Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([O:10][C@@H:11]1[C@H:15]([O:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C@@:14](COS(C)(=O)=O)([CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:13][C@@:12]1([SiH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])(=O)C.CCOC(C)=O>CO>[C:18]1([CH2:17][O:16][C@@H:15]2[C@@:14]3([CH2:7][O:10][C@H:11]2[C@:12]([SiH:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)([N:40]2[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]2=[O:42])[O:13]3)[CH2:28][O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2cccc3ccccc23)[C@](COC(C)(C)C)(COS(C)(=O)=O)O[C@]1(n1ccc(=O)[nH]c1=O)[SiH](c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1OCc1cccc3ccccc13)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
Solid K2CO3 (11.1 g, 80 mmol) was added to a solution of compound 10 (29.4 g, 38 mmol) in methanol (350 mL). After stirring at room temperature for 5 hours, mixture was poured into EtOAc, washed with aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to a yellow foam. Purification by silica gel chromatography (1% methanol in CH2Cl2) yielded 20.0 g (83%) of nucleoside 11 as a pale yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH2:17][NH2:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:17][NH:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
N-((1R)-1-Aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (830 mg, 3.14 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (0.44 ml, 3.14 mmol) was added. The solution was cooled to −78° C. A solution of methanesulfonyl chloride (0.24 ml, 3.14 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with dichloromethane (100 ml) and washed with saturated sodium chloride solution (100 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (65 g), using ethyl acetatelheptane (2:1) as eluent, to give 990 mg of N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([N:10]=[C:11]=[O:12])([CH3:9])[CH3:8].[Cl:13][C:14]1[C:15]([O:24][C:25]2[C:29]([CH3:30])=[C:28]([CH3:31])[NH:27][N:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>CN(C=O)C>[CH:7]([NH:10][C:11]([N:27]1[C:28]([CH3:31])=[C:29]([CH3:30])[C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][N:16]=2)=[N:26]1)=[O:12])([CH3:9])[CH3:8]
Reactant: Cc1[nH]nc(Oc2ncc(C(F)(F)F)cc2Cl)c1C
Reactant: CC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ncc(C(F)(F)F)cc2Cl)nn(C(=O)NC(C)C)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol) and isopropyl isocyanate (0.26 g, 3.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4,5-dimethylpyrazole (0.88 g, 3.0 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-isopropyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4,5-dimethylpyrazole-1-carboxamide (0.55 g, yield: 48.7%) mp: 78-80° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (d, J=6.6 Hz, 6H), 1.78 (s, 3H), 2.58 (s, 3H), 3.95-4.15 (m, 1H), 6.70-6.95 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C>C(O)(=O)C>[C:1]1([N:7]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:13][CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=NC(=O)c1ccncc1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: c1ccc(-n2ncnc2-c2ccncc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.9 g. of phenylhydrazine in 100 ml. of acetic acid is added 10.0 g. of N-(dimethylaminomethylene)-isonicotinamide. The reaction mixture is stirred at 90° C. for 1.5 hours and then evaporated in vacuo to an organce oil. This oil is dissolved in 250 ml. of chloroform, washed with 60 ml. of saturated sodium bicarbonate solution, then with 60 ml. of water, dried over sodium sulfate and filtered. The chloroform is removed and the residue is dissolved in 60 ml. of ether. Cooling produces 8.8 g. of the desired product as tan crystals, mp. 92°-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][N:9]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccnc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Brc1cc(CN2CCCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromoisonicotinaldehyde (400 mg) and pyrrolidine (0.197 mL) in acetonitrile (16 mL) was added sodium triacetoxyborohydride (547 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (445 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:16](=[O:39])[C@@H:17]([NH:19][C@H:20]([C:29]([O:31]CC2C=CC=CC=2)=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:18])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[H][H].[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:16](=[O:39])[C@@H:17]([NH:19][C@H:20]([C:29]([OH:31])=[O:30])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:18])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 83.9 %

Procedure:
1.0 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is dissolved in 20 ml of methanol, and 50 mg of palladium black are added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere for two hours under an atmospheric pressure. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is triturated with ether, whereby 0.7 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 83.9% The physico-chemical properties of this product are identical with those of the sample obtained in Example 8-(2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[OH:27]O>O1CCCC1.O.CCOC(C)=O.C[Re](=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=4[O-:27])[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: OO
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Agent: C[Re](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
Methyltrioxorhenium(VII) (2 mg, 0.008 mmol) was added to a solution of 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (20 mg, 0.06 mmol) from Example 15, in tetrahydrofuran (2 mL) at room temperature and then 3.0 M hydrogen peroxide in water (0.04 mL) was added. The reaction mixture was heated to 80° C. for 20 min. allowed to cool and was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by preparative HPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 10 to give the title compound as a white amorphous solid (0.007 g, 30%). LCMS calc. for C19H17N4O4 (M+H)+: m/z=365.1. found: 365.1. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 7.39 (td, J=7.2, 6.5, 2.0 Hz, 1H), 7.25 (td, J=7.7, 0.9 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.63 (dd, J=7.9, 2.0 Hz, 1H), 5.84 (d, J=2.2 Hz, 1H), 4.78 (dd, J=11.6, 1.3 Hz, 1H), 4.36 (dd, J=11.6, 3.4 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([CH2:25][CH2:26][OH:27])[CH:24]=[CH:23][N:22]=[N:21]1.O[C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:47])[N:34]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH:35]=[N:36]2)=[CH:31][C:30]=1[O:48][CH3:49].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:49][O:48][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:29]=1[O:27][CH2:26][CH2:25][N:20]1[CH:24]=[CH:23][N:22]=[N:21]1)[N:36]=[CH:35][N:34]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C:33]2=[O:47]
Reactant: OCCn1ccnn1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 276.8 %

Procedure:
Triphenylphosphine (2.82 g, 10.7 mmol) was added to a solution of 2-(1,2,3-triazol-1-yl)ethanol (609 mg, 5.4 mmol), (J. Antib. 1993, 46, 177), and 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin4-one (1.1 g, 3.6 mmol), (prepared as described for the starting material in Example 5), in methylene chloride (70 ml), diethyl azodicarboxylate (600 μl, 10.7 mmol) was then added. After stirring for 2 hours at ambient temperature, the volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,3-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin4-one (4 g, 97%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][NH2:18]>CN(C)C=O>[CH3:9][O:8][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:18][CH2:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: COCCCN
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: COCCCNc1cccc(OC)c1[N+](=O)[O-]
Temperature: -15 °C
Yield: 79.8 %

Procedure:
Into a 25 mL round bottomed was added 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.92 mmol) and N,N-dimethylforamide (5.8 mL). The flask was cooled to −15° C. and 3-methoxypropylamine (313 mg, 3.5 mmol) in N,N-dimethylforamide (2.2 mL) was slowly added. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was purified by column chromatography (20% ethylacetate:hexanes) to give 3-methoxy-N-(3-methoxypropyl)-2-nitroaniline (37A) as a yellow oil (560 mg, 80% yield). ESI-MS:m/z 241.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([NH:18][C:19]([O:21]C(C)(C)C)=O)[C:12]2=[O:26])=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:51][C:52]1[CH:61]=[C:60]2[C:55]([C:56]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[CH:57][C:58]([NH2:62])=[N:59]2)=[CH:54][CH:53]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:18][C:19]([N:66]3[CH2:67][CH2:68][N:63]([C:56]4[C:55]5[C:60](=[CH:61][C:52]([Cl:51])=[CH:53][CH:54]=5)[N:59]=[C:58]([NH2:62])[CH:57]=4)[CH2:64][CH2:65]3)=[O:21])[C:12]2=[O:26])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)Oc2ccc(F)cc2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Oc4ccc(F)cc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid-4-fluorophenyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 555 (M++1). 1H NMR (CDCl3): δ 1.54˜2.10 (m, 5H), 2.16–2.24 (m, 1H), 3.14 (m, 4H), 3.54 (dd, 1H), 3.68 (m, 4H), 4.52 (dd, 1H), 4.84 (br.s, 2H), 4.90 (ddd, 1H), 5.94 (d, 1H), 6.15 (s, 1H), 7.06–7.13 (m, 2H), 7.13–7.20 (m, 3H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4cc(C(F)(F)F)ccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step, a, using 2,5-dimethylindole and 4-chloro-7-trifluoromethylquinoline.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:39]>>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28]([NH2:39])=[O:29])[CH2:26][CH2:27]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(C3(C(N)=O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 68 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 68% of theory; LC (method 1): tR=2.45 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=[O:3])[CH3:2].CO>C(Cl)Cl>[C:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([C@H:1]([OH:3])[CH3:2])[CH:16]=[CH:15][CH:14]=1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](O)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
In a dry flask under nitrogen, (S)-oxazaborolidine (4.81 mmol) was dissolved in dry CH2Cl2 (12 mL). This solution was maintained between −20° C. and −25° C. as a solution of tert-butyl (3-acetyl)benzoate (4.20 mmol) in dry CH2Cl2 (12 mL) was added dropwise over 20 minutes. The reaction mixture was then allowed to warm to room temperature for 45 minutes. This mixture was then cooled to −78° C. and methanol (20 mL) added dropwise. The mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure then the residue dissolved in methanol and concentrated under reduced pressure twice more. The dried residue was purified by silica gel chromatography in 10-30% ethyl acetate/hexanes to yield 865 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.00 (m, 1H); 7.92 (m, 1H); 7.58 (d, J=7.5 Hz, 1H); 7.42 (t, J=7.7 Hz, 1H); 4.98 (m, 1H); 1.62 (s, 9H); 1.54 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>CN(C)C=O.O.O1CCCC1>[CH3:28][NH:30][C:25](=[O:26])[CH2:24][C@@H:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]12
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (7.0 g) and triethylamine (2.73 ml) are added to a mixed solvent of dimethylformamide (70 ml) and tetrahydrofuran (30 ml). The mixture is cooled to -5° C., and pivaloyl chloride (2.38 ml) is dropwise added at said temperature. Ten minutes later, a solution of methylamine (0.69 g) in dimethylformamide (5 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away, and the residue is recrystallized from water/methanol to give 2.29 g of (S)-N-methyl-4-(4-chloro-phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]-[1,4]diazepine-6-acetamide 1/4 hydrate, melting point 143°-145° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44]>C(Cl)Cl.O>[CH2:46]([O:45][C:43]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7](=[O:8])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=1)(=[O:26])=[O:25])=[O:44])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 3-[3-(2-imidazol-1-ylacetyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (50.5 mg, 0.110 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.22 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. CH2Cl2 (30 mL) was added to the residue and this was washed with water. The organic phase was dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (52.4 mg, 0.495 mmol), water (2 mL) and butyl chloroformate (34.3 μL, 0.270 mmol), and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound as a white solid in 32% yield, over two steps, (18 mg, 0.036 mmol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)(F)F)cc1F
Temperature: 55 °C
Yield: 95 %

Procedure:
To a oven dried round bottom flask with stir bar was added 2-fluoro-4-(trifluoromethyl)benzaldehyde (5 g, 26.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methyl propane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13 (t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)+, Rt 1.02 min.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>ClCCCl>[N:24]1([S:20]([C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][CH2:19][N:10]([C:7](=[O:9])[CH3:8])[CH2:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:21])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1
Reaction time: 3 h
Yield: 66.5 %

Procedure:
Pyridine (0.85 ml, 10.5 mmol) was added to a stirred solution of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (0.96 g, 3.5 mmol) and 2,3-dihydro-1H-indole (0.42 g, 3.5 mmol) in 1,2-dichlorethane (40 ml) at room temperature. After 3 h, the solution was washed with water (40 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by column chromatography over silica gel eluting with a gradient of dichloromethane/methanol to afford the title compound (D5) as an oil (0.83 g, 67%), MS: m/z (MH+) 357.