Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13]OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13][N:29]=[N+:30]=[N-:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: ClCCl
Product: [N-]=[N+]=NCC1(C(F)(F)F)CCN(Cc2ccccc2)C1

Procedure:
The compound (2.43 g) from step 456c was dissolved in acetonitrile, then reacted with tetrabutylammonium azide at 80° C. for 16 hours. The mixture was diluted with methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 0.751 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:15]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1=C(CCC(F)(F)F)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(CCC(F)(F)F)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OCC)c1-c1ccc(C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
4-[2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3,5-bis(ethoxycarbonyl)-6-(3,3,3-trifluoropropyl)-1,4-dihydro-4-pyridinyl]benzoic acid (3.21 g, 6.91 mmol) was dissolved in a 50:50 mixture of acetonitrile:H2O. To the mixture cerium ammonium nitrate was added (8.96 g, 13.8 mmol) and stirred for 45 minutes. The reaction mixture was dissolved in 100 mL of ethyl acetate and washed with H2O (2×50 mL) and brine. The organics were then dried over sodium sulfate, filtered and concentrated to yield a orange/red oil that was purified by column chromatography (ethyl acetate/hexanes (4:1)). Mixture carried on without purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)(=[O:5])=[O:4]>CO.[Pd]>[CH3:1][NH:2][S:3]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)C1CCNC1
Reaction time: 24 h
Yield: 96.6 %

Procedure:
A mixture of the above benzyl carbamate (173 mg, 0.580 mmol) and 10% Pd on carbon in MeOH (15 mL) was hydrogenated for 24 hrs. The reaction mixture was filtered through celite, the celite pad was washed with MeOH, and the solvent was removed under vacuum to give N-methyl-3-pyrrolidinesulfonamide (92 mg, 97%) which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 6.89 (br s, 1H), 3.62 (qd, J=8.9, 6.3 Hz, 1H), 2.99 (m, 2H), 2.82 (m, 1H), 2.72 (m, 1H), 2.59 (s, 3H), 1.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]([NH2:15])=[S:14].BrBr>ClC1C=CC=CC=1>[NH2:15][C:13]1[S:14][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[C:3]=2[N:12]=1
Reactant: COC(=O)c1cccc(NC(N)=S)c1C
Agent: BrBr
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc2sc(N)nc2c1C
Temperature: 0 °C

Procedure:
56 g of N-(2-methyl-3-methoxycarbonylphenyl)thiourea (0.25 mol) were dissolved in 2 l of chlorobenzene, and the mixture was cooled to 0° C. 40 g of bromine (0.25 mol) in 100 ml of chlorobenzene were then added dropwise. The reaction mixture was heated at 90° C. for 3 h, and the precipitate was filtered off with suction and washed with methylene chloride. The precipitate was then dissolved in ethyl acetate and extracted with sodium bicarbonate solution. After washing and drying, the product was obtained by stripping off the solvent. Yield: 43 g (80%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([NH2:18])[CH3:17].C[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>ClCCl>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:16]([CH3:17])[N:18]([C:25]([C:24]4[CH:28]=[CH:29][C:21]([OH:20])=[CH:22][CH:23]=4)=[O:26])[C:4]=2[CH:5]=1)=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3
Reactant: CC(N)c1cc(F)ccc1-c1ccc(F)cc1F
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
4-Methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzamide—A stirred solution of 1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethylamine (0.71 g, 2.84 mmol) in dichloromethane (5 mL) was treated with 4-methoxybenzoyl chloride (0.51 g, 3.0 mmol), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol). The reaction was stirred at room temperature for twelve hours, and the solvent evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl tert-butyl ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.98 g, 2.54 mmol, 90%) as a homogeneous, colorless, crystalline solid, m.p. 163-165° C.; MS [(+ESI), m/z]: 386 [M+H]+; IR (Solid), vmax: 3257, 1620, 1606, 1503, 1329, 1249, 1175, 1032, 844, 777, 670 cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (d, J=5.4 Hz, 3H), 3.80 (s, 3H), 4.93 (broad s, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.14 (td, J=8.5, 2.7 Hz, 1H), 7.22 (dd, J=8.5, 5.9 Hz, 2H), 7.37 (t, 2H), 7.46 (d, J=9.1 Hz, 1H), 7.61 (d, J=4.7 Hz, 1H), 7.83 (d, J=7.2 Hz, 2H), 8.66 (d, J=3.9 Hz, 1H), exists as approximate 2:1 mixture of rotamers; Anal. calcd for C22H18F3NO2: C, 68.57; H, 4.71; N, 3.63. Found: C, 68.65; H, 4.80 N, 3.48.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(Br)cc(C(=O)O)cc1C=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(Br)cc(C(=O)Cl)cc1C=O
Yield: 98.1 %

Procedure:
5-Bromo-3-formyl-4-methoxybenzoic acid (480 mg, 1.84 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the solution was flushed with dry nitrogen for 5 minutes. Oxalyl chloride (1.2 mL, 2.4 mmol, 1.3 eq) was added slowly to the solution while vigorous stirring and then a catalytic amount of dry dimethylformamide was added. The mixture was stirred for 1 hour and then concentrated by rotary evaporation and dried on high vacuum to give 5-bromo-3-formyl-4-methoxybenzoyl chloride (501 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (34 mg, 0.094 mmol) was added DCM (0.9 mL), triethylamine (26 μl, 0.188 mmol), and methanesulfonyl chloride (11 μl, 0.141 mmol) before it was stirred at ambient T for 1 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 5 N NaOH (aqueous), washed 3 times with 75 mL of 5 N NaOH (aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to the title compound. MS (ESI) m/z: Calculated: 517.1; Observed: 518.0 (M++1).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>CCOC(C)=O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1CCCCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
An aqueous KOH (0.25 g in 4.4 mL water) solution was added to p-fluorobenzaldehyde Compound 10a (1.04 mL, 10 mMol) and the mixture was heated to 65° C. Cyclohexanone Compound 2a (1.03 mL, 10 mMol) was added dropwise over 10 min and the reaction mixture was refluxed for 5 hrs, then cooled to r.t. and stirred at r.t. overnight. The reaction mixture was acidified with 1N HCl (26 mL) and diluted with EtOAc. The organic layer was separated and washed with brine, then dried with anhydrous sodium sulfate and filtered. The solvent was evaporated to provide a crude product which was then purified by silica gel column (eluted with 6% EtOAc in hexane) to give 2-(4-fluoro-benzylidene)-cyclohexanone Compound 10b (1.1 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CC1CCCO1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)c1ccc(F)cc1Oc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloropyridin-3-ol (2.41 g) in 2-methyltetrahydrofuran (20 mL) and N,N-dimethylformamide (4 mL) was added potassium tert-butoxide (1.0M in tetrahydrofuran) (18.60 mL). The reaction was stirred for 15 minutes, then methyl 2,4-difluorobenzoate (3.52 g) was added as a solution in 2-methyltetrahydrofuran (2 mL). The reaction was then heated to 80° C. and stirred under a nitrogen atmosphere for 3 days. The reaction was cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g), eluting with 10% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cnc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
2-Amino-5-methylpyrazine (5.16 g, 47 mmol) was dissolved in CH2Cl2 (52 mL), stirred and cooled to 0° C. under N2. To this, pyridine (4.8 mL, 59 mmol) was added followed by phenyl chloroformate (6.2 mL, 59 mmol), dropwise, over 15 min, causing a precipitate to form. The mixture was stirred at 0° C. for 1 h. Then the reaction was quenched with 0.25 M HCl (40 mL) and anhydrous ether (50 mL), and stirred at 0° C., for 30 min. The precipitate was isolated by filtration, washed with DI H2O (20 mL) and ether (2×25 mL), and dried under vacuum to give the product (7.4 g) as a white fluffy powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and butyric acid chloride (butyryl chloride)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=1>C1(C)C=CC=CC=1.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][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: Cn1cncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nccc(Cl)c2s1
Yield: 79.4 %

Procedure:
Nitrogen was bubbled through a mixture of the tin derivative 6 (7.19 g, 15.7 mmol) and 5-bromo-1-methyl-1H-imidazole (2.02 g, 12.5 mmol) [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057. b) Begtrup, M.; Bull. Soc. Chim. Belz.; 97; 8-9; 1988; 573-598. c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.] in toluene (20 mL) for 5 minutes. Pd(PPh3)4 (1.50 g, 1.30 mmol) was added and nitrogen was bubbled for additional 5 minutes. Finally, the mixture was refluxed under nitrogen overnight, the resultant yellow suspension was concentrated under reduced pressure and then purified with flash chromatography (eluent EtOAc/MeOH 90:10), to afford title compound 16 as a yellow solid (2.48 g, 79% yield). MS (m/z): 250.0 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=1[F:27].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:22][C:21]=1[F:27]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)c1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (0.11 g, 0.51 mmol), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.14 g, 0.51 mmol), triethyl amine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide(0.030 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.16 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.14 g, 79%).
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C@H:9]([CH2:21][OH:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[Si:29]([O:22][CH2:21][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:23])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CN(Cc1ccccc1)[C@H](CO)CCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 91 %

Procedure:
A solution of Nα-benzyl-Nδ-Boc-Nα-methylornithinol (560 mg), dimethylformamide (1.5 ml), and t-butyldimethylsilyl chloride (330 mg), triethylamine (290 μl) and 4-(N,N-dimethylamino)pyridine (21 mg) was stirred at 0° C., under nitrogen atmosphere, for 1 hr. Then the mixture was stirred, at 25° C., for 10 hrs and then poured into water (20 ml) and extracted with dichloromethane (2×20 ml). The combined organic phase was washed with water and brine, and dried over sodium sulfate. Evaporation of the solvent afforded titled compound (690 mg) as a clear solid: 1H NMR (400 MHz, CDCl3) δ0.06 (s, 6H), 0.91 (s, 9H), 1.43 (s, 9H), 1.45-1.73 (m, 4H), 2.22 (s, 3H), 2.68 (m, 1H), 3.12 (m, 2H), 3.62 (dd, J=10.4; 5.2 Hz, 1H), 3.68 (d, J=13.6 Hz, 1H), 3.78 (m, 2H), and 7.30 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1F
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To a solution of 3.00 g of 2,3-difluoro-6-nitroaniline in 30 ml of dimethylformamide, 6.14 g of N-bromosuccinimide was added, followed by an hour's stirring at 90° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/6) to provide 3.21 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:49])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[N:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[O:42][N:41]=4)=[CH:36][CH:35]=3)[CH2:31][CH3:32])[O:27]N=2)=[CH:21][C:20]=1[F:48])(C)[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:51]1C=C(C2N=C(C(OC3C=CC(C4N=C(C(C)C)ON=4)=CC=3)CC)ON=2)C=CC=1C(N[C@H](C)CO)=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:49])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]4[N:44]=[C:43]([CH:45]([CH3:46])[CH3:47])[O:42][N:41]=4)=[CH:38][CH:39]=3)[CH2:31][CH3:32])[O:27][CH:51]=2)=[CH:21][C:20]=1[F:48])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)N[C@H](C)CO)c(F)c2)no1
Reactant: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)NC(C)(C)COC(=O)CNC(=O)OC(C)(C)C)c(F)c2)no1
Product: CCC(Oc1ccc(-c2noc(C(C)C)n2)cc1)c1nc(-c2ccc(C(=O)N[C@@H](C)COC(=O)CNC(=O)OC(C)(C)C)c(F)c2)co1

Procedure:
The synthesis was carried out in the same manner as in Reference Example 14, except that the compound obtained in Example 18 that will be described below (20.0 mg, 39.3 μmol) was used in place of 2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4-(5-{1-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)benzamide. Thus, the title compound (26 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]([O:9][C@@H:10]2[CH2:20][O:19][C@@H:12]3[C@@H:13]([OH:18])[C@@H:14]([O:17][C@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>COCCOC.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@@H:13]1[C@H:12]2[O:19][CH2:20][C@@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@H:11]2[O:17][C@H:14]1[O:15][CH3:16]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1O
Reactant: CI
Agent: O=[Ag-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside (1.03 g, 3.7 mmol), silver (1) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DME (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1ccco1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccco2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetylfuran (prepared according to the method of S. Kajigaeshi et al., Bull. Chem. Soc. Jpn., 1987, 60, 1159-1160). tlc: Rf=0.4 (33% ethyl acetate in hexanes)
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[C:4]([OH:6])=[O:5])#[N:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[C:4]([O:6][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:5])#[N:2]
Reactant: N#CC(=Cc1ccccc1F)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#CC(=Cc1ccccc1F)C(=O)ON1C(=O)CCC1=O
Yield: 44.2 %

Procedure:
The same procedures as in Example 119 were carried out from α-cyano-2-fluorocinnamic acid (12.0 g), N-hydroxysuccinic acid imide (10.8 g), WSC.HCl (18.1 g), and methylene chloride (300 mL), to give the captioned compound (8.0 g, 44%) as crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:1]([N:3]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCNc1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CC)c1cccc2ccccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
N-Ethyl-1-naphthylamine 8 (11.4 gm, 0.066 moles), diisopropylethylamine (11.2 gm, 0.087 moles), and ethyl 4-bromobutyrate (19 gm, 0.097 moles) were heated at 110-120° C. for 16 hours under argon at which time, HPLC indicated the reaction was complete. The mixture solidified upon cooling to room temperature. The solid was partitioned between DCM and water. The aqueous layer was extracted with two portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over MgSO4, filtered, concentrated under reduced pressure by rotary evaporation to give 22 gm of a crude solid. The solid was purified by flash chromatography, eluting with ethyl acetate and hexane, to give ethyl 4-(ethylnaphthylamino)butanoate 9 (6.04 gm, 32% yield) as an orange oil. 1H NMR (CDCl3) δ 8.3, 1H, m; 7.8, 1H, m; 7.35-7.55, 4H, m; 7.15, 1H, m; 4.05, 2H, q; 3.18, 4H, m; 2.32, 2H, t; 1.8, 2H, m; 1.20, 3H, t; 1.05, 3H, t.