Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:27].C(OCC)C.CCCC(C)C>C(#N)C>[Br-:24].[F:35][C:31]1[CH:30]=[C:29]([NH:28][C:26]([CH2:25][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Reactant: O=C(CBr)Nc1cccc(F)c1
Solvent: CC#N
Solvent: CCCC(C)C
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccs3)CCCCCC1)C2)Nc1cccc(F)c1
Product: [Br-]
Reaction time: 8 h
Yield: 55.3 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (96 mg) and 2-bromo-N-(3-fluoro-phenyl)-acetamide (Example 8a) (67 mg) were dissolved in acetonitrile (2 mL) and left overnight. Diethyl ether (10 mL) and isohexane (8 mL) were added and the mixture was left overnight. The resulting crystals were filtered off and washed with diethyl ether to afford the titled compound (90 mg).
Reaction SMILES: Cl.Cl[C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.C([O-])([O-])=O.[K+].[K+].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC#N>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:3]1[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=1
Reactant: Clc1nc2ncccc2s1
Reactant: OCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of 2-chloro[1,3]thiazolo[4,5-b]pyridine hydrochloride (1.0 equiv.) in CH3CN (0.25 M), was added K2CO3 (powder, 325 mesh; 2.1 equiv.). The mixture was stirred at 50° C. under N2 for 3 h prior to the addition of 4-hydroxymethyl-phenol (1.0 equiv.). The reaction mixture was heated at reflux for 3 h and cooled to rt. Some product precipitated out from the reaction solution and was dissolved by adding CH2Cl2. The insoluble inorganic salt was then filtered off and washed with CH2Cl2. The filtrate solution was concentrated to give the title compound (99%), which was used without further purification. MS (ESI): mass calcd. for C13H10N2O2S, 258.1; m/z found, 258.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (ddd, J=4.9, 1.7, 0.4, 1H), 8.02 (ddd, J=7.9, 1.7, 0.4, 1H), 7.48-7.38 (m, 4H), 7.21 (ddd, J=7.9, 4.8, 0.4, 1H), 4.74 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25](O)[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:48]1C=CN=C1.[N:53](C(OC(C)C)=O)=[N:54]C(OC(C)C)=O>C(Cl)Cl>[N:48]([C@H:25]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]([CH3:28])([CH3:27])[CH2:24]1)=[N+:53]=[N-:54]
Reactant: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C[C@@H](N=[N+]=[N-])c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the product of Example 325, Step A (9.8 g, 22.5 mmol), Zn(N3)2/bis-pyridine complex (Synthesis 1990, 130) (13.9 g, 45.1 mmol), triphenylphosphine (11.8 g, 45.1 mmol), and imidazole (6.1 g, 90 mmol) in 100 mL of CH2Cl2 was added diisopropyl azodicarboxylate (8.8 mL, 45.1 mmol) dropwise at rt. The mixture was allowed to stir at rt for 16 h. The supernatant was separated and washed with diluted HCl (1.0 N, 3×50 mL), saturated aq NaHCO3 (3×50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on Biotage 40+M cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.47 (s, 3H), 1.59 (s, 3H), 2.11 (dd, J=9.6, 13.5, 1H), 2.32 (dd, J=6.1, 13.6, 1H), 4.75 (dd, J=6.0, 9.6, 1H), 7.04 (d, J=8.5, 2H), 7.19-7.28 (m, 5H), 7.78 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:13][C:14](Cl)([Cl:19])[C:15]([F:18])([F:17])[F:16].[Cl-].[NH4+]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]([OH:6])[C:14]([Cl:19])([Cl:13])[C:15]([F:18])([F:17])[F:16])[CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 50 °C
Reaction time: 10 h
Yield: 57 %

Procedure:
To a solution of 174 mg (1.02 mmol) of ethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate in 1 ml of DMF, 96 mg (1.47 mmol) of zinc powder and 0.356 ml (3.00 mmol) of 1,1,1-trichlorotrifluoroethane were added, and the mixture was stirred at 0° C. for 2 hours and at 50° C. for 10 hours. Then, 2 ml of a saturated ammonium chloride aqueous solution was added thereto, and the mixture was extracted with diethyl ether (2 ml×3 times). The ethereal extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 188 mg of ethyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers in a ratio of 94:46).
Reaction SMILES: P(O[CH2:6][C@@H:7]([OH:12])[C@@H:8]([OH:11])[CH:9]=[O:10])(O)(O)=O.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=O.[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[CH2:16]1[C:14]([C:13]([OH:18])=[O:17])=[CH:6][C:7](=[O:12])[C@@H:8]([OH:11])[C@@H:9]1[OH:10]
Reactant: CC(=O)C(=O)[O-]
Reactant: O=C[C@H](O)[C@H](O)COP(=O)(O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Na+]
Product: O=C(O)C1=CC(=O)[C@@H](O)[C@H](O)C1
Reaction time: 2 h
Yield: 90 %

Procedure:
D-Erythrose 4-phosphate (0.45 mL, 12 mM, pH 7.0), sodium pyruvate (0.054 mL, 100 mM, pH 7.0), CoCl2 (0.027 mL, 10 mM), NAD (0.054 mL, 1 mM), DHQ synthase (2 units) and DHQ dehydratase (2 units) are incubated with KDPGal aldolase (100 units) from E. coli at room temperature for 2 h. Protein is subsequently removed by ultrafiltration using Millipore PM-10 membrane. 3-Dehydroshikimate was formed in 90% yield, as determined by 1H NMR analysis.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CCO>[OH:16][NH:15][C:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C@@H:2]([OH:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)=[NH:13]
Reactant: NO
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CCC[C@H]2O
Temperature: 70 °C
Yield: 29 %

Procedure:
Prepared using General Procedure 1. To a stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (79.1 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (34.9 mg, 0.50 mmol) and sodium bicarbonate (42.2 mg, 0.50 mmol). The mixture was heated at 70° C. for 18 h. The product was purified by chromatography (MeOH/DCM) to provide 27.3 mg (29%) (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 as a white solid. LCMS-ESI (m/z) calculated for C11H11NO: 173.2; found 174.1 [M+H]+, 156.1 [M−NH4]+, tR=2.60 min.(S)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-5 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=3)[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cccc(Br)c1

Procedure:
To 16.2 g. (0.1 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of chloroform was added with stirring 15.1 g. (0.07 mole) of 3-bromobenzoyl chloride. After stirring for 1 hour, the solution was extracted with dilute sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized twice from ethyl acetate-isopropyl ether. The impure crystalline material was then partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and the residue recrystallized from ethyl acetate-isopropyl ether solvent. The yield was 9.1 g. (36.6%); m.p. 128°-130°C.
Reaction SMILES: B([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)(O)O.Br[C:17]1[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC#N.CO>[NH2:10][C@@H:9]([CH2:8][C:7]1[CH:14]=[CH:15][C:4]([C:17]2[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=2[O:23][CH3:24])=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cnn(C)c(=O)c1Br
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
4-Borono-L-phenylalanine (0.30 g, 1.0 mmol), 4-Bromo-5-methoxy-2-methyl-2H-pyridazin-3-one (0.35 g, 1.0 mmol), tetrakistriphenylphosphine palladium(0) (0.09 g), and 2.0 M aqueous sodium carbonate (3.0 mL) were refluxed in MeCN (900 mL) for 4 d. The mixture was acidified with 2.0 N HCl and treated with MeOH. The solid was filtered off and the mixture was concentrated in vacuo. The crude solid was purified using a Gilson HPLC containing a Kromasil column (10 u, 100 Å C18, column length 250×50 mm, gradient 100:0 to 10:90 H2O:MeCN) to give 2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid. MS (ES+) 304.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].O>CC(O)=O>[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([I:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccccc1N
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(I)ccc1N
Reaction time: 3 h

Procedure:
A solution of iodine monochloride (16.7 g, 0.1 mol) in glacial AcOH (30 mL) as added dropwise over 15 min to a stirred solution of 2-aminobenzonitrile (11.8 g, 0.1 mol) in glacial AcOH (125 mL) at room temperature. The mixture was stirred for 3 h and then poured into H2O (1000 mL). The resulting pinkish-brown solid was filtered, washed with H2O, and dried in vacuo. Crystallization from cyclohexane-toluene (9:1) gave 2-amino-5-iodobenzonitrile (9) as translucent plates (14.9 g, 64%): mp 85-86° C. (lit. 85-86° C.); 1H NMR (CDCl3) δ 7.60 (d, J=1.6 Hz, 1H, H-6), 7.57 (dd, J=9.2 Hz, 1.6 Hz, 1H, H-4), 6.53 (d, J=9.2 Hz, 1H, H-3), 4.45 (br s; 2H, NH2). The product was used directly in the next reaction (Step 2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=[N:13]O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: ON=Cc1ncc(C(F)(F)F)cc1Cl
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde oxime (1.0 eq.) and Burgess reagent (1.5 eq.) in tetrahydrofuran (0.5 M) was heated to 65° C. and stirred for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo to give a solid that was carried onto the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Cl-].O[NH3+].C([N:17](C(C)C)CC)(C)C.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].C(N=C=NC(C)C)(C)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:17]=[C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)[O:29][N:7]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Product: Cc1cc(Br)ccc1-c1noc(-c2ccco2)n1
Yield: 29.2 %

Procedure:
In a 500 mL round-bottom flask, 4-bromo-2-methylbenzonitrile (5 g, 25 mmol) was dissolved in 200 mL of methanol. To the mixture was added hydroxylammonium chloride (1.72 g, 25 mmol) followed by DIEA (diisopropylethylamine) (8.7 mL, 50 mmol). The mixture was heated at reflux for overnight. The solvents were removed. The residue was dissolved in 200 mL of CHCl3. To the mixture was added 2-furoyl chloride (3.97 ml, 25 mmol) followed by DIEA (8.7 mL, 50 mmol). After reaction completion, the mixture was extracted with chloroform and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 200 mL of dioxanes. To the mixture was added 1 eq of DlC (N,N′-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture was then heated at reflux overnight. After reaction completion, the mixture was cooled down. The solvents were removed in vacuo. The residue was then extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel in a 0-20% ethyl acetate/hexanes gradient to afford 2.23 g of the desired compound 3-(4-Bromo-2-methyl-phenyl)-5-furan-2-yl-[1,2,4]-oxadiazole as a white powder in an overall yield of 36%.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8](=[CH2:17])[C:9]([O:11]C(=O)C(C)=C)=[O:10].O=O>>[CH3:3][CH:2]([CH2:4][CH2:17][C:8](=[CH2:7])[C:9]([OH:11])=[O:10])[C:1]([OH:6])=[O:5]
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Reactant: C=C(C)C(=O)O
Agent: O=O
Product: C=C(CCC(C)C(=O)O)C(=O)O
Temperature: 120 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a mechanically stirred solution of 2 moles of hydroxyquinone dissolved in 3 moles of methacrylic acid at 120° C. and atmospheric pressure was added dropwise (30 min) 1 mole of methylacrylic acid anhydride and the mixture was maintained at 120° C. with stirring for additional 4 hrs (NMR analysis). Throughout the course of the reaction 8% oxygen was admitted to the system. At the end of the reaction, the methacrylic acid was recovered by distillation under reduced pressure (110° C. and 200 mmHg), and the unreacted excess hydroquinone was precipitated out by the addition of toluene (1 liter) to the reaction mixture. A low level (1-2%) of the monomer 2-methyl-5-methylenehexanedioic acid was formed. This monomer was separated from the mixture by a washing step with distilled water. After phase separation, the desired 4-hydroxyphenyl methacrylate was obtained at 97% yield by the distillation of toluene under reduced pressure. {mp. (Uncorrected) 120° C.; Anal. Calcd. For C10H10O3: C, 67.41: H, 5.66; O, 26.94. Found: C, 67.37; H, 5.62}.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1.[C].[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
Into a reaction vessel were charged 31.7 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 0.76 parts by weight of 5% palladium-carbon (E-type, manufactured by N. E. Chemcat Corporation), thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 145° C. and an internal pressure of 0.15 MPa for 14 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 45 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 73.0 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The combined 1,1,3-trimethyl-4-aminoindane had an optical purity of 0.7% ee and a recovery rate of 97.7%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:24](O)=[O:25])[C:14]3[C:15]([CH3:23])=[CH:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:7][CH2:6]1)[CH3:3].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:24]([C:13]1[C:14]2[C:15]([CH3:23])=[CH:16][N:17]([CH:20]([CH3:21])[CH3:22])[C:18]=2[CH:19]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7]2)[CH:12]=1)=[O:25]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cn(C(C)C)c2cc(N3CCC(CN(C)C)CC3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCC(CN(C)C)CC3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 6-{-4-[(dimethylamino)methyl]-1-piperidinyl}-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (62 mg, 0.173 mmol) in dimethyl sulfoxide (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (42.5 mg, 0.225 mmol), N-methylmorpholine (0.095 mL, 0.867 mmol), 1-hydroxy-7-azabenzotriazole (47.2 mg, 0.347 mmol) and EDC (66.5 mg, 0.347 mmol), and the mixture was stirred overnight. The mixture was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; 30 mL/min, 8% ACN/H2O, 0.1% formic acid to 38% ACN/H2O, 0.1% formic acid) to give the title compound (52 mg, 55%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.26 (m, 2H), 1.35-1.41 (m, 6H), 1.57-1.71 (m, 1H), 1.80 (d, J=11.12 Hz, 2H), 2.10 (d, J=10.36 Hz, 6H), 2.22 (s, 3H), 2.26-2.33 (m, 8H), 2.57-2.72 (m, 2H), 3.61 (d, J=12.13 Hz, 2H), 4.31 (d, J=5.05 Hz, 2H), 4.58-4.72 (m, 1H), 5.86 (s, 1H), 6.69 (d, J=2.02 Hz, 1H), 6.92 (d, J=1.77 Hz, 1H), 7.05 (d, J=1.01 Hz, 1H), 7.92-7.99 (m, 1H). MS: (M+H)+=492.1.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[Si:12]([O:5][CH2:4]/[CH:3]=[CH:2]/[CH2:1][OH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC/C=C/CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC/C=C/CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of (2E)-2-butene-1,4-diol (8.22 mL, 0.10 mol) and imidazole (8.50 g, 0.125 mol) in DMF (50 mL) at 0° C., was added tert-butyldimethylsilyl chloride (7.50 g, 0.050 mol) in several portions over 10 minutes. The resulting mixture was warmed to room temperature and stirred (2 h), then poured into H2O (200 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed (brine), dried (Na2SO4) and purified by silica gel column chromatography (hexanes:EtOAc) to yield 5 as a colorless oil (9.0 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 5.60-5.50 (m, 2H), 4.18 (m, 2H), 4.09 (m, 2H), 2.76 (br, 1H), 0.83 (s, 9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 136.3, 135.4, 64.8, 63.8, 31.1, 23.6.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:26]([C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:30]=1[NH2:31])([CH3:28])[CH3:27].OS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:31]/[C:30]2[C:32]([CH:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=[CH:35][C:29]=2[CH:26]([CH3:28])[CH3:27])/[CH3:10])[C:3]=1[OH:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: C/C(=N\c1c(C(C)C)cccc1C(C)C)c1cc(C)cc(Br)c1O
Temperature: 170 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
In a 50 mL Claisens flask under argon atmosphere, a mixture of 10.6 g (46.3 mmol) of 29, 20.2 g (97.2 mmol) of Si(OEt)4, and 9.03 g (50.9 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.37 mL of 96% H2SO4 was added. This mixture was stirred for 5 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: hexanes and then hexanes-diethyl ether, 100:1, vol.). The isolated product was additionally washed with 3×30 mL hexanes and dried in vacuum. This procedure gave 14.7 g (82%) of yellowish solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH3:9][O:10][N:11](C)[C:12]([C@@H]1C[C@H]1C)=O>>[CH3:9][O:10][N:11]([CH3:12])[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1C
Reactant: O=C(O)[C@@H]1CCCO1
Product: CON(C)C(=O)[C@@H]1CCCO1

Procedure:
(2S)-Tetrahydrofuran-2-carboxylic acid was converted to the product using the method described for the synthesis of (1R,2R)—N-methoxy-N,2-dimethylcyclopropanecarboxamide (C79) in Example 20. The resulting product was used in the next step without further purification. Yield: 24.6 g, ≦0.153 mol, ≦90%.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[CH:16]([C:33](=C)[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:38])[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry ice acetone cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-chloro-2-propen-2-yl)acetate (160 mg) in a mixture of methylene chloride (3.2 ml) and methanol (0.3 ml) is introduced ozone until the reaction mixture shows blue color. Then excess ozone is purged with oxygen, mixed with an aqueous solution of 95% sodium hydrogen sulfite (100 mg), warmed to room temperature to decompose the ozonide. After 1.5 hours, the solution is washed with 5% sodium hydrogen carbonate and water, dried, and concentrated to remove methylene chloride. The resultant oil (132 mg) is purified over thin-layer chromatographic plate (Merck 60F-254) using a mixture of benzene and ethyl acetate (1:1) as developing solvent to give diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (44 mg) as glass.