9 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and (2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amine (0.083 g, 0.50 mmol) and TEA (0.07 mL, 0.50 mmol) in MeCN (2 mL) was heated in a microwave reactor at 100° C. for 45 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography using a 15-25% EtOAc in petroleum ether mixture as eluant, to give the title compound (0.139 g, 65%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.45 (m, 3H), 6.92-6.82 (m, 4H), 5.65 (t, 1H), 4.12-4.04 (m, 1H), 3.86 (dd, 1H), 3.68 (dd, 1H), 3.17 (t, 2H), 1.75 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.5, 142.9, 142.3, 135.1, 131.7, 130.2, 129.2, 124.8, 122.2, 122.1, 117.7, 117.5, 108.7, 71.4, 65.3, 61.9, 44.1, 27.9; Mass Spectrum: [M+H]+ 429.
Reaction SMILES: [CH2:1]([C@H:8]([NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([O-:30])=[O:29])=[O:24])[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([C@H:8]([NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([OH:30])=[O:29])=[O:24])[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C(=O)[O-])ccc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C(=O)O)ccc2C)c1
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino) carbonyl]-4-methylbenzoate (200 mg, 0.42 mmol) is treated with lithium hydroxide (39 mg, 0.96 mmol) in tetrahydrofuran/methanol/water (2/1/1, 2 ml), and the mixture stirred overnight at 20-25 degrees C. The mixture is decanted and the supernatant concentrated to give 3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-4-methylbenzoic acid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:6][C:5]=1[F:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:6]=1
Reactant: COC(=O)c1ccc(NCc2ccc(OC)cc2)nc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(CO)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic acid methyl ester (43, 70 g, 241 mmol) in 350 mL of tetrahydrofuran, lithium aluminum hydride (362 mL, 1 M in tetrahydrofuran, 362 mmol) is added dropwise while cooling. The reaction is stirred at room temperature for 2 hours, then quenched with dropwise addition of 14 mL of water, 14 mL of 15% aqueous sodium hydroxide, and 42 mL of water, sequentially. Then 500 mL of methyl tert-butyl ether is added and solids are removed by filtration. The filtrate is concentrated under vacuum and the resulting solid is dissolved in dichloromethane, passed through a plug of silica gel and eluted with 50-100% ethyl acetate in heptane. The solvent is removed under vacuum to provide the desired compound as an off-white solid (44, 63 g, 240 mmol, 100% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[C:17]([CH3:27])([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:17]([CH3:27])([CH3:26])[C:16]([OH:28])=[O:15])=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Product: CC(C)Sc1cccc(COc2ccc(CC(C)(C)C(=O)O)cc2)n1
Yield: 81.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:21])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])[NH2:10].N1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[CH3:21][C:12]1[CH:11]=[C:9]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=[C:7]([CH3:6])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(C)(=O)=O)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of 1.7 g (14.8 mmol) of methanesulphonyl chloride in 5 ml of anhydrous tetrahydrofuran is added dropwise to a solution, maintained under a nitrogen atmosphere, of 2.7 g (11.0 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline and 1.6 g (20.2 mmol) of pyridine, dried over potassium hydroxide, in 50 ml of anhydrous tetrahydrofuran. The mixture is stirred for 6 h 30 min at room temperature and is then refluxed for 4 h. 1.1 g (9.60 mmol) of methanesulphonyl chloride are then added and refluxing is continued for 1 h 30 min. A further 1.1 g (9.60 mmol) of methanesulphonyl chloride are added and refluxing is continued for 4 h. After cooling, the reaction medium is poured into ice-cold water and extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is crystallized from a cooled mixture of hexane and methylene chloride and is purified by recrystallization from a mixture of hexane and ethyl acetate, to give 1.1 g (yield=22%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]methanesulphonamide containing 14 mol % of ethyl acetate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:15]=O.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=[CH:15]1
Reactant: N#Cc1ccccc1
Reactant: CN(C=O)Cc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of di-iso-propyl-amine (11.2 mL, 79.9 mmol ) in 150 mL of THF at −78° C. was added n-butyllithium (31.9 mL of 2.5 M solution, 79.9 mmol). To the resulting mixture was added a solution of N-methyl-N-[4-picolyl]formamide (10 g, 66.5 mmol) in THF. The resulting orange-brown solution was stirred at −78° C. for 20 min, at which time benzonitrile (13.6 mL, 133 mmol) was added. The resulting dark brown mixture was allowed to warm to rt and stirred for 1 h, heated to reflux for 4 h, and then cooled to rt and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a light tan solid (5.83 g, 37%): mp 158-159° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][CH2:11]O.S(Cl)([Cl:15])=O.Cl.[OH-].[Na+]>O.CCOCC.C1C=CC=CC=1>[Cl:15][CH2:11][CH2:10][CH2:9][N:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCCCl

Procedure:
A stirred solution of 171 g. of cis-2,6-dimethyl-1-piperidinepropanol in 400 ml. of benzene is cooled to 0°-5° and 143 g. of thionyl chloride is added dropwise over a period of 30 minutes. The mixture is then heated at reflux for 2 hours, cooled and diluted with 1 l. of ether. The resulting precipitate of cis-1-(3-chloropropyl)-2,6-dimethylpiperidine hydrochloride is collected by filtration; m.p. 173°-174° C. after crystallization from 2-propanol-ether. The free base is prepared as needed by dissolving the hydrochloride in a minimum amount of water, cooling and adding a slight excess of 50% aqueous sodium hydroxide. The liberated base is immediately extracted with several portions of benzene. The extracts are combined, dried and evaporated to give the free base, cis-1-(3-chloropropyl)-2,6-dimethylpiperidine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31].[CH3:32]I>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([O:30][CH3:32])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31]
Reactant: Cn1c(=O)ccc2cc(COc3cc(C(F)(F)F)cc(C4(O)CCOCC4)c3)ccc21
Reactant: CI
Product: COC1(c2cc(OCc3ccc4c(ccc(=O)n4C)c3)cc(C(F)(F)F)c2)CCOCC1
Yield: 95 %

Procedure:
Using the procedure described in Example 11, 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyran was reacted with methyl iodide to give 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxytetrahydropyran in 95% yield, m.p. 103° C.
Reaction SMILES: Cl[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][CH2:6]2.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(#N)C>CS(C)=O>[N:20]1([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[NH:7][CH2:6]3)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C1NCc2cc(C(Cl)c3ccccc3)ccc2N1
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C1NCc2cc(C(c3ccccc3)n3ccnc3)ccc2N1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A mixture of 3.6 parts of 6-(chlorophenylmethyl)-3,4-dihydro-2(1H)-quinazolinone, 5.3 parts of 1H-imidazole, 60 parts of acetonitrile and 27.5 parts of dimethyl sulfoxide was stirred for 4 hours at reflux temperature. After concentration, the residue was washed twice with water, dissolved in a mixture of trichloromethane and methanol (90:10 by volume), dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a 45 parts of ethyl acetate and a few drops of water. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried, yielding 2.3 parts (58.1%) of 3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinazolinone; mp. 222.5° C. (comp. 16).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][P:18](Cl)(Cl)=[O:19].[OH2:22]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][P:18]([CH3:17])(=[O:19])[OH:22])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CP(=O)(Cl)Cl
Reactant: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(=O)(O)OCc1ccc(Br)cc1
Yield: 4.5 %

Procedure:
A solution containing 4-bromobenzyl alcohol (49.4 g, 0.26 mol) and Et3N (39 mL, 0.28 mol) in CH2Cl2 (150 mL) was slowly added to a cold (0° C.) solution of methyl phosphonic dichloride (36.96 g, 0.28 mol) in 200 mL of CH2Cl2, under N2. When the reaction was substantially complete, as determined by HPLC, an additional 39 mL of Et3N was added, followed by 20 mL of H2O resulting in an exotherm up to 27° C., followed by an additional 30 mL of H2O. According to HPLC, the reaction mixture contained 55% of the compound of Preparation 6, 4.5% of the desired compound and 20% of the compound of Preparation 1A. The reaction mixture was transferred to a separatory funnel and washed with 1N HCl (2×150 mL). The organic layer was combined with 150 mL of 2N NaOH and 50 mL of H2O, stirred overnight to hydrolyze the compound of Preparation 6 to the desired compound and then separated. The aqueous layer was washed with CH2Cl2 (2×150 mL), acidified with 22 mL of 12N HCl and then extracted with CH2Cl2 (400 mL). The organic extract was dried over Na2SO4, filtered and then dried in vacuo to provide 53.74 g of a white solid which was suspended in EtOAc (110 mL), stirred vigorously for 3 h, isolated by filtration and then dried in vacuo (at 50° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccc(Cl)cc2)n1
Temperature: 110 °C
Yield: 102.4 %

Procedure:
N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino} ethyl)acetamide (1.00 g) and piperazine (2.66 g) were dissolved in DMSO (40 ml) and sodium hydrogencarbonate added (1.29 g). The mixture was heated to 110° C. for 6 hrs. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was washed further with ethyl acetate (2×100 ml) and the combined organics subsequently washed with saturated brine solution (50 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (1.18 g).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[C:25](=[O:42])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[O:41])=[CH:31][CH:30]=4)[CH2:27][CH2:28][C:23]=3[C:22]([C:43]([NH2:45])=O)=[N:21]2)=[CH:16][CH:15]=1.N1C=CC=CC=1>CC#N>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[C:25](=[O:42])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[O:41])=[CH:31][CH:30]=4)[CH2:27][CH2:28][C:23]=3[C:22]([C:43]#[N:45])=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dimethylformamide (0.2 mL, 2.6 mmol) in CH3CN (20 mL) at 0° C. was added oxalyl chloride (0.23 mL, 2.6 mmol) and the reaction was stirred 0.5 h. The amide from Example 27 was added and the reaction was stirred cold 0.5 h. Pyridine (0.37 mL, 4.6 mmol) was added and the reaction was allowed to warm to rt and stirred for 24 h. The solvent was stripped, the residue was partitioned between CH2Cl2 and 1N HCl, and the layers separated. The aqueous layer was basified with 1N NaOH and extracted with EtOAc. The organic layers were combined and dried (MgSO4). Purification by chromatography on silica gel using 3% MeOH in CH2Cl2 and recrystallization from CH2Cl2/hexanes afforded 117 mg (89%); 1H NMR (CDCl3) δ 7.50 (d, j=8.8 Hz, 2H), 7.44 (m, 5H), 7.31 (m, 1H), 6.97 (d, j=9.2 Hz, 2H), 6.71 (d, j=9.5 Hz, 2H), 6.28 (m, 1H), 4.24 (t, j=6.6 Hz, 2H), 3.85 (s, 3H), 3.24 (t, j=6.6 Hz, 2H) ppm; LRMS (M+H)+ 438.4.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.9 %

Procedure:
To a solution of 5 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 100 ml of tetrahydrofuran are dropwise added 1.82 ml of pyridine and a solution of 2.86 g of benzoyl chloride in 20 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere. After 20 minutes, the reaction mixture is warmed up to room temperature. After additional 2 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with an aqueous sodium sulfate and condensed under reduced pressure to yield 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C>[C:14]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 4.24 g. 6-aminoindole in 300 ml. methylene chloride was stirred at 0° C. and 5.4 ml triethylamine followed by 4.2 ml. hexanoyl chloride was then added. The dark mixture was stirred for 1 hour and then filtered to remove a white precipitate. The filtrate was diluted with methylene chloride; washed sequentially with 10% w/v sodium hydrogen sulphate water, and brine; dried (MgSO4); and evaporated. The residue was crystallized from ethyl acetate and hexane to give 6-hexanamidoindole (E) as a white solid. Partial evaporation of the mother liquor gave a second crop of solid giving a combined yield of 4.5 g. (65%); NMR: 0.9 (t, 3H, CH3), 1.4 (m, 4H, CH3CH2CH2), 1.8 (m, 2H, CO.CH2CH2), 2.4 (t, 2H, CO.CH2), 6.5 (m, 1H, H3), 6.8 (dd, 1H, H5), 7.2 (m, 2H, CO.NH+H2), 7.5 (d, 1H, H4), 8.1 (bs, 1H, H7), 8.3 (br, 1H, NH).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]2[CH2:13][CH2:14][CH2:15][C:9]2=[N:8]1.N1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:25]=1[C:26]([NH:12][C:11]1[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:8]=[C:9]2[CH2:15][CH2:14][CH2:13][C:10]=12)=[O:27]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Reactant: Nc1c2c(nn1C[C@@H]1CCCO1)CCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1c2c(nn1C[C@H]1CCCO1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of the product of Example 32A (340 mg, 1.64 mmol) and pyridine (535 μL, 6.56 mmol) in CH2Cl2 (20 mL) was added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (470 mg, 1.97 mmol) dropwise. The mixture was stirred at ambient temperature for 1 h. The mixture was concentrated under reduced pressure and was purified by column chromatography (SiO2, 40% hexanes/EtOAc) to provide the title compound 550 mg (82%). MS (DCI/NH3) m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[O:4]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 71592 %

Procedure:
In a 3 L 3 neck flask with a mechanical stirrer, DMAP (11.5 g, 0.10 mmol) was added to a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (105 g, 0.95 mmol) and in pyridine (750 mL). A solution of (BOC)2O (222 g, 1.02 mol) in pyridine (750 mL) was slowly added to the previous solution while the temperature was kept between 20 and 25° C. The mixture was stirred under nitrogen for 20 h. The reaction mixture was evaporated to dryness then triturated in 500 mL of MeOH at rt for 3 h then 30 min at 0° C. The suspension was filtered on a buchner funnel and washed with cold ethanol. The white solid was dried to afford 175 g (70%) of 3-tert-Butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([OH:38])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-hydroxypiperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N4O3 [(M+H)+] 623.255, observed 623.2547.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][C:16]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCl)Nc1cnc2ccccc2c1Cl
Temperature: 50 °C
Yield: 78.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (6.00 g, 33.59 mmol) and 3-chloropropionyl chloride (4.8 mL, 50.39 mmol) dissolved in 200 mL of 1,2-dichloroethane was heated to 50° C. in an oil bath. After 20 hrs the temperature of the oil bath was increased to 90° C. After an additional 26 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 7.12 g of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide as a tan solid.