Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[NH:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CNc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3 mmol), K2CO3 (1.4 g, 10.3 mmol), 1-[4(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3 mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux under nitrogen for 23 hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p.=151°-153° C.
Reaction SMILES: [C:1](Cl)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1.Cl>C(=S)=S>[CH3:3][CH:2]1[CH:4]([CH3:5])[C:11]2[C:10](=[C:9]([CH3:8])[CH:14]=[CH:13][C:12]=2[CH3:15])[C:1]1=[O:6]
Reactant: Cc1ccc(C)cc1
Reactant: C/C=C(\C)C(=O)Cl
Agent: Cl
Solvent: S=C=S
Product: Cc1ccc(C)c2c1C(=O)C(C)C2C
Temperature: -10 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Under an argon atmosphere A1Cl3 (64 g, 0.48 mol) and CS2 (250 ml) were placed in a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and p-xylene (42.8 ml, 0.35 mol) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −10° C. the mixture was allowed to come to ambient temperature and was stirred at that temperature overnight. The brown reaction mixture was then refluxed for 3 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the mixture was transferred into a separation funnel, the lower CS2 layer was separated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed in a rotary evaporator to give a red brown liquid. This residue was rectified using a 35 cm Vigreux column to afford 2,3,4,7-tetramethyl-1-indanone (35) (34 g, 52%, 95-100° C., 1.5-1.2 mbar) as a pale yellow liquid. (35) was found to be a mixture of the two isomers of 2,3,4,7-tetramethyl-1-indanone (35a to 35b approximately 3:1). The 1H NMR spectrum was identical with the literature (S. Barlow, D. R. Cary, M. J. Drewitt, D. O'Hare, J. Chem. Soc. Dalton Trans. 1997 3867-3878).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:8][CH:7]=1.Cl>ClCCl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Aluminum chloride (4.1 g; 30.7 mmol) was suspended in 9 mL t-butylthiol and cooled to 0° C. Ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropionate (5.0 g; 10.2 mmol), prepared as in step 3, in 12 mL dichloromethane was added and the reaction mixture was stirred at 0° C. for 10 min and then at ambient temperature for 3 hours. The reaction mixture was poured into ice and acidified with 10% aqueous HCl. The mixture was extracted three times with dichloromethane. The combined extracts were rinsed with brine, dried over magnesium sulfate and concentrated. The dark brown residue was filtered through silica gel eluting with 10% diethyl ether in dichloromethane. Evaporation of the solvent afforded ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropionate. m.p. 151°-152° C. 1H NMR (300 MHz, DMSO-d6) δ1.10 (t, J=7 Hz, 3H), 1.12 (s, 6H), 1.20 (s, 9H), 3.19 (bs, 2H), 4.04 (q, J=7 Hz, 2H), 5.41 (s, 2H), 6.58 (dd, J=9, 3 Hz, 1H), 6.83 (d, J=9 Hz, 2H), 6.98 (d, J=3 Hz, 1H), 7.13 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 2H), 8.88 (s, 1H). MS (DCI/NH3) 474 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)ccc1F
Temperature: 85 °C
Reaction time: 13 h
Yield: 91.8 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (32 g, 0.2 mol) in pyridine (100 mL) was added malonic acid (43 g, 0.4 mol) and piperidine (3 mL, 0.03 mol). The reaction solution was stirred at 85° C. for 13 hr. Upon cooling, the resulting suspension was added to cold water (500 mL) and acidified with conc. HCl (80 mL). The white solid was filtered off, washed with water and dried to yield 36 g (92%) of 3-(4-fluoro-3-methoxyphenyl)-acrylic acid. RP-HPLC: 3.71 min. 1H-NMR (DMSO-d6) δ (ppm) 3.85 (s, 3), 6.53 (d, 1, J=16), 7.20 (m, 2), 7.50 (m, 1), 7.52 (d, 1, J=16).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl.C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
53 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.8 ml of methanol/water (10/1), and 0.387 ml of a solution of 1N potassium hydroxide in methanol/water (10/1) was added thereto. The mixture was stirred at room temperature for 50 minutes. The mixture was neutralized with 1N hydrochloric acid under cooling with ice, and 20 ml of ethyl acetate was added thereto. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol/acetic acid=15/1/0.15). The fractions containing the desired product were collected, and the organic layer was washed with a 4% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 49 mg of L-Nα -[(2RS)-3-ethylsulfonyl--2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9](NC(OC(C)(C)C)=O)([NH:13]C(OC(C)(C)C)=O)[C:8]1=[O:29])[CH3:6])[CH3:2].C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5N=C(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[C:8]1=[O:29])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1CCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C1=O
Agent: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)c[nH]1)C(C)C
Product: CCOC(=O)C(C)N1CCCC(N)C1=O

Procedure:
2-(3-Amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester was prepared using method 804 substituting 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C10H18N2O3 calculated 214.2 observed [M+1]+ 215.2; rt=1.21 min.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1nc2ccccc2s1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2nc3ccccc3s2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1,3-benzothiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ8.04 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.54-7.46 (m, 1H), 7.43-7.35 (m, 1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.53 (d, J=16.2 Hz, 1H), 5.24 (d, J=16.2 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.24-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 165.9, 155.3, 152.9, 144.7, 141.2, 138.3, 135.3, 132.1, 128.9, 126.3, 125.5, 124.0, 123.9, 123.2, 121.9, 120.8, 111.8, 109.2, 99.4, 64.5, 63.9, 58.0, 42.6; MS (ES+) m/z 442.8 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1.I[CH2:22][C:23]([NH2:25])=[O:24]>CN(C)C=O.C(OCC)(=O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7](=[N:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:8]([CH2:22][C:23]([NH2:25])=[O:24])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2CC(N)=O)cc1
Reaction time: 0.33 h

Procedure:
Sodium hydride (5.0 g, 0.21 mol) in N,N-Dimethylformamide (370 mL) was treated portion wise with N-(5-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonamide (compound a, 50 g, 0.2 mol). After stirring for 20 minutes, iodoacetamide (30 g, 0.2 mol) was added in one portion. The reaction stirred overnight at room temperature. The solvent was removed to give a brown solid. The crude material was diluted with 500 ml of ethyl acetate and 100 mL of water and stirred for 2 hours. The solid was collected by filtration and dried to afford 36 g of 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide. Rf 0.37, neat ethyl acetate MS m/z 324 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:18])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17].CC1C=CC=C(C)N=1.Cl>C(#N)C.O.O1CCCC1.[Pt].[Ni]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:18])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ni]
Agent: [Pt]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 60.4 %

Procedure:
A solution of 0.5 gram of 3-methoxy-13β-methylgona-1,3,5 -(10)-trien-17-one, 0.5 milliliter of 2,6-dimethylpyridine, 1.97 grams of tetrabutylammonium fluoborate [(C4H9)4N-BF4 ] in 40 milliliters of acetonitrile, 10 milliliters of water and 10 milliliters of tetrahydrofuran was electrolyzed between a platinum anode having a surface area of 21 square centimeters and a nickel cathode having a surface area of 20 square centimeters while a potential of 1.7 volts measured at the anode against a saturated calomel standard electrode was maintained between the electrodes. At the completion of the electrolysis, which was established by thin-layer chromatography, the electrolyte solution was made slightly acid by adding hydrochloric acid thereto and the acidified solution was then allowed to stand at room temperature for a period between 20 and 30 minutes. Water was then added to the solution and the mixture was then extracted with diethyl ether. The ether layer was then separated, dried over anhydrous sodium sulfate, and the solid was distilled therefrom at a subatmospheric pressure. The residue was taken up in a mixture of dichloromethane and methanol and recrystallized therefrom. In this manner, 0.3 gram of 3-methoxy-13β-methylgona-1,3,5(10), 9(11)-tetraen-17-one having a melting point of 139°-143° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:12]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Yield: 80 %

Procedure:
Subsequently, 2.0 g (13.9 mmol) of the 4-bromobenzohydrazide obtained in (i) above was put in a 300-mL three-neck flask, 7 mL of N-methyl-2-pyrrolidone (abbreviation: NMP) was added thereto, and the mixture was stirred. Thereafter, a mixture of 2.5 mL of N-methyl-2-pyrrolidone and 2.5 mL (21.5 mmol) of benzoyl chloride was dripped through a 50-mL dropping funnel, and the mixture was stirred at 80° C. for 3 hours. The obtained solid was washed with water and a sodium carbonate aqueous solution in this order and collected by suction filtration. Then, the solid was recrystallized with acetone; thus, 3.6 g of a white solid of 1-benzoyl-2-(4-bromobenzoyl)hydrazine that was an object was obtained in the yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1.Cl([O-])=[O:15].[Na+].S(=O)(=O)(O)N.CCOC(C)=O>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([C:9]([OH:15])=[O:10])=[N:7][CH:8]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cnc(C=O)cc1[N+](=O)[O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cnc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-methoxy-4-nitropicolinaldehyde (4 g, 0.02 mol) in acetone and water (1:1, 100 mL) was added sodium chlorite (5.9 g, 0.065 mol, spectrochem, india) and sulfamic acid (6.3 g, 0.065 mol, Rankem, India) and the reaction mixture was stirred for 1 h at rt. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion, the reaction mixture was concentrated to get a white precipitate which was filtered and dried to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.6 (brs, 1H) 8.90 (s, 1H), 8.41 (s, 1H), 4.15 (s, 3H). MS (ESI, positive ion) m/z: 197.8 (M+H).
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)[Si](OCc1ccc(N)cc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of 13 (5.00 g, 12.77 mmol) in ethanol (100 ml) was added Pd/C (10%, 1.50 g) and ammonium formate (4.60 g) at room temperature. After 1.5 h the catalyst was removed by filtration, the filtrate concentrated to dryness under vacuum and the residue partitioned between EtOAc:H2O. The organic layer was dried (MgSO4) and concentrated under vacuum to give 14 as an oil; yield: 4.24 g (92%); vmax /cm-1 (film): 3433, 3378 (NH2), 2931, 2857 (CH2, asym., sym.); 1H-NMR, dH : 1.00 (9H, s, t-Bu), 4.57 (2H, s, CH2), 4.98 (2H, s broad, NH2), 6.52 (2H, d, J=8.25, Harom3+5), 6.96 (2H, d, Harom2+6), 7.42-7.46 (5H, m, Ph), 7.62-7.65 (5H, m, Ph); MS, (EI), (361.56); m/z: 361 (M+, 8), 304 (M - t-Bu, 100), 199 (Ph2SiOH+, 100); C23H27NOSi.
Reaction SMILES: [CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][N:5](C(=O)C2C=CC(F)=CC=2)[C:4]1=[O:17])[CH3:2].N>C(O)C.C(OC(C)C)(C)C>[CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][NH:5][C:4]1=[O:17])[CH3:2]
Reactant: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Agent: N
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCC1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 3-ethyl-1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (1.1 g) obtained in Step G in ethanol (15 mL) was added dropwise 28% aqueous ammonia solution (5 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained crude crystals were dissolved in diisopropyl ether, and the remaining solid was removed by filtration. The solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration, and washed with diisopropyl ether to give the title compound (82 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][C:16]([Br:21])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCn2c(cnc2C(F)(F)F)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Yield: 57.1 %

Procedure:
In a 100 mL dried flask, the compound obtained from the previous step, 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27a (300 mg, 1.04 mmol) was dissolved in 50 mL of ethanol under stirring, and N-bromosuccinimide (369 mg, 2.08 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for an hour until the reaction was complete. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27b (220 mg, yield 57.8%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: Clc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-bromo-3-chlorophenol (2.0 g, 0.0096 mol), phenylboronic acid (3.5 g, 0.029 mol), TEA (8.1 mL, 0.058 mol), cupric acetate (3.2 g, 0.017 mol) and DCM (40 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 24 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.74 (dd, J=8.84, 2.78 Hz, 1H), 6.94-7.02 (m, 2H), 7.06 (d, J=2.78 Hz, 1H), 7.14 (t, J=7.33 Hz, 1H), 7.29-7.38 (m, 2H), 7.48 (d, J=8.84 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][C:14]1[CH:19]=[N:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 110 °C

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (3.00 g), 5-chloro-2-nitropyridine (3.08 g), and potassium carbonate (4.87 g) were added to dimethyl sulfoxide (50 mL), heated to 110° C. for one hour, cooled, added to water, and extracted with ethyl ether. The ether was washed with brine and dried on anhydrous sodium sulfate. The solution was filtered and concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes and increasing again to 30% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].S(=O)(=O)(O)O.N1C=CC=CC=1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 1.5 mg (0.015 mmol) of sulfuric acid and 11.9 mg (0.15 mmol) of pyridine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.