Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (130 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous off-white substance (129 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:31])=[O:30])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:30])=[O:31])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(-c2cc(Cl)ccc2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) was added to 2,5-dichlorophenylboronic acid (57 mg, 0.30 mmol) in DMF (0.25 mL) and a DMF stock solution of 0.5M 2-[(3-bromophenyl)sulfonylamino]benzenesulfonamide (0.5 mL, 0.25 mmol). The reaction mixture was stirred at RT under argon for 15 minutes before addition of 2M Na2CO3 (0.5 mL). The reaction was stirred overnight at 90° C., filtered and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (15 mg, 13%) as a white solid.
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[C:29]([NH:37][NH2:38])(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(O)=O.C(Cl)Cl>[CH:22]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:8]1[C:9](=[O:11])[CH2:10][C:4]2[N:5]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:37][N:38]=2)[C:6]2[CH:28]=[CH:27][CH:26]=[CH:25][C:7]1=2)([CH3:24])[CH3:23]
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (71.14 g, 0.187 mol) in 1.04 L of AcOH was added benzoic acid hydrazide (27.28 g, 0.196 mol) in one portion. The reaction was heated to 80° C. and was stirred for 4 hours. The reaction was cooled to room temperature and the AcOH was removed in vacuo to give an off-white solid. The solid was dissolved in 1 L of methylene chloride. The organic solution was washed with 1 L of saturated NaHCO3 solution followed by brine and was dried over Na2SO4. The methylene chloride solution was diluted with an equal volume of methyl tert-butyl ether and the resulting solution was concentrated in vacuo to low volume causing a white solid to precipitate. The precipitate was collected on a sintered glass funnel and was rinsed with methyl tert-butyl ether. The solid was dried in vacuo to give 81.41 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide as a white solid. 1H NMR (CD2Cl2) δ 7.57-7.35 (m, 10H), 7.27 (br s, 1H), 7.21 (br s, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 4.89 (m, 1H), 4.19-3.99 (m, 3H), 3.53 (d, 1H), 1.03 (m, 6H); MS 452.3 (M+1), 450.5 (M−1).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[OH:18][CH:17]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)nc2)CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of 5-bromo-2-(trifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2° C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2° C. as a solid. The reaction mixture was warmed to 10° C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated and used crude in the next step.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.[CH3:32]COCC>CN(C=O)C>[CH3:32][N:22]1[C:23]2[C:19](=[CH:18][C:17]([S:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@H:9]3[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:16])=[O:15])=[CH:25][CH:24]=2)[C:20](=[O:27])[C:21]1=[O:26]
Reactant: CCOCC
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of 10 (193 mg, 0.5 mmol) in DMF (3 mL) was added 60% NaH (30 mg, 0.75 mmol) at room temperature. The mixture was stirred 15 min, then iodomethane (0.5 mL) was added. The mixture was stirred overnight at ambient temperature, then ether (75 mL) was added, washed with water (30 mL) and saturated NaCl (30 mL), and dried over Na2SO4. After evaporation of the solvent, the crude product was purified with ether to afford 85 mg (43%) of 11a as a yellow solid, mp 160.1-160.9° C. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 8.01 (s, 11H), 7.25 (t, J=8.4 Hz, 2H), 6.92 (m, 3H), 6.81 (d, J=7.8 Hz, 2H), 4.15 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 3.26 (s, 3H), 2.04 (m, 2H), 1.81 (m, 2H). Anal. Calcd for C20H20N2O5S: C, 59.99, H, 5.03; N, 7.00. Found: C, 59.80, H, 5.03; N, 6.91.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23])[O:9][CH2:8][CH2:7][CH:6]2[C:24]([O:26][CH3:27])=[O:25])#[N:2].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH2:70])=[CH:64][CH:63]=1.Cl>CN(C=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH:70][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[C:15]([CH3:23])[CH:16]=2)=[O:20])=[CH:64][CH:63]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(C#N)cc21
Reaction time: 48 h
Yield: 33.6 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)-3-methylbenzoic acid (0.013 g, 0.03539 mmol) in 1 ml dry DMF was treated with N-ethyl-N-isopropylpropan-2-amine (0.01233 ml, 0.07078 mmol), HBTU (0.01610 g, 0.04247 mmol) and 2-(4-chlorophenyl)ethanamine (0.009843 ml, 0.07078 mmol) at ambient temperature. After 48 h, the reaction was poured into 10% aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated to provide the crude material as a yellow film. Purification of the crude material on silica gel, eluting with 1% MeOH/DCM, provided the title compound (6 mg, 34%)
Reaction SMILES: C([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[ClH:22].O1CCOCC1>C1COCC1>[ClH:22].[NH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C#CCN)cc1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-(N-Boc-3-aminoprop-1-ynyl)benzoate (3.40 g, 11.7 mmol) in THF (25 ml) was added 4M HCl/dioxane (25 ml, 100 mmol). The reaction mixture was stirred for 1 h. The formed precipitate was collected, washed with diethyl ether (200 ml) and dried in vacuo providing methyl 4-(3-aminoprop-1-ynyl)benzoate hydrochloride (2.46 g) as white solid. Alternatively, the N-Boc protected amine can be dissolved in methanol instead of THF. In this case the solvent was removed in vacuo and the precipitate was washed with diethyl ether.
Reaction SMILES: CN1CCN(C(N)=S)[CH2:4][CH2:3]1.N1(C(N)=S)CCNCC1.Cl.Cl.[N:22]1([C:28]2[S:29][CH:30]=[C:31]([C:33]([CH3:36])(C)C)[N:32]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[N:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33][CH2:36][CH2:3][CH3:4])[N:32]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)c1csc(N2CCNCC2)n1
Reactant: CN1CCN(C(N)=S)CC1
Agent: Cl
Agent: NC(=S)N1CCNCC1
Agent: [Na+]
Product: CCCCc1csc(N2CCNCC2)n1

Procedure:
By using the process described in Example 1, but replacing 4-methyl-1-piperazinyl-thiocarboxamide by an equivalent amount of 1-piperazinyl-thiocarboxamide, 2-piperazinyl-4-tert.buty-thiazole dihydrochloride, having a M.P. of 190°-196°, is obtained. The free base is obtained therefrom by treatment with an aqueous sodium hydroxide solution.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+]>CO>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 65 °C

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70° C. and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with conc. HCl. The resulting solution was stirred over night at 25-30° C. The product was filtered and washed with water. The product was dried at 60° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([OH:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:57][CH2:58][C:59](O)=[O:60].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:33])[CH3:34])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([O:37][C:59](=[O:60])[CH2:58][Cl:57])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)cc2OCC3)n(C(C)C)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4OC(=O)CCl)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.9 %

Procedure:
Racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.215 g, 0.42 mmol) was suspended in dry THF (10 mL) and triphenylphosphine (0.22 g, 0.85 mmol) and chloroacetic acid (82 mg, 0.85 mmol) were added. Diethyl azodicarboxylate (0.133 mL, 0.85 mmol) was added dropwise and the mixture was stirred at room temperature for 24 h. The mixture was concentrated and the resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM). The resultant impure material was dissolved in dry DCM (5 mL) and triphenylphosphine, chloroacetic acid and diethyl azodicarboxylate were added (quantities as above). The mixture was stirred at room temperature for 16 hr, then concentrated in vacuo, the crude product was triturated with ether and the liquor was concentrated. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give impure racemic-cis-3-(2-Chloro-acetoxy)-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.297 g), which was used in the subsequent step without further purification. LCMS RT=4.61, [M+H]+=585/587.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:18][C:19]#[N:20]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]([CH2:18][C:19]#[N:20])[C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(=O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(CC#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofuran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane:dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([OH:14])[CH:10]=[CH:11][CH2:12][OH:13].[H-].[Na+]>CN(C=O)C.[Cl-].[NH4+]>[CH2:1]([O:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OCC=CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: OC/C=C\COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl bromide (8.0 g, 47 mmol) was added over a period of 30 minutes to a mixture of but-2-ene-1,4-diol (25.0 g, 281 mmol) and sodium hydride (2.2 g, 94 mmol) in DMF (100 mL) at 0° C. The mixture was stirred for 16 hours at room temperature. The mixture was then diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (methanol/ethyl acetate) to afford (2Z)-4-(benzyloxy)but-2-en-1-ol. 1H NMR (400 MHz, CD3OD) δ 7.34-7.27 (m, 5H), 5.75-5.64 (m, 2H), 4.50 (s, 2H), 4.12-4.09 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[Br:23][Br-]Br>O1CCCC1>[Br:23][CH:3]1[CH2:4][C@@H:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][C@@H:9]2[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(Br)C(=O)[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3aR,6aS)-tert-butyl 4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4 g, 17.76 mmol), in tetrahydrofuran (30 mL) at 0° C. was added pyridinium bromide perbromide (6.62 g, 18.64 mmol). The mixture was stirred for 3 hours at room temperature, wherein an ice bath was needed to keep the mixture at about room temperature. The reaction mixture was quenched with 1 N NaHCO3 solution (80 mL) and 1 N sodium thiosulfate (20 mL). The mixture was stirred for 0.5 hours and extracted with ethyl acetate. The organic layer was separated and concentrated. The crude product was purified chromatographically using a 40 g silica gel cartridge and eluting with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (3aR,6aS)-tert-butyl 5-bromo-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate: MS (ESI+) m/z 321 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=3)=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(C(=O)O)cnc1F
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Yield: 39.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (661 mg) described in Preparation Example 53, the title compound (440 mg) was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24](OC)=[O:25])[CH:20]=3)[N:15]=2)=[CH:11][CH:10]=1.Cl>C1COCC1>[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][OH:25])[CH:20]=3)[N:15]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2nc(Oc3ccc(OC)cc3)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc3cc(CO)ccc3n2)cc1
Yield: 100 %

Procedure:
To a THF (39 mL) suspension of LiAlH4 (0.15 g) was slowly added methyl 2-(4-methoxyphenoxy)quinoline-6-carboxylate (1.22 g) at 0° C., then the resultant mixture was stirred over night at room temperature. The reaction mixture was acidified with 6 M aqueous HCl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford [2-(4-methoxyphenoxy)quinolin-6-yl]methanol (1.11 g) as a pale yellow amorphous powder.
Reaction SMILES: [Cl:1][CH2:2][S@:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=O.ClC[S@@](C1C(=O)C2C(=CC(F)=CC=2)N(C)C=1)=O.FC1C=C2C(C(=S)C(C)=CN2C)=CC=1>>[Cl:1][CH2:2][S:3][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1
Reactant: Cn1cc([S@](=O)CCl)c(=O)c2ccc(F)cc21
Agent: Cc1cn(C)c2cc(F)ccc2c1=S
Agent: Cn1cc([S@@](=O)CCl)c(=O)c2ccc(F)cc21
Product: Cn1cc(SCCl)c(=O)c2ccc(F)cc21

Procedure:
FIG. 9 depicts the second step in the synthesis of e.e.(S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone and (R)-(−)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In this step, 7-fluoro-1-methyl-3-methylthio-4-quinolone is chlorinated as described to produce 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH3:30]
Reactant: CCOc1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+.