Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:13][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1sccc1CBr
Yield: 52.1 %

Procedure:
A solution of 135.7 g (0.73 mol) of methyl 3-methylthien-2-ylglyoxylate, 131.2 g (0.73 mol) of N-bromosuccinimide and 1.35 g of azobisisobutyronitrile in 1000 ml of carbon tetrachloride is refluxed for 3 hours. Thereafter, the mixture is filtered and the filtrate is evaporated down. The residue is taken up in diethyl ether and the solution is washed with water, dried and evaporated down. 166.4 g of crude product are obtained, which is recrystallized from methanol. 100 g of the abovementioned compound are obtained as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[C:5]=1[OH:11])([O-:3])=[O:2].[F-].[Cs+].Br[CH:15](Br)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[C:5]2[O:11][CH2:16][CH2:15][O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1cccc(O)c1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1OCCO2
Temperature: 110 °C
Yield: 20.8 %

Procedure:
To a solution of compound 8A (3.0 g, 19.4 mmol) in DMF (40 mL) was added CsF (14.7 g, 96.8 mmol), followed by dibromoethane (1.84 mL, 21.3 mmol). The mixture was heated to 110° C. for 1.5 h, then cooled to rt, partitioned between water and Et2O. The separated Et2O layer was washed with water, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% MeOH in CH2Cl2 to afford the title compound (0.73 g).
Reaction SMILES: COC1C=CC(C[SH:8])=CC=1.[H-].[Na+].[C:13]1([CH2:19][CH:20]([N:28]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH:30]([NH:41][C:42](=[O:60])[CH:43](Br)[CH2:44][CH2:45][CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:29]2=[O:61])[C:21]([O:23]C(C)(C)C)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([CH2:19][CH:20]([N:28]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH:30]([NH:41][C:42](=[O:60])[CH:43]([SH:8])[CH2:44][CH2:45][CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:29]2=[O:61])[C:21]([OH:23])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)N1CCC(c2ccccc2)CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Product: O=C(NC1CC(c2ccccc2)CCN(C(Cc2ccccc2)C(=O)O)C1=O)C(S)CCCCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
Combine p-methoxybenzylmercaptan (0.08 mL, 0.57 mmol) and sodium hydride (17 mg, 60% oil dispersion, 0.42 mmol) in degassed dimethylfornamide (3 mL). After 1 hour, tetra-n-butylammonium iodide (about 5 mg) and N-[hexahydro-1-[1-(phenylmethyl)-1-t-butoxycarbonylmethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-a-bromo-1,3-dioxo-2H-isoindole-2-hexanamide (0.20 g, 0.27 mmol). After 20 hours, quench be the addition of a saturated aqueous ammonium chloride solution and dilute with water (about 5 mL). Extract with ethyl acetate (about 75 mL). Separate the layers and extract the organic layer with brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=3)[CH:19]=[CH:18][N:5]2[C:6](=[O:17])[C:7]=1/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN(C)C=O.C(N(C(C)C)CC)(C)C.I[CH2:47][CH:48]1[CH2:52][CH2:51][O:50][CH2:49]1>[Cl-].[Na+].O.C(OCC)(=O)C>[CH:29]([C:27]1[N:28]=[C:24]([CH2:23][CH2:22][C:20]2[CH:19]=[CH:18][N:5]3[C:6](=[O:17])[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])=[C:2]([O:1][CH2:47][CH:48]4[CH2:52][CH2:51][O:50][CH2:49]4)[N:3]=[C:4]3[CH:21]=2)[S:25][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Reactant: ICC1CCOC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(OCC4CCOC4)nc3c2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
tert-Butyl (E)-3-(2-hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-2-propenoate (17 mg) was added with dimethylformamide (3 ml), diisopropylethylamine (500 ml) and 3-(iodomethyl)tetrahydrofuran (50 ml), and then the mixture was stirred at 80° C. for 16 hours. The reaction mixture was added with ethyl acetate and saturated brine, and the organic layer was further washed twice with saturated brine and dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (14 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:45])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:41])[NH:32][C:33]5[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=5)=[CH:27][C:26]=4[N+:42]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:45])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:41])[NH:32][C:33]5[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=5)=[CH:27][C:26]=4[NH2:42])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c(N)c2)cn1
Temperature: 80 °C
Yield: 92 %

Procedure:
The product of Example 201A (200 mg, 0.3233 mmol), ammonium chloride (113 mg, 2.118 mmol), and iron powder (111 mg, 1.988 mmol) in a mixture of water (3 mL), ethanol (6 mL) and tetrahydrofuran (6 mL) was heated at 80° C. under a nitrogen atmosphere for 75 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to give the product as a light beige solid (175 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2N)[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2NC(C)=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 2-(2-amino-5-chlorobenzoyl)-6-chloro-3-(propionylamino)indole (Example 389, 217 mg, 0.576 mmol) and pyridine (0.12 ml, 1.50 mmol) in dichloromethane (10 ml) was added acetyl chloride (53 μl, 0.749 mmol) at 0° C. After stirring at room temperature for 1 h, the mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The solution was washed with 2N aqueous HCl (30 ml×2), saturated aqueous sodium bicarbonate (30 ml), and dried (MgSO4). Removal of solvent gave a crystalline residue. Recrystallization from ethyl acetate gave 163 mg (68%) of the title compound. m.p.: 264-266° C. IR (KBr) ν: 3260, 1676, 1655, 1578, 1547, 1508, 1313, 1234, 1205, 1006, 918, 841 cm−1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3([CH3:24])[CH3:23])=[CH:11][CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3([CH3:24])[CH3:23])=[CH:11][CH:10]=[C:9]1[C:30]#[N:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)C(=O)N2
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a solution 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester (0.39 g, 1.2 mmol) in THF (anhydrous, 9 mL) at −78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.12 mL, 1.4 mmol). After 120 min, DMF (20 eq, 1.8 mL, 23 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (1:3 ethyl acetate/hexane) gave 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.21 g, 50%) as a white solid; mp 158.6; 1H NMR (DMSO-d6; 300 MHz): δ 1.27 (s, 6H), 1.33 (s, 9H), 6.40 (d, 1H, J=3.8 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=1.8, 8.0 Hz), 7.30 (d, 1H, J=1.5 Hz), 10.50 (s, 1H). MS m/z 350 (M−H)−. Calcd for C19H22N2O3: C, 68.36; H, 6.02; N, 11.96. Found: C, 66.79; H, 6.03; N, 11.02.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>CN(C)C=O.C1(C)C=CC=CC=1>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Oc1ccc(C(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Sodium hydride (55% suspension in oil, 5.22 g) was added to a solution of 4-isopropylphenol (15.0 g) in a mixture of dimethylformamide (63 ml) and toluene (75 ml). The mixture was stirred at ambient temperature for 1 hour. To the reaction mixture, diethyl 2-chloromalonate (18.5 g) was added. The mixture was stirred at 60° C. for 2.5 hours. At the end of this time ethyl acetate was added to the reaction mixture. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (21.5 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20].Cl.[CH3:22][O:23][C:24]([C:26]1([CH3:30])[CH2:29][NH:28][CH2:27]1)=[O:25].CCN(C(C)C)C(C)C.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:22][O:23][C:24]([C:26]1([CH3:30])[CH2:29][N:28]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([NH:11][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:20])[CH:4]=3)[CH2:9][CH3:10])[CH:13]=2)[CH2:27]1)=[O:25]
Reactant: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Reactant: COC(=O)C1(C)CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1cccc(CN2CC(C)(C(=O)OC)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of INT 7 (250 mg, 0.87 mmol) and INT 14 (158 mg, 0.88 mmol) in MeOH (8.6 mL) was added DIPEA (0.18 mL, 1.04 mmol). Then HOAc (0.099 mL, 1.74 mmol) was added followed by NaCNBH3 (55 mg, 0.87 mmol). The reaction mixture was stirred at room temperature for 4 hours. A solution of INT 14 (50 mg, 0.091 mmol), DIPEA (0.060 mL, 0.021 mmol) and HOAc (0.040 mL, 0.70 mmol) in MeOH (1.0 mL) was added. The mixture was stirred at room temperature for another hour. The mixture was concentrated. The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to give INT 15.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[CH2:6]([O:8][C:9](=[O:38])[CH:10]=[CH:11][C@@H:12]1[CH2:16][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][N:13]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])[CH3:7]>>[CH2:6]([O:8][C:9](=[O:38])[CH2:10][CH:11]([NH:2][CH3:1])[C@@H:12]1[CH2:16][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][N:13]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)=[O:26])[CH3:7]
Reactant: CCOC(=O)C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: CCO
Product: CCOC(=O)CC(NC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A 5.3M methylamine-ethanol solution (5 ml, 26.6 mmol) was added to 3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]acrylic acid ethyl ester (2.94 g, 6.15 mmol, compound of Reference Example 1-6 of Japanese Patent Application No. 342,948/1989) at room temperature, and the mixture was left to stand at the same temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, ethyl acetate) to obtain 3-methylamino-3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]propionic acid ethyl ester (1.67 g, yield: 53.3%).
Reaction SMILES: Cl[Sn]Cl.[CH2:4]([C:12]1[N:13]([CH2:24][CH3:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][CH:15]=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:4]([C:12]1[N:13]([CH2:24][CH3:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH2:21])=[CH:16][CH:15]=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCn1c(CCc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CCc2ccccc2)cc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
SnCl2 (1.2 g, 6.3 mmol) was added to a solution of 2-phenethyl-1-ethyl-5-nitro-1H-indole (0.17 g, 0.57 mmol) in THF (50 ml). The mixture was kept under stirring at 70° C. overnight. After cooling, the mixture was poured in H2O, neutralized with NaHCO3, and extracted with ethyl acetate (3×50 ml). After evaporation of the solvent under reduced pressure, the solid was purified on a chromatographic column using CHCl3 as eluent to give 2-phenethyl-1-ethyl-1H-indol-5-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH2:15][C@H:14]2[N:11]([C:12](=[O:33])[C@H:13]2[C:16]([CH3:32])([O:18]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:17])[C:10]=1[C:34]([O:36]CC1C=CC([N+]([O-])=O)=CC=1)=[O:35].C(O)C.P([O-])([O-])(O)=O.[K+:55].[K+].O>O1CCOCC1.O.[Pt](=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH2:15][C@H:14]2[N:11]([C:12](=[O:33])[C@H:13]2[C:16]([OH:18])([CH3:32])[CH3:17])[C:10]=1[C:34]([O-:36])=[O:35].[K+:55]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3N)C[C@H]12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccccc3N)C[C@H]12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A mixture of 4-nitrobenzyl (5R,6R)-3-(2-aminophenylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (490 mg) and platinum (IV) oxide monohydrate (200 mg) in a mixture of dioxane (60 ml), ethanol (5 ml), 0.1M aqueous dipotassium hydrogen phosphate (22.7 ml) and water (25 ml) was shaken for 50 minutes under a hydrogen atmosphere (40 psi) at ambient temperature. The catalyst was filtered off and the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was dissolved in water (250 ml), and potassium chloride (12.5 g) was added thereto. The aqueous solution was chromatographed on non-ionic adsorption resin "Diaion HP-20 AG" (3.1×33 cm) eluting with water (1 liter) and aqueous isopropyl alcohol (5 to 30%, 1 liter). The fractions, whose UV spectra showed λ max 303 nm, were combined and lyophilized to give potassium (5R, 6R)-3-(2-aminophenylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (130 mg).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:21][C@@H:22]([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[CH2:23][CH2:24][OH:25])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CCO)c3ccc(C(F)(F)F)nc3)c2C1

Procedure:
A reaction mixture of 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (35 mg, 0.10 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (22 mg, 0.10 μmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) was subjected to microwave irradiation at 200° C. for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-70% CH3CN-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)O)[C:11](=[O:17])[O:12]C(C)(C)C)[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:18][CH2:19][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[O:12][C:11]2=[O:17])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC(c2ccc(F)cc2)OC1=O

Procedure:
To a stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-hydroxypropyl)carbamate (474 mg, 1.05 mmol) in dry THF (10 mL) was added 60% NaH in oil (250 mg, 10.4 mmol). The mixture was heated at reflux for 3 h. The mixture was diluted with water (20 mL) and. EtOAc (80 mL). The organic layer was separated, washed with 5% aq HCl (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (348 mg). A portion of the crude product was purified by preparative HPLC to afford 3-((1S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a 2:1 mixture of diastereomers based on 1H NMR. LC-MS (3 min) tR=1.92 min, m/z=380, 378. 1H NMR (CDCl3) S [selected resonances of major and minor diastereomers] 1.52 (d, major), 1.59 (d, minor), 3.06 (m, major), 3.31 (m, minor), 5.20 (dd, major), 5.25 (dd, minor).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: CCOC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 84.2 %

Procedure:
2.5g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 2.4 g of ethyl 2-chloroethoxyacetate (prepared as described in Preparation 1 or 2), 3.82 g of sodium carbonate and 0.14 g of sodium iodide were added to 80 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 18 hours. At the end of this time, it was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel, and 3.2 g (yield 84%) of the title compound were obtained as a light brown oil from the fractions eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[Ba+2].C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Reactant: COc1ccc(N)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(OC)cc1CO
Yield: 43.8 %

Procedure:
A solution of 2-amino-5-methoxybenzyl alcohol (5 g; 32.7 m.mol) and trans-1-chloro-2-ethoxycarbonylaminoindane (7.83 g; 32.7 m.mol) in dimethylformamide (80 ml) was treated with barium carbonate (3.37 g; 17 m.mol) in a manner similar to that in Description 3 to give the title compound (5.1 g; 44%), m.p. 142°-144° (from ethyl acetate).