Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOC1CC2=NOCC2C(O)C1OC(=O)OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: COCOC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1OC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4-Hydroxy-5-methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (275 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, and washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentration was effected under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 285 mg of 4-(tert-butyldimethylsilyloxy)-5- methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 73%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].S(OC)(O[CH3:13])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([O:6][CH3:13])=[O:5])[CH3:2]
Reactant: CCC(CC)C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 116 g (1 mol) of 2-ethylbutyric acid, 135 g (1.05 mol) of dimethyl sulfate, and 155 g (1.12 mol) of potassium carbonate in 500 ml of acetone was stirred at room temperature under nitrogen overnight, and then was allowed to reflux under nitrogen for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the residual solid was washed with 500 ml of ether. The combined filtrate was concentrated in vacuo, the residue was redissolved in ether, the ether solution was washed successively with water and brine and then dried. The solvent was concentrated and the residual liquid was distilled to afford 70 g (53.8 %) of methyl 2-ethylbutyrate, b.p. 135°-137° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccn(CCc3ccc(CN4CCCC4)cc3)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 55 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1b) in 1.5 mL DMF is added at RT 44 μL (0.53 mmol) pyrrolidine. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters SunFire, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: O.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7])=[O:17]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)CC[C@H](NC(=O)CCl)C(=O)O
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixed solvent of 1750 ml of water and 497 ml of toluene was added 733.7 g (5 mol) of L-glutamine at room temperature. The solution was cooled to 0° to 5° C. and adjusted to pH 11 with 5N sodium hydroxide. To the solution was added dropwise a solution of 565.3 g (5 mol) of chloro-acetyl chloride in 497 ml of toluene while maintaining the pH of the reaction mixture at 11 with 5N sodium hydroxide. After stirring at 0° to 5° C. for 1 hour, toluene was removed from the reaction mixture by liquid-liquid separation. The aqueous layer separated was adjusted to pH 2 by addition of 410 ml of concentrated hydrochloric acid. After seeding, the reaction mixture was subjected to crystallization at room temperature for 1 hour and then at 0° to 5° C. for 3 hours. The resulting crystals were collected by filtration and dried under reduced pressure to give 992.6 g (89.2 mole percent (mol %) yield) of crude N-chloroacetyl-L-glutamine (sodium chloride content: 13.6 weight percent (wt %)). The crystals were analyzed by high performance liquid chromatography (HPLC) (column: Shim-pack CLC-ODS, 6 ×150 mm (manufactured by Shimadzu Corporation); eluent: 0.01M sodium 1-octanesulfonate/0.01M KH2PO4 buffer (pH 2.5)/1% methanol; detection: UV 210 nm). The purity of the crystals was found to be 99.0% as calculated from the HPLC relative area ratio.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccccc4F)CC3)cccc2n1
Yield: 60 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2-fluorobenzoyl chloride (57 mg; 0.36 mmol) via Method AA to yield 43 mg. (60% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.49 (m, 1H), 7.33 (m, 4H), 7.17 (br s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.56 (br d, J=12.8 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.42 (br d, J=12.8 Hz, 1H), 3.12 (m, 1H), 2.86 (t, J=11.2 Hz, 1H), 2.22 (br s, 1H), 1.89 (br d, J=13.6 Hz, 1H), 1.73 (br d, J=11.2 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 396 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>O1CCOCC1.[Ag]=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:15]=4)=[CH:34][CH:33]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Temperature: 70 °C

Procedure:
To a stirred solution of 1-methylindole-6-carboxylic acid methyl ester (Example 10, part i) (1.5 g) and 4-(quinolin-2-ylmethoxy)benzyl chloride (2.43 g) in dioxan (15 ml), silver oxide (2 g) was added and the suspension heated at 70° C. overnight. The solvent was removed in vacuo, the residue ultrasonicated with ethylacetate and insoluble material removed by filtration through celite. The filtrate was evaporated to dryness and the residue purified by chromatography on flash silica, eluting with petroleum spirit 40°-60° C./diethyl ether (1:1) to give the product as a white solid. A small quantity was crystallised from petroleum spirit 40°-60° C./diethyl ether (1:1).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[CH:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1>>[CH2:26]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:31][CH:32]=1)[C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-hydroxydiphenylmethane in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H24O4[M−H]−: 399.
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][NH:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1.[O-]CC.[Na+]>C(O)C>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:13][CH2:14][CH2:15][NH:16][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: Cc1ccc(Cc2cnc(NCCS)[nH]c2=O)cn1
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
2-Guanidino-4-chloromethylthiazole hydrochloride is reacted with 2-(2-mercaptoethylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone and sodium ethoxide in ethanol to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].[C:18]([N:26]=[C:27]=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21)c1ccccc1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 909 mg (4.0 mmole) of 3-(2-furoyl)-2-oxindole and 706 mg (4.8 mmole) of benzoyl isocyanate in 25 ml of toluene was heated to reflux and then it was heated at reflux temperature for 7 hours. The mixture was allowed to stand at room temperature overnight and then the precipitate which had formed was removed by filtration, giving 1.3 g of crude product. The crude product was recrystallized from ca 30 ml of acetic acid, giving 920 mg of the title compound, mp 184° C. (dec).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(O)C>[NH:3]([CH2:1][CH3:2])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a stirring solution of ethylamine (24 mL, 300 mmol) and triethylamine (14 mL, 100 mmol) in ethanol (200 mL) at 0° C., was added via addition funnel a solution of t-butyl bromoacetate (19.5 mL, 100 mmol) in ethanol (50 mL). The cold bath was left unattended and the mixture was allowed to slowly warm to room temperature. After 24 hours, the solvents were removed in vacuo. The residue was dissolved in ethyl acetate, and extracted twice with 1N citric acid. The combined aqueous layers were basified to pH 10 with solid Na2CO3, and then extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 9.8 g (62%) of a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[S:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]1=[O:19])[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][O:29][C:30](=[O:32])[N:31]=2)=[CH:23][CH:22]=1.IC1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[OH:1][CH:2]([CH:6]1[S:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]1=[O:19])[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:31][C:30](=[O:32])[O:29][N:28]=2)=[CH:25][CH:26]=1)=[O:5]
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: Cc1ccc(N2CCSC(C(O)C(=O)O)C2=O)cc1
Agent: FC1(F)CCNCC1
Agent: O=C(O)c1cccc(I)c1
Product: Cc1ccc(N2CCSC(C(O)C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)C2=O)cc1
Yield: 60.4 %

Procedure:
According to the Step 77-1 in synthetic method for EXAMPLE 77, compound 112-2 (0.55 g) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (0.52 g) were used instead of 3-iodobenzoic acid and 4,4-difluoropiperidine to obtain compound 112-3 (0.52 g) as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:16]([C:12]12[CH2:11][O:10][C:7]([CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])([O:9][CH2:15]1)[O:8][CH2:13]2)[CH2:17][CH3:18]
Reactant: C#CCOCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: C#CCOCCC12OCC(CCC)(CO1)CO2

Procedure:
4-n-Propyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynyloxy)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[N:2].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C=O)C>[NH:23]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:2][N:25]=[N:24]1
Reactant: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(CCCCc2nnn[nH]2)c2ccccc12

Procedure:
A mixture of 578 mg of 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated at 120° overnight. After cooling the mixture is filtered and the filtrate diluted with ca. 25 ml of water. After the pH is adjusted to 10-11 with 3 N NaOH, the solution is washed with ether to remove unreacted nitrile. The aqueous phase is adjusted to pH 5-6 with 2 N HCl and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated in vacuo. The solid residue is slurried in petroleum ether and collected to give 1-[4-(5-tetrazolyl)-butyl]-3-methyl-2-(3-pyridyl)indole, m.p. 177°-179°.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])[CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1csc(Br)c1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1

Procedure:
Compound a was prepared by coupling commercially available 5-bromothiophene-3-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128 to afford a tan solid. HPLC Ret time=3.02 min. LCMS [M+H]+ 379.0.
Reaction SMILES: O[C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.CCN(S(F)(F)[F:41])CC>C(Cl)Cl>[F:41][C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccccc3)CC2)C1
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(F)(c3ccccc3)CC2)C1
Temperature: 25 °C

Procedure:
N-{[1-(4-Hydroxy-4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide (as prepared in Example 30, 680 mg, 1.43 mmol) in DCM (5 mL) was treated with DAST (Aldrich, 418 μL, 4.29 mmol) dropwise at −78° C. for 4 hours. The reaction was quenched with MeOH, warmed to room temperature and partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and the residue was purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compound as white solid: less polar isomer.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.C1(=O)OC(=O)C2=CC=CC=C12.[OH-].[Na+]>O.CCCCCC.C(OCC)C>[CH2:14]([CH:21]1[CH2:22][CH2:23][CH2:24][C:19](=[O:25])[CH2:20]1)[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: O=C1C=CCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C1OC(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To 30 ml of anhydrous diethyl ether were added 3.8 g (20 mmol) of cuprous iodide and 4.0 g (20 mmol) of tri-n-butylphosphine, and the mixture was stirred for about 1 hour at room temperature in an atmosphere of nitrogen and then cooled to -78° C. Then, 25.6 ml (40 mmol) of a 15 % by weight hexane solution of n-butyllithium was added, and the mixture was stirred for 30 minutes, and 1.92 g (20 mmol) of 2-cyclohexenone was added. The mixture was further stirred for 1 hour at -78° C. Then, 5 ml of hexamethylphosphoric tiramide was added, and the mixture was stirred for about 10 minutes. Phthalic anhydride (2.96 g, 20 mmol) was further added, and the mixture was stirred for 3 hours at room temperature. After the reaction, a solution of 4 g (100 mmol) of sodium hydroxide in 50 ml of water was added, and the mixture was stirred for about 1 hour. It was extracted with ether, washed, and dried to afford 6.22 g of a crude product. The crude product was distilled to afford 1.62 g (10.5 mmol) of 3-n-butylcyclohexanone in a yield of 53%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 2-dimethylaminoethylchloride.HCl (72 mg, 0.5 mmol) and K2CO3 (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. Dilute reaction mixture with EtOAc and filtered. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting 100% DCM then 90% DMAW 90 to give the title compound as an off white gel (79 mg). MS: [M+H]+ 565
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=O)[C:6](=[O:15])[N:7]2[CH:12]([CH3:14])[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:30]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH2:41])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>ClCCl.Cl>[ClH:1].[CH2:30]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:16]([C:5]2[C:6](=[O:15])[N:7]([CH:12]([CH3:13])[CH3:14])[C:8]3[C:3]([CH:4]=2)=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=3)=[O:18])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN1CCC(CN)CC1
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCN1CCC(CNC(=O)c2cc3c(Cl)cccc3n(C(C)C)c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 117.1 %

Procedure:
To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.376 mmol, step 4) in dichloromethane (1 mL) was added oxalyl chloride (0.10 mL, 1.13 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 1.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL) and [(1-butylpiperidin-4-yl)methyl]amine (128 mg, 0.753 mmol) in dichloromethane (1 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo gave a colorless oil. The resultant oil was dissolved in 10% methanolic hydrogen chloride (5 mL) and stirred for 16 h. The formed precipitate was filtrated and washed with methanol to give 100 mg (59%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].C(O)(=O)C.Cl>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c(N)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 79 %

Procedure:
A 10.43 g (30.6 mmol) portion of ethyl 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate was mixed with 150 ml of acetic acid and 150 ml of concentrated hydrochloric acid and then heated under reflux for 1 hour. After completion of the reaction, the reaction solution was spontaneously cooled and mixed with 700 ml of water. The thus formed crystals were collected by filtration, washed with water (100 ml×2), ethanol (300 ml×1) and ether (300 ml×1) in that order and then dried to yield 7.52 g (79%) of the title compound.