Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH2:51]([O:58][CH:59]([CH3:68])[CH2:60][CH2:61][C:62]1[C:63](=[O:67])[CH2:64][CH2:65][CH:66]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCCCC>C(OCC)C>[CH2:51]([O:58][CH:59]([CH3:68])[CH2:60][CH2:61][CH:62]1[CH2:66][CH2:65][CH2:64][C:63]1=[O:67])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(CCC1=CCCC1=O)OCc1ccccc1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: CCCCC
Product: CC(CCC1CCCC1=O)OCc1ccccc1
Yield: 94 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-benzyloxybutyl-cyclopent-2-enone (0.146 g, 0.6 mmol) gave, after 30 h at 0° C. and flash chromatography (1:2 pentane:diethyl ether), the title compound as a clear oil (0.139 g, 94% yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.23 (m, 5H), 4.50 (s, 2H), 3.47 (t, J=6.3 Hz, 2H), 2.43-2.04 (m, 5H), 1.78 (ddd, J=18.0, 9.6, 1.2 Hz, 1H), 1.70-1.56 (m, 2H), 1.56-1.34 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 219.8, 138.6, 128.4, 127.7, 127.6, 73.1, 70.3, 45.4, 38.7, 37.4, 35.7, 30.0, 29.7, 24.8. IR (neat): 2934, 2860, 1741, 1455, 1405, 1363, 1158, 1100, 737, 699 cm−1. HRMS m/z calcd for C16H22O2 246.1620, obsd 246.1615. [α]D25° C.−89° (c 1.4, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 94% ee.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].C(N(CC)CC)C.[CH3:18][O:19][P:20]([O-:23])[O:21][CH3:22]>C(OCC)(=O)C>[CH3:18][O:19][P:20]([CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1)[OH:2])(=[O:23])[O:21][CH3:22]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COP([O-])OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)c1cccc(C#N)c1
Yield: 74 %

Procedure:
A mixture of 3-formyl-benzonitrile (10 g, 76.26 mmol), triethylamine (9.26 g, 91.05 mmol) and dimethyl-phosphite (10.91 g, 99.14 mmol) was stirred in ethyl acetate at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with a saturated ammonium chloride solution (1×50 ml), dried (Na2SO4) and the filtrate was evaporated affording the crude [(3-cyanophenyl-hydroxymethyl]-phosphonic acid dimethyl ester as a yellow solid (13.60 g, 56.43 mmol, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:18]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:18])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cc(C)nc(-n2ccnc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)c1cc(C)nc(-n2ccnc2)n1
Yield: 69.6 %

Procedure:
A solution of (benzhydrylidene-amino)-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester (460 mg, 1.10 mmol) in THF (4 mL), water (3 mL) and hydrochloride acid (1 mL, 37%) was stirred at r.t for 0.5 h. The saturated K2CO3 solution was added to make the solution basic (pH 9). The mixture was extracted with ethyl acetate (2×100 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent and purification by column chromatography gave 200 mg (70%) of amino-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester. [M+H]+ 262.64.
Reaction SMILES: ClC1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5](OC)=O.[CH3:13]NS(C)(=O)=O.Cl[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24]>>[CH3:5][C@H:4]1[CH2:3][CH:9]1[C@H:10]([NH:11][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[N:28]=1)[C:23]([OH:25])=[O:24])[CH3:13]
Reactant: CNS(C)(=O)=O
Reactant: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Product: C[C@H]1CC1[C@@H](C)Nc1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1

Procedure:
Prepared from Methyl 2,6-dichloroisonicotinate, methyl(methylsulfonyl)amine and intermediate 3.6.5 following a similar procedure as described for the preparation of intermediate 4.2c.1. MS M+1=328.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:16])[NH:7][C:6]=2[CH:17]=1.O1CCOC[CH2:19]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([S:16][CH3:19])=[N:7][C:6]=2[CH:17]=1
Reactant: C1COCCO1
Reactant: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 1.1 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-thione in 15 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 1.3 g. of potassium hydroxide in 15 ml. of methanol and 1.1 g. of methyl sulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml., diluted with water and the precipitate is collected. Recrystallization from methanol-water gives deep yellow crystals, m.p. 156°-158°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[N+:17](=[CH2:19])=[N-:18].CC(O)=O>C1COCC1>[N+:17](=[CH:19][C:14]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:15])=[N-:18]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2ccccc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [N-]=[N+]=CC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 3-nitro-napthalene-1-carbonyl chloride (8.4 g, 35.7 mmol) in anhydrous THF (70 mL) was added an ethereal solution of diazomethane (250 mL) dropwise at 0° C. The reaction mixture was stirred for 5 h, and then warmed to RT overnight. Excess diazomethane was decomposed by the dropwise addition of AcOH (50 mL). The mixture was extracted with Et2O (3×150 ml), washed with brine and saturated NaHCO3 aqueous solution, dried and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography to yield 2-diazo-1-(3-nitronaphthalen-1-yl)ethanone (7.0 g, 81% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.35 (s, 1H), 7.84 (t, J=7.2 Hz, 2H), 7.76 (t, J=7.8 Hz, 2H), 6.84 (s, 1H); MS (ESI) m/z: 242 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[S:26]([N:29]1[CH2:30][CH2:31][N:32]([S:50]([C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=2)(=[O:52])=[O:51])[CH2:33][CH2:34]1)(=[O:27])=[O:28]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCNCC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution ethyl 5-bromo-1-(phenylsulfonyl)-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxylate hydrochloride (20 mg, 0.034 mmol) in 1.0 mL of dichloromethane at room temperature was added triethylamine (0.019 mL, 0.14 mmol), followed by 4-(methoxy)benzenesulfonyl chloride (8.0 mg, 0,041 mmol). After stirring overnight, the solvent was removed under a stream of nitrogen to provide the titled compound.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH3:4][O:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2.Cl.[NH:21]1[CH2:26]CO[CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>O.C(OCC)C>[CH3:4][O:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([CH2:26][N:21]1[CH2:22][CH2:23][O:3][CH2:1][CH2:2]1)[CH2:10][CH2:9]2
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Reactant: CCO
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1[N+](=O)[O-])CCC(CN1CCOCC1)C2=O

Procedure:
In 100 ml. of ethanol is dissolved a mixture of 1 g. of 6-methoxy-5-nitro-3,4-dihydro-1(2H)-naphthalenone and 3 g. of morpholine hydrochloride and the mixed solution is reacted at 80° C. for 10 hours. The reaction mixture is cooled and, following addition of 500 ml. of water, it is shaken with 100 ml. of diethyl ether. The water layer is neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. By the above procedure is obtained 6-methoxy-2-morpholinomethyl-5-nitro-3,4-dihydro-1(2H)-naphthalenone as an oily product. This product is dissolved in 50 ml. of methanol and, after addition of 1 g. of sodium borohydride, the solution is stirred at room temperature for 30 minutes. To this reaction mixture is added 500 ml. of water and the mixture is extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. The above procedure provides an oil of 6-methoxy-2-morpholinomethyl-5-nitro-1,2,3,4-tetrahydro-1-naphthalenol. This product is dissolved in 20 ml. of ethanolic hydrochloric acid and the solution is heated at 80° C. for 1 hour. Following the addition of 50 ml. of ethyl acetate, the solution is cooled, whereupon 0.35 g. of 7-methoxy-3-morpholinomethyl-8-nitro-1,2-dihydronaphthalene hydrochloride is obtained as pale-yellow prisms melting at 200°-270° C. (gradually decomposed).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[F:28])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 926.5 %

Procedure:
To a stirred solution of 8.7 (0.100 g, 0.29 mmol) in DMF (2.00 mL, 26 mmol) at 23° C., was added 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.100 g, 0.59 mmol), potassium carbonate (0.12 g, 0.88 mmol), followed by tetrakis(triphenylphosphine)palladium (0.034 g, 0.029 mmol). The mixture was heated to 100° C. After 2 hours, the reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3×50 mL) and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 8.8 as a colorless oil (0.85 g, 71%). MS ESI (pos.) m/e: 317.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[H-].[Na+]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:13]=[CH:12][N:11]=1
Reactant: O=C(NCCCl)Nc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccnc(Cl)c1
Yield: 91 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloroethyl)-3-(2-chloro-pyridin-4-yl) urea (I-33a: 7.0 g, 30.042 mmol) in dry THF (40 mL) was reacted with 60% NaH (1.08 g, 45.06 mmol) in dry THF (30 mL) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 5.40 g of the product (92% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].Cl>C1COCC1.C(OCC)(=O)C>[CH2:13]([NH:15][C:16]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:17])[CH3:14]
Reactant: CCN=C=O
Reactant: c1cn[nH]c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1cccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
To a solution of pyrazole (1.7 g, 25 mmol) and 4 mL triethylamine in 50 mL dry THF was added ethyl isocyanate (2 g, 28 mmol) at 0° C. and the resulting reaction solution was stirred at RT for 18 h. Ethyl acetate and 2N HCl were added. The aq layer was separated and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated in vacuo to give an oil. The oil was triturated with cold hexane to give 2.5 g of N-ethyl-1H-pyrazole-1-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[CH:10][C:11]=1[CH3:17]
Reactant: Cc1ccc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2-methyl-benzoic acid (310 mg, 2.07 mmol, 1.0 eq) in CH2Cl2 (30 mL) at 0° C. was added (COCl)2 (0.52 mL, 6.0 mmol, 3.0 eq) and DMF (2-3 drops). The reaction was stirred at 0° C. for 2 h, and then the solvent was removed in vacuo. The residue was taken up in THF (30 mL) and added to a suspension of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (195.4 mg, 2.07 mmol, 1.0 eq) and NaHCO3 (339.1 mg, 6.2 mmol, 3.0 eq) in THF (70 mL) at 0° C. The reaction was stirred for 3 h at 0° C. then quenched by addition of water and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (DCM:MeOH, 1:0 to 20:1) to give the title compound as a solid (230 mg, 48%).
Reaction SMILES: CC1CCCO1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1.[CH3:21][N:22]1[C:26]([CH:27]=O)=[N:25][CH:24]=[N:23]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>>[F:7][C:8]1[CH:16]=[C:15]2[C:11](/[C:12](=[CH:27]/[C:26]3[N:22]([CH3:21])[N:23]=[CH:24][N:25]=3)/[O:13][C:14]2=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1
Reactant: Cn1ncnc1C=O
Reactant: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CC1CCCO1
Product: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15-25° C., anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4-nitroisobenzofuran-1(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (49.6-52.6% concentration in dichloromethane by GC, 3.59-3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09-9.10 kg, 89.0-89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20-30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85-95° C.) for 80-90 minutes, and the mixture was refluxed for another 70-90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to ≦5%. The resulting slurry was cooled down to 5-15° C. for 150-250 minutes. The slurry was aged at 5-15° C. for another 80-90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2 L×3). The wet cake was dried under vacuum at 40-50° C. for 8 hours to give 2.65-2.76 kg of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroisobenzofuran-1(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3%, purity: 98.6-98.8% by HPLC). LC-MS (ESI) m/z: 291 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 8.58-8.61 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:8](=[O:15])[N:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[O-]S([Cl:33])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:45]1([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[ClH:33].[CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][N:12]([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:11][CH2:10]2)[C:8](=[O:15])[N:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=S([O-])Cl
Reactant: OCCCCCCc1ccccc1
Reactant: CCCCN1C(=O)N(CC(C)C)C(=O)C12CCNCC2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1C(=O)N(CC(C)C)C(=O)C12CCN(CCCCCCc1ccccc1)CC2
Product: Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To a solution of the compound prepared in Example 1 (28 mg) and N,N-diisopropylethylamine (155 mg) in acetonitrile (3 mL) were added benzenesulfonylchloride resin (Argonaut, product name PS-TsCl, product number 800276, 1.22 mmol/g, 0.20 mmol) (164 mg) and sulfonyl resin (175 mg) which is prepared from 6-phenylhexanol (345 mg). The mixture was stirred for 18 hours at 70° C. and then filtrated. The resin was washed with acetonitrile (3 mL, three times). The filtrate and rinsed solution were combined and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=25:1), added 4N hydrochloric acid in ethyl acetate and concentrated to give the title compound (28 mg) having the following physical data.
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([N:17]([CH3:31])[C:18]([CH2:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[O:30])=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1.C1C=CC=CC=1.[Zn]>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22](=[O:23])[CH2:21][CH2:20][C:18](=[O:19])[N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:31])[OH:30])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1

Procedure:
Zinc powder (482 mg) and a small amount of iodine were added to a solution of ethyl bromoacetate (0.70 ml) in THF (6 ml). The mixture was refluxed for 30 mins. The solution was added dropwise to a solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (1.21 g) in benzene (10 ml). The mixture was refluxed for 30 mins. After reaction, 1N hydrochloric acid was added to the mixture. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (1.21 g) having the following physical data:
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH:6]([F:8])[F:7].[Li+].[OH-]>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([F:7])[F:8])[C:3]([OH:20])=[O:2])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CC(F)F)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 250 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid methyl ester in 2 ml THF was added a solution of 21 mg LiOH in 0.5 ml water at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 229 mg
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.5 g, 2 7 mmol) was dissolved in methanol (25 mL). Isovaleraldehyde (0.233 g, 2 7 mmol) was added followed by acetic acid (1 mL). The solution continued to stir at 25° C. for 10 min. Sodium cyanoborohydride (0.424 g, 6.75 mmol) was added and the mixture was stirred at 25° C. for 5 h. The mixture was poured into aqueous half-saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-(3-methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.43 g, 1.7 mmol, 63%), as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C15H27NO2 253.2, found 254.1 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:15]2)=[O:13])=[CH:7][C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:32])[C:12]([CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:15]2)=[O:13])=[CH:7][C:6]=1[OH:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N1CC(C(=O)Nc2ccc(C(C)(C)C)c(O)c2)Oc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC(C(=O)N(C)c2ccc(C(C)(C)C)c(O)c2)Oc2ccccc21
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
To a solution of ethyl 2-(4-tert-butyl-3-hydroxyphenylcarbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (50 mg, 0.13 mmol) in THF at 0° C. was added NaH (10 mg, 0.25 mmol) and the mixture stirred for 10 min. Methyl iodide (23 mg, 10 μL, 0.16 mmol) was added and mixture was stirred for 1 h at room temperature. HPLC purification (20-99% MeOH/water) provided ethyl 2-((4-tert-butyl-3-hydroxyphenyl) (methyl)carbamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (18 mg, 32% yield). LC/MS m/z 413.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, J=6.9 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.1 Hz, 1H), 6.88-6.79 (m, 4H), 4.79 (br s, 1H), 4.21-4.11 (m, 2H), 4.02-3.98 (m, 1H), 3.65 (d, J=13.4 Hz, 1H), 3.10 (s, 3H), 1.35 (s, 9H), 1.24 (t, J=7.1 Hz, 3H).