Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1)[CH3:23]
Reactant: CI
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a stirred solution of 2.4 g (8.1 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 389 mg (8.9 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.72 g (12.1 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielded 0.78 g (31%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+) and 0.53 g (21%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][NH:19][CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][N:19]([CH2:34][C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:25]([CH3:24])[CH:26]=4)[CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Reactant: Cn1cc(C=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cc(CN2CC3CN(CCNS(=O)(=O)c4ccc(C#N)cc4)CC(C2)O3)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
A mixture of 4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide (0.101 g, 0.30 mmol) and 1-methyl-1H-indole-3-carbaldehyde (0.081 g, 0.51 mmol) in 1,2-dichloroethane (4 mL) was agitated for 1.5 hours at room temperature. Sodium triacetoxyborohydride (0.216 g, 1.02 mmol) was added and resulting mixture was agitated over night at room temperature. An aqueous solution of Na2CO3 (3 mL) was added and the aqueous layer was extracted with dichloromethane (3×4 mL). The combined organic layers were concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 76 mg (52.8%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[OH-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:29])([CH3:30])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:31])=[O:2])=[CH:11][CH:10]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:27][CH2:28]1
Reactant: COC(=O)C(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionic acid methyl ester (Intermediate 169, 0.022 g, 0.05 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title product (0.008 g, 40%).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][C:24]=3[CH:33]3[CH2:35][CH2:34]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[O:38]1[CH2:43][CH2:42][CH:41]([C:44](Cl)=[O:45])[CH2:40][CH2:39]1>N1C=CC=CC=1.CCOC(C)=O>[C:1]([C:3]1[CH:37]=[CH:36][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][C:24]=3[CH:33]3[CH2:34][CH2:35]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[N:11]([C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[O:45])[C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCOCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (93 mg, 187 μmol) in pyridine (374 μl) was added tetrahydro-2H-pyran-4-carbonyl chloride (139 mg, 935 μmol) dropwise. The reaction was stirred at 80° C. for 2 h, then cooled to rt, diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (69 mg, 61%) as an off-white solid. MS m/z 610 (MH)+.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9](C(O)=O)([CH2:10]4)[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[K+].Cl>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:1]1([C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:21])([CH2:10]4)[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: NC12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a stirred solution of 1-phenyltricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.6 g, 2.48 mmol) obtained from step I and triethylamine (1.0 mL, 7.44 mmol) in toluene (10 mL) under N2 atmosphere at ice bath temperature was added diphenylphosphoryl azide (0.64 mL, 3.0 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, then it was refluxed for 4 h. The reaction mixture was cooled to r.t., washed with water and stirred with aq. KOH solution (50% w/v, 5.0 mL) and nBu4NI (92 mg, 0.25 mmol) for 2 h at r.t. The reaction mixture was cooled to ice bath temperature, acidified with conc. HCl to pH 2, extracted with diethyl ether. The aqueous layer was basified with aq. NaOH solution (50% w/v) and extracted with chloroform. The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to obtain 1-phenyltricyclo[3.3.1.03,7]nonan-3-amine (0.33 g) as viscous liquid in 62% yield. m/z (M+1) 214; 1H NMR (CDCl3) 300 MHz δ 7.40-7.22 (m, 4H), 7.22-7.15 (m, 1H), 2.42-2.35 (m, 1H), 2.20-2.05 (m, 2H), 2.02-1.52 (m, 9H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][C:27]1[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:28]=1[CH2:29][N:30]1[C@H:33]([CH2:34][CH:35]=O)[C@H:32]([N:37]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:31]1=[O:57]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:35][CH2:34][C@@H:33]1[C@H:32]([N:37]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:31](=[O:57])[N:30]1[CH2:29][C:28]1[CH:58]=[CH:59][C:60]([O:62][CH3:63])=[CH:61][C:27]=1[O:26][CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=C(Br)Br)cc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of PPh3 (302.4 mg, 1.15 mmol) in DCM (1 mL) at 0° C. was added CBr4 (192 mg, 0.58 mmol). After 10 min, a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(2-oxoethyl)azetidin-3-yl)(4-methoxybenzyl)carbamate (152.7 mg, 0.29 mmol) in DCM (800 μL) was added dropwise followed by DCM (800 μL) wash. After 20 min, the reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted with DCM (2×). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (0-40% EtOAc-Hept) to afford the title compound (162 mg, 82%). LCMS: Rt=1.2 min, m/z=689.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]2[O:9][CH:5]2[CH2:4]1)=[CH2:2].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:9]1[CH:6]2[CH:5]1[CH2:4][CH:3]([CH2:1][CH2:2][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10])[CH2:8][CH2:7]2
Reactant: C=CC1CCC2OC2C1
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CO[Si](CCC1CCC2OC2C1)(OC)OC
Temperature: 89 °C
Reaction time: 0.3 h
Yield: 90 %

Procedure:
The apparatus of Example B was charged with 148.8 g (1.2 mol) of 1-vinyl-3,4-epoxycyclohexane, 1.3 g of a carboxylic acid promoter, and 0.15 ml of 10% chloroplatinic acid catalyst solution. The flask contents were heated to 89° C. and dropwise addition of 122.8 g {[1.0 mol) of trimethoxysilane was begun. The reaction temperature was controlled at 90°-95° C. with an ice bath. Reaction was maintained at that temperature for half an hour after completion of addition, which took 18 minutes. Analysis by gas chromatography showed a yield of 90% of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane. This example demonstrates a standard preparation of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane using commercial chloroplatinic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1([CH3:44])[O:12][C@H:11]([C:13]2[CH2:14][S:15][C@@H:16]3[C@H:32]([NH:33]C(=O)CC4C=CC=CC=4)[C:31](=[O:43])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])[CH2:10][CH2:9]1.CN1CCOCC1.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:20])=[C:13]([C@@H:11]3[CH2:10][CH2:9][C:8]([CH3:7])([CH3:44])[O:12]3)[CH2:14][S:15][C@H:16]12
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCC(C)(C)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)C2=C([C@@H]3CCC(C)(C)O3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
Phosphorus pentachloride (48mg, 0.23mmol) in dichloromethane (1.2ml) was added to 4-methoxybenzyl (6R,7R)-3-[(S)-5,5-dimethyltetrahydrofuran-2-yl]-7-phenylacetamidoceph-3-em-4-carboxylate (93mg, 0.15mmol) and N-methylmorpholine (34μl, 0.31mmol) in dichloromethane (3ml) at -25° C. The reaction was stirred at -10±5° C. for 45min., then methanol (0.5ml) was added, and stirring continued for 45min. at room temperature. Water (1ml) was then added, and the mixture vigorously stirred for a further 1h. After evaporation of the dichloromethane in vacuo, the pH of the aqueous residue was adjusted to 7 by the addition of ammonium hydroxide in the presence of ethyl acetate. The mixture was extracted with ethyl acetate (x2), dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 70% ethyl acetate in hexane yielding the title compound (25mg, 39%); (Found: M+ 418.1566. C21H26N2O5S requires M+ 418.1562); vmax (CH2Cl2) 2970, 1777, 1721, 1613 and 1516cm-1 ; δH (CDCl3, 250MHz) 1.21 (3H, s), 1.27 (3H, s), 1.68-1.81 (3H, m), 2.25 (1H, m), 3.48 and 3.62 (2H, ABq, J 18.7Hz), 3.56 (2H, br s, exch.), 3.79 (3H, s), 4.73-5.25 (5H, m), 6.87 (2H, d, J 8.6Hz) and 7.30 (2H, d, J 8.6Hz).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromoaniline (4.0 g, 23.3 mmol), (4-(tert-butyl)phenyl)boronic acid (4.6 g, 25.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.5 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: C([O:5][CH:6](OCCCC)[C@H:7]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[NH:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])CCC.S(=O)(=O)(O)O.[OH-].[Na+]>C(#N)C>[CH2:25]([O:24][C:22]([N:17]1[C:18](=[O:21])[CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([CH:6]=[O:5])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])=[O:33])=[O:32])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Yield: 95.5 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamyl-L-prolyl-L-argininal dibutylacetal 1/2 sulfate (0.61 g, 0.90 mmol) in acetonitrile (90 ml) was added 1N sulfuric acid aqueous solution (45 ml). The mixture was reacted at 36° C. for 4 hours with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 5.6 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were filtered off. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 0.43 g (87%) of N-benzyloxycarbonyl-L-pyroglutamyl-L-prolyl-L-argininal.1/2 sulfate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH2:17]([N:20]=[C:21]=[O:22])[CH2:18][CH3:19].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:20][C:21]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1)=[O:22])[CH2:18][CH3:19]
Reactant: CCN(CC)CC1CCc2ccc(O)cc21
Reactant: CCCN=C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCNC(=O)Oc1ccc2c(c1)C(CN(CC)CC)CC2
Yield: 39.6 %

Procedure:
2 g of 6-hydroxy-N,N-diethyl-1-indan-methylamine and 1.5 g of propylisocyanate were refluxed in 25 ml of dry toluene for 16 hours. The reaction mixture was poured into 100 ml of 0.1M acetic acid, and the organic phase was separated. The water phase was made alkaline with dil. NH4OH and extracted with 2×50 ml diethyl ether. The combined organic phases were dried (MgSO4) and the solvent evaporated. The residue was purified by column chromatography yielding 1.1 g of the title compound as an oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][N:18]1[C@@H:35]2[CH2:36][C:23]3[CH:24]=[CH:25][C:26]([O:37][CH3:38])=[C:27]4[O:28][C@H:29]5[C:30]([CH2:32][CH2:33][C@@H:34]2[C@:21]5([C:22]=34)[CH2:20][CH2:19]1)=[O:31].Cl>O1CCOCC1>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][N:18]1[C@@H:35]2[CH2:36][C:23]3[CH:24]=[CH:25][C:26]([O:37][CH3:38])=[C:27]4[O:28][C@H:29]5[C:30]([CH2:32][CH2:33][C@@H:34]2[C@:21]5([C:22]=34)[CH2:20][CH2:19]1)=[O:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Leu-Hydrocodone was added 25 ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (1.96 g, 97% yield): 1H NMR (DMSO-d6) δ 0.94 (d, 6H), 1.52 (m, 1H), 1.75-1.90 (m, 4H), 2.22 (dt, 1H), 2.34 (dt, 1H), 2.64 (q, 1H), 2.75 (s, 3H), 2.95-3.23 (m, 4H), 3.74 (s, 3H), 3.91 (d, 1H), 4.07 (s, 1H), 5.10 (s, 1H), 5.72 (d, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 8.73 br s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([O-])=O>CO.[Pd]>[O:19]1[CH2:20][CH2:21][N:16]([C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][C:4]=2[NH2:1])[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cc(-c2cccnc2)ccc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(-c2cccnc2)ccc1N1CCOCC1

Procedure:
A solution of 4-(2-nitro-4-(pyridin-3-yl)phenyl)morpholine (300 mg, 0.24 mmol) in MeOH (140 mL) was reduced using a continuous flow hydrogenation reactor (flow rate: 1 mL/min, 10% mol Pd/C, temperature 40° C., H2 pressure: 10 bar) to give 2-morpholino-5-(pyridin-3-yl)aniline.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:21][CH:22]([OH:40])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[O:24][CH2:23][CH:22]([OH:40])[CH2:21][N:12]3[CH2:13][CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11]3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: Brc1ccc2cn[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OC(COc1cccc(-c2ccc3cn[nH]c3c2)c1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 16.9 %

Procedure:
To a solution of 6-bromo-1H-indazole (64.2 mg, 0.326 mmol) in dioxane (4 ml) and water (1 mL) was added 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (200 mg, 0.489 mmol), Pd(dppf)Cl2 (24 mg, 0.03257 mmol) and K2CO3 (135 mg, 0.98 mmol) at 16° C. The reaction mixture was stirred for 16 h at 100° C. TLC (PE:EA=1:1) showed that the reaction was completed. The mixture was concentrated to provide a crude product which was purified by HPLC separation to give the title compound (22.0 mg, 11.3%) as a white solid. 1HNMR (CD3OD, 400 MHz) δ: 8.49 (br, 1H), 8.07 (s, 1H), 7.85-7.83 (m, 1H), 7.76-7.71 (m, 1H), 7.44-7.10 (m, 8H), 7.03-6.98 (m, 1H), 4.50-4.42 (m, 1H), 4.30 (s, 2H), 4.15-4.13 (m, 2H), 3.49-3.40 (m, 2H), 3.36-3.31 (m, 2H), 3.19-3.10 (m, 2H). LCMS (m/z): 400.2 [M+H]+
Reaction SMILES: S(=O)=O.[C:4]([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:22]2[C@@H:21](O)[CH2:20][C@@:18]2([CH3:19])[C@H:14]3[C@@H:15]3[CH2:29][C@@H:16]3[C:17]2=[O:28])[CH2:9]1)(=[O:6])[CH3:5]>CS(Cl)(=O)=O.CN(C)C=O.CC1C=C(C)N=C(C)C=1.C(OCC)(=O)C>[C:4]([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10](=[CH:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[C@@H:15]3[CH2:29][C@@H:16]3[C:17]2=[O:28])[CH2:9]1)(=[O:6])[CH3:5]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Agent: CS(=O)(=O)Cl
Agent: O=S=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3C2=CC[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.6 ml of a solution of 5% by weight sulphur dioxide in methanesulphonic acid chloride are added to a solution of 1.75 g of 3β-acetoxy-11β-hydroxy-15β,16β-methyleneandrost-5-en-17-one in 10.5 ml of dimethylformamide and 3.5 ml of γ-collidine and the whole is stirred for 20 minutes, the internal temperature being allowed to rise to approximately 45°. While stirring, the mixture, including the precipitate that has formed, is poured onto 17.5 ml of ice-water and stirring is continued for a further 10 minutes. The oil that separates out is taken up in ethyl acetate and washed in succession with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution. Evaporation of the solvent yields 3β-acetoxy-15β,16β-methyleneandrosta-5,9(11)-dien-17-one that is uniform according to thin-layer chromatography and is processed further without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2]>CCO.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (1.5 g), Fe (2.6 g), and CaCl2 (260 mg) in EtOH (30 mL) and H2O (6.0 mL) was heated at 100° C. for 6 h. After cooling to rt, the precipitate was removed by Celite, and the filtrate was concentrated. The residue was partitioned between AcOEt and sat.NaHCO3aq. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=3/2 to 1/1). The obtained solid was rinsed with iPr2O-hexane to give N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g) as a pale pink solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([Cl:24])=[C:11]([Cl:25])[CH:10]=2)=O)C.[NH4+:26].[Cl-].N>>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:25])[N:8]=[CH:7][C:6]([C:4]([NH2:26])=[O:3])=[C:15]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(Cl)cc2c1Nc1ccccc1C
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Product: Cc1ccccc1Nc1c(C(N)=O)cnc2cc(Cl)c(Cl)cc12

Procedure:
A mixture of Ethyl-6,7-dichloro-4-(2-methylanilino)-3-quinolinecarboxylate (0.050 g, mmol) and NH4Cl was heated in a pressure vessel with NH3-saturated methanol for five days. The mixture was evaporated and the residue was recrystallized from EtOH.