Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[C:9]1=[O:15].[OH2:16]>>[CH3:7][CH:8]([CH2:13][CH2:12][CH2:11][C:10](=[O:2])[CH3:14])[C:9]([OH:15])=[O:16]
Reactant: CC1CCCC(C)C1=O
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(=O)CCCC(C)C(=O)O
Temperature: 30 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A suspension of potassium permanganate (195.7 g, 1.24 mol) in water (1390 ml) was added carefully to a mixture of 2,6-dimethylcyclohexanone (120.0 g, 0.95 mol) and water (600 ml) while stirring vigorously the mixture at 30° C. or lower over a period of about 1 hour, and the mixture was stirred at room temperature overnight. The produced manganese dioxide was filtrated, and the filtration cake was washed with methyl tert-butyl ether (250 ml) and water (250 ml). The organic layer of the filtrate was separated, and the aqueous layer was adjusted to pH 1.0 with 35% concentrated hydrochloric acid (about 150 ml), and sodium chloride (400 g) was added and the mixture was extracted with ethyl acetate (300 ml×5), and the organic layer was dried over anhydrous magnesium sulfate, then, the solvent was distilled off under reduced pressure, and the resultant residual oil was distilled under reduced pressure by a vacuum pump. Fractions of boiling points of 130 to 144° C./267 Pa were collected, to obtain 79.92 g (yield 53.2%) of a racemate of 2-methyl-6-oxoheptanoic acid.
Reaction SMILES: C1([CH:7]2[N:11](CCC3C=CC(OC)=C(OC)C=3)C[CH:9](CO)[O:8]2)C=CC=CC=1.C1(C)C=C[C:29]([S:32](Cl)(=[O:34])=[O:33])=CC=1.[C:37]([O-:40])([O-])=[O:38].[K+].[K+]>N1C=CC=CC=1.O>[S:32]([O-:34])(=[O:38])(=[O:33])[CH3:29].[O:8]1[CH2:9][C:37](=[O:40])[N:11]=[C-:7]1
Reactant: COc1ccc(CCN2CC(CO)OC2c2ccccc2)cc1OC
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)[O-]
Product: O=C1CO[C-]=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 266.6 %

Procedure:
A solution of 2-phenyl-3-(3,4-dimethoxyphenylethyl)-5-(hydroxymethyl)oxazolidine 1 (25.76 g, 0.075 m) in pyridine (30 mL) was cooled to 10° C. and p-toluenesulfonyl chloride (14.30 g, 0.075 m) was added over 30 minutes, keeping the temperature below 25° C. After stirring at 25° C. for 3 hours, a cold solution of K2CO3 (10.37 g, 0.075 m) in H2O (70 mL) was added and the mixture was extracted with CHCl3 (3×125 mL). The extracts were washed with H2O, dried and concentrated under reduced pressure below 50° C., initially using water aspiration and finally high vacuum to yield the tosylate 2 (35.83 g, 96%). Sodium hydride (3.36 g, 0.070 m, 50% dispersion in mineral oil) was added to a solution of p-(2-oxazolyl) phenol 3 (11.29 g, 0.070 m) prepared according to the procedure of H. Jones, et al. [J. Med. Chem., 21, 1100 (1978)] in dimethylformamide (125 mL) under nitrogen and the mixture was heated at 60° C. for 30 min. A solution of the tosylate 2 (35.83 g., 0.072 m) in dimethylformamide (110 mL) was added and the mixture was refluxed for 16 hours. The solvent was removed under reduced pressure, saturated Na2CO3 solution (210 mL) added and the mixture extracted with ethyl acetate (2×250 mL) and CHCl3 (2×250 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was heated on a steam bath for 1.5 hours with 1.5N HCl (685 mL), the resulting solution cooled, and extracted with ether (2×300 mL). The acid layer was rendered alkaline with 20% NaOH solution and extracted with CHCl3 (3×500 mL). The solvent was concentrated under reduced pressure and the residue was chromatographed on silica gel and eluted with 5% MeOH--CHCl3 saturated with NH3. The product was crystallized from acetonitrile to yield 4 (7.0 g, 25%, m.p. 122°-3° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([N:20]([CH3:21])[CH3:19])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N(C)C)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (110 mg; 0.36 mmol; 1 eq.) is dissolved in anhydrous THF (10 ml). Under nitrogen, dimethylamine (0.27 ml; 0.55 mmol; 1.5 eq) and triethylamine (0.08 ml; 0.55 mmol; 1.5 eq) are added. The reaction mixture is stirred at RT for 1 hour. The solvents are evaporated and the crude product is directly purified by preparative HPLC, affording Compound (61) as a white-off solid (65.0 mg; 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([NH2:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CCCN1
Reactant: NC(=O)CBr
Product: NC(=O)CN1CCC[C@@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(2R)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione and 2-bromoacetamide following General Procedure H.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.[H-].[Na+].[CH3:16]I>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:16])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2
Reactant: OCCCc1nc2cccnc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CCCO)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.40 g of 2-(3-hydroxypropyl)-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 33), 0.81 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.2 ml of methyl iodide and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatograpy through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 3.10 g of the title compound, melting at >300° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[N:32][CH:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:34]1[N:35]=[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:31]=[N:32][CH:33]=1)#[N:37]
Reactant: N#Cc1cncc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(C#N)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0513 g, 0.134 mmol) and 6-chloropyrazine-2-carbonitrile (0.0326 g, 0.234 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 300 watts, 120° C. for 30 minutes on the Biotage microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.66 (s, 1H), 8.35 (s, 1H), 8.22 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.75 (s, 2H), 3.90 (t, J=5.3, 2H), 3.74 (d, J=4.4, 4H), 3.50 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.81 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br.O>C(COC)OC>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:15]=1[F:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Cc1cccc(CBr)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(C)c1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a suspension of sodium hydride (215 mg, 4.92 mmol) in dimethoxyethane (3 ml) was added dropwise a solution of diethyl malonate (868 mg, 5.42 mmol) in dimethoxyethane (2 ml) in an inert atmosphere at rt. Stirring was continued for 1 h followed by the addition of a solution of 2-fluoro-3-methyl-benzylbromide (1 g, 4.92 mmol) in dimethoxyethane (15 ml). The reaction mixture was refluxed for 90 minutes, cooled again to rt and water (5 ml) was carefully added. The diemthoxyethane was removed under reduced pressure, DCM (100 ml) was added and the organic layer was washed with water (100 ml), dried over magenisum sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silicagel, DCM/heptane=4/1) to give 973 mg (70%) of 2-(2-fluoro-3-methyl-benzyl)-malonic acid diethyl ester. LC-MS: tR=1.03 min; [M+H]+=283.22.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin triazole (0.1 mmol, the title compound of Example 3220) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 3222.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(F)c3)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(F)c3)cc2)S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a stirring solution of 5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.62 g, 1.70 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and the solution was cooled to 0° C. Added phosphorus pentoxide (0.49 g, 1.72 mmol) followed by triethylamine (1.1 mL, 7.72 mmol). The reaction mixture was allowed to slowly warm to RT. After 2 hours, HPLC shows that the reaction was complete. Added water and separated phases. The pH of the aqueous phase was adjusted to ca. 7 with 2M NaOH and the aqueous phase was then extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.25 g (40%) of the title compound as a white solid. MS (ESI−) for C18H14FNO4S m/z 358.0 (M−H)−.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([Br:14])[CH:9]=1)C.[BH4-].[Na+].CO.O>O1CCCC1>[Br:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][N:11]=1)[C:7]([NH:6][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH2:4][OH:3])=[O:15]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(CO)NC(=O)c2ccnc(Br)c2)cc1OC
Yield: 88.2 %

Procedure:
To a solution of N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)alanine ethyl ester (12.8 g) in tetrahydrofuran (100 ml) is added sodium borohydride (3.3 g), and thereto is added dropwise methanol (15 ml) with heating under reflux over a period of three hours. The reaction mixture is cooled with ice, and thereto is added water. The mixture is extracted with chloroform, and the extract is washed, dried, and concentrated to give 2-(2-bromoisonicotinoylamino)-3-(3,4-dimethoxyphenyl)-1-propanol (10.2 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[F:27][C:28]1[CH:29]=[C:30]([CH:35]([CH2:54][CH2:55]N2CCC(C3C=CC=CC=3[S@](C)=O)CC2)[CH2:36][N:37]([CH3:53])[C:38]([C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=2)=[O:39])[CH:31]=[CH:32][C:33]=1[F:34]>O>[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[F:27][C:28]1[CH:29]=[C:30]([CH:35]([CH2:54][CH2:55][N:11]2[CH2:12][CH2:13][CH:8]([N:3]3[CH2:4][CH2:5][CH2:6][NH:7][C:2]3=[O:1])[CH2:9][CH2:10]2)[CH2:36][N:37]([CH3:53])[C:38]([C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=2)=[O:39])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CN(CC(CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: O=C1NCCCN1C1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
Using standard reductive amination conditions 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine (Miller, S C; Jacobs, R T; Shenvi, A B. EP 739891) was reacted with N-[2-(3,4-difluorophenyl)-4-oxobutyl]-N-methyl-3-nitro-1-naphthamide [Example 13] and converted to the citrate salt. MS m/z 580 (M+H); analysis for C31H35F2N5O4.1.07 C6H8O7.1.06 H2O: calculated: C, 55.88; H, 5.72; N, 8.71. found: C, 55.94; H, 5.54; N 8.51.
Reaction SMILES: [CH3:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].C(N([CH2:15][CH3:16])CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(OCC)C>[S:17]([O:4][CH2:3][C:2]([CH3:1])([N+:7]([O-:9])=[O:8])[CH2:5][O:6][S:17]([C:16]1[CH:15]=[CH:24][C:23]([CH3:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(C)(COS(=O)(=O)c2ccc(C)cc2)[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
To a solution of 2-methyl-2-nitro-1,3-propanediol (80 g, 0.592 mol) and triethylamine (131.8 g, 1.303 mol) in diethyl ether (250 ml) is added a solution of tosyl chloride (225.7 g, 1.184 mol) in diethyl ether (800 ml) between −15° and −20° C. The resulting suspension is stirred at 0° C. for 1 hour, then 18 hours at ambient temperature. The reaction mixture is filtered, the solid residue is taken up twice in ethyl acetate and stirred, the suspension being filtered again. The combined ethyl acetate layers are evaporated to dryness giving a first crop of crude product (175.8 g). The ether filtrate is washed with water (2×) and brine, dried (Na2SO4), filtered, and partly concentrated. The suspension is filtered giving another 15.0 g of product. The crude solid product (190.8 g, 73%) is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[ClH:14].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[O:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Cl)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [I-].C[N+:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:5]=2[CH:4]=1.C(CN)O>O>[CH:4]1[C:5]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[C:6]=2[CH:7]=[CH:8][N:3]=1
Reactant: C[n+]1ccc2c(c1)-c1ccccc1Cc1ccccc1-2
Agent: [I-]
Solvent: NCCO
Solvent: O
Product: c1ccc2c(c1)Cc1ccccc1-c1cnccc1-2
Temperature: 160 °C
Reaction time: 2 h

Procedure:
A mixture of 19.9 g 2-methyl-9H-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyridinium iodide (formula IV) and 100 ml ethanolamine is heated with stirring in an oil bath at 160° C. for 2 hours. The reaction mixture is then poured out into H2O and extracted with ether. The organic phase is extracted with dilute HCl, after which the acid aqueous layer is made alkaline and extracted with ether. The ether layer is washed with H2O until neutral, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:41])[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:23]([OH:33])=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:42](=[O:45])(O)N.[CH2:46]=C.O>CN(C=O)C.[Br-].C([N+](CC)(CC)CC)C>[N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:41])[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:23]([O:33][CH2:46][CH2:42][OH:45])=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Reactant: C=C
Reactant: NC(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCCCCCCn1ccc2ccccc21)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
To a solution of N-(8-indol-1-yl-octyl)-3,5-bis(3-chlorophenyl)4-hydroxybenzamide (0.205 g, 0.35 mmol) in DMF (2 ml) was added ethylene carbamate (0.039 g, 0.438 mmol) and tetraethylammonium bromide (0.007 g, 0.035 mmol). The reaction mixture was warmed to 140° C. After 2.5 h, the reaction mixture was poured into water (50 ml) and extracted with EtOAc (3×20 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the product as a viscous yellow oil (0.185 g, 84%); 1H NMR (300 MHz, DMSO-d6) δ1.25 (broad s, 8H), 1.44-1.55 (m, 2H), 1.65-1.77 (m, 2H), 3.07-3.17 (m, 2H), 3.20-3.30 (m, 4H), 4.14 (t, J=7.5 Hz, 2H), 4.44 (broad s, 1H), 6.38 (d, J=3 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.34 (d, J=3 Hz, 1H), 7.40-7.52 (m, 6H), 7.56 7.65 (m, 2H), 7.70 (s, 2H), 7.88 (s, 2H), 8.54 (t, J=4 Hz, 1H); mass spectrum [(+)ESI], m/z 629 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1.CN1CCOCC1.[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31]>CN(C=O)C>[OH:31][CH2:30][C@@H:29]([NH:28][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 67.4 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile (0.7 g, 2.19 mmol) in DMF (15 mL) were added N-methylmorpholine (0.66 g, 6.57 mmol) and (S)-(−)-2-amino-3-phenyl-1-propanol (0.40 g, 2.63 mmol). The reaction mixture was heated to 80° C. for 6 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (3% MeOH/CH2Cl2) to yield the title compound (0.59 g, 68%) as a yellow foam. 1H NMR (400 MHz, CD3OD) δ 7.74 (1H, s), 7.63 (1H, s), 7.12–7.27 (6H, m), 6.07 (1H, d, J=7.5 Hz), 3.97 (1H, m), 3.74 (2H, t, J=5 Hz), 3.14 (1H, dd, J=5.5, 14.0 Hz), 2.94 (1H, dd, J=7.9, 14.0 Hz), 2.60 (3H, s). LCMS (M+H)+ m/z 400 (t=1.71 min.).
Reaction SMILES: [CH2:1]([CH:10]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:38])[CH:17](C(OC(C)(C)C)=O)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[CH:13]([CH:39]([O:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)=[O:43])[CH3:40])[C:12]1=[O:55])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:56]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:38])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[CH:13]([CH:39]([O:41][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])[CH3:40])[C:12]1=[O:55])[C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone was dissolved in 120 ml of dried methylene chloride, and 10 ml of trifluoroacetic acid was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel chromatography to obtain 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone.