Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([I:13])=[C:5]([C:10](O)=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].Cl.C[N:16](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(Cl)Cl.CO.O>[C:1]([C:3]1[C:4]([I:13])=[C:5]([C:10]([NH2:16])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1sc(C(=O)O)c(I)c1C#N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CSc1sc(C(N)=O)c(I)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylic acid (2.85 g, 7.93 mmol) in methylene chloride (30 mL), were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.28 g, 17.1 mmol) and 1-hydroxybenzotriazole (2.27 g, 16.8 mmol). The reaction mixture was stirred at room temperature for two hours and ammonium hydroxide (15.4 mL) was added and the biphasic mixture was stirred at room temperature for two hours. Water (100 mL), methanol (50 mL), methylene chloride (200 mL) was added. The organic layer was removed. The aqueous layer was extracted five times with a solution of 20% methanol in methylene chloride (100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to the title compound as dark red oil (1.47 g, 57%). LCMS: (FA) ES+ 325.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][Si:11]([CH3:15])([CH3:14])[C:12]#[CH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:13]#[C:12][Si:11]([CH3:15])([CH3:14])[CH3:10])=[CH:7][N:6]=1
Reactant: CNc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CNc1ccc(C#C[Si](C)(C)C)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 4.3 g (23.0 mmol) 5-bromo-2-methylamino-pyridine and 4.5 mL (32.2 mmol) 1-trimethylsilyl-ethyne using 134 mg (0.71 mmol) CuI, 601 mg (2.3 mmol) triphenylphosphine, 420 mg (0.60 mmol) PdCl2(PPh3)2 and 32 mL (101 mmol) triethylamine in 40 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 4.0 g (85%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CCNc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CCNc2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline (16.07 g, 0.098 mol) in dichloromethane (100 mL) at 0° C. were added sequentially triethylamine (16.3 mL, 0.12 mol), tert-butyldiphenylsilylchloride (28.4 g, 0.103 mol) and 4-(dimethylamino)pyridine (0.6 g, 4.9 mmol). After 30 minutes, the solution was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with dichlormethane (200 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layers were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 22.1 g (56%) of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[C:23]=1[CH:24]=[O:25].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([N:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:16])[C:23]=1[CH:24]=[O:25]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(Br)cncc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cncc(Br)c3C=O)ncc2c1
Temperature: 110 °C
Yield: 29.2 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 6-tert-butyl-8-fluoro-1,2-dihydrophthalazin-1-one 101h (220 mg, 1.0 mmol), 3,5-dibromopyridine-4-carbaldehyde (530 mg, 2.0 mmol), CuI (190 mg, 1.0 mmol), 4,7-dimethoxy-1,10-phenanthroline (244 mg, 1.0 mmol), Cs2CO3 (652 mg, 2.0 mmol) and dioxane (8 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 5 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:3, V/V) to afford 109a (118 mg, 29.3%) as a solid. LCMS: [M+H]+ 406
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]3(OC)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C:19]([CH2:28][OH:29])([CH2:26][OH:27])[O:18]3)[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]34[O:18][C@@:19]([CH2:28][OH:29])([CH2:26][O:27]3)[C@@H:20]([OH:25])[C@H:21]([OH:24])[C@H:22]4[OH:23])[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3R,4S,55)-2-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (0.5 g, 1.04 mmol) in dry DCM (20 mL), was added trifluoracetic acid (4.6 mL, 62.43 mmol) dropwise at 0° C. and the reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as monitored by TLC, the reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with water (2×10 mL) and NaHCO3 (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The crude compound was used as such in the next reaction (440 mg, 94.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1(=O)[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of zinc chloride (8.39 g, 1.14 mmol, 1 eq) in toluene at ambient temperature, ethyl 3-(4-fluorophenyl)-3-oxopropanoate (13 g, 2.74 mmol, 1 eq) was added and stirred at 70° C. for 15 min. Benzoquinone (6.66 g, 0.72 mmol, 1 eq) was added portion wise into the reaction mixture and stirred at the same temperature for 15-20 min. Dean-stark apparatus was assembled and the reaction mixture was heated at 140° C. for 12 h and cooled to ambient temperature. Reaction completion was judged by TLC. EtOAc was added to the reaction mass and filtered through the filter paper, to remove the inorganic material. Brine was added to the reaction mixture (filtrate) and extracted, dried over sodium sulphate and concentrated to get the crude material. Further it was purified by column chromatography using 10% EtOAc/Hexane system. Yield: 8.0 g (43%). 1H NMR (400 MHz, CDCl3): δ 1.38-1.42 (t, 3H, J=7.14 Hz), 4.37-4.42 (q, 2H, J=7.13 Hz), 5.2 (br s, 1H), 6.87-6.9 (q, 1H, J=3.81 Hz), 7.14-7.18 (q, 2H, J=5.82 Hz), 7.36-7.39 (d, 1H, J=8.80 Hz), 7.50-7.51 (d, 1H, J=2.56 Hz), 8.00-8.03 (m, 2H). LCMS: (ES+) m/z=301 (M+H).
Reaction SMILES: CC1C=C(OCCCN2CCOCC2)C=CC=1N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])=O.[NH4+]>[Fe].C1(C)C=CC=CC=1.O>[Cl:19][C:20]1[CH:21]=[C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:32]=[CH:33][C:34]=1[NH2:35]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1Cl
Agent: [Fe]
Agent: Cc1cc(OCCCN2CCOCC2)ccc1N
Agent: O=C[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(OCCN2CCOCC2)cc1Cl

Procedure:
2-Chloro-4-(2-morpholinoethoxy)aniline was prepared in a manner analogous to that used for 2-methyl-4-(3-morpholinopropoxy)aniline in Example 69. 4-(2-(3-chloro-4-nitrophenoxy)ethyl)morpholine was reduced using ammonium formate and iron powder in refluxing toluene-water mixture to give 2-chloro-4-(2 morpholinoethoxy)aniline in 87% yield. 1H-NMR (DMSO-d6) δ 6.53 (s, 1H), 6.40 (d, 1H), 6.29 (d, 1H), 5.85 (br s, 2H), 4.06 (t, 2H), 3.56 (t, 4H), 2.69 (t, 2H), 2.50 (t, 4H). (MS (EI): 257 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH:23](O)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(=O)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
1-Acetyl-4-piperidinone (77 g) was dissolved in dichloromethane (300 ml), and trimethylsilyltrifluoromethanesulfonate (200 ml) and benzhydrol (92 g) were added thereto with stirring under ice-cooling. The mixture was allowed to stand at room temperature overnight, and then water (500 ml) and sodium acetate (50 g) were added thereto and the reaction mixture was vigorously stirred. The dichloromethane layer was preparatively separated, washed with an aqueous sodium bicarbonate solution, dried, and then the solvent was evaporated under reduced pressure. The residue was treated with ethyl ether to obtain 1-acetyl-3-benzhydryl-4-piperidinone as colorless crystals (132.6 g, 86%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][C@@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CC#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)CCN)cc1
Reaction time: 20 h

Procedure:
To a solution of (R)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.4 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4. 0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (R)-3-hydroxy-4-(p-toluenesulfonyloxy)butylamine hydrochloride (18.4 g). Yield, 91 %.
Reaction SMILES: [OH:1][CH:2]([CH3:5])[C:3]#[CH:4].I[C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1.[OH-].[Na+].[NH4+].[Cl-]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Cu]I.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.C1C=CC=CC=1>[OH:1][CH:2]([CH3:5])[C:3]#[C:4][C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1
Reactant: C#CC(C)O
Reactant: Ic1ccc(-c2cccs2)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: c1ccccc1
Product: CC(O)C#Cc1ccc(-c2cccs2)s1
Yield: 93 %

Procedure:
To the mixture of 1 g (14.3 mmole) of 3-hydroxy-1-butyne, 10 ml of benzene and 2.78 g of 5-iodo-2,2'-bithiophene (9.52 mmole) was added 0.15 g of CuI, 0.15 g of benzyltriethylammonium chloride, 0.2 g of Pd(PPh3)4 and then 15 ml of NaOH solution (2.5 N) at room temperature and stirred for 2 hours. 4 ml of NH4Cl solution was then added. The reaction solution was extracted with ethyl acetate. The extract was washed with 10 ml of HCl (10%) for 3 times, 50 ml of water twice, and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel column chromatography. From the eluate of ethyl acetate/n-hexane (3/1) 2.07 g of yellow solid product (93%) was obtained.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH2:46][C:45]([F:48])([F:47])[CH2:44]2)=[N:41][CH:42]=1>>[F:48][C:45]1([F:47])[CH2:46][N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:44]1
Reactant: FC1(F)CN(c2ncc(Br)cn2)C1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(N3CC(F)(F)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(3,3-difluoroazetidin-1-yl)pyrimidine. LC (method 5): tR=1.7 min; Mass spectrum (ESI+): m/z=523 [M+H]+; 1H NMR (CD3OD) δ 0.94 (s, 3H), 1.25 (s, 3H), 1.54 (d, 3H), 2.14 (s, 2H), 2.20 (m, 1H), 2.46 (m, 2H), 3.03 (m, 1H), 4.51 (m, 4H), 5.57 (q, 1H), 7.07 (d, 2H), 7.25-7.40 (m, 7H), 8.60 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CO.[H][H]>[Pd].O1CCCC1>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][C:11]([O:13][CH3:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)cc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)cc(OC)c1N

Procedure:
A mixture of methyl 3,5-dimethoxy-2-nitrobenzoate (Ger 501,609, April 2, 1927; CA. 24, 47929) (39.0 g; 0.162 mole), 5% Pd on charcoal (2.0 g), methanol (200 ml) and tetrahydrofuran (200 ml) is shaken in an atmosphere of hydrogen at 52 lb pressure for 46 h when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from methanol. Yield 28.6 g; mp 93°-5°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling a -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20]C)=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:26](=[O:28])[CH3:27])OC(=O)C)[CH3:2].[Li].N.CO>O1CCOCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[C:26](=[O:28])[CH3:27])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@]2(OC(C)=O)C(C)=O
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2C(C)=O
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)-triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes and methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)[CH2:35][CH3:36])[CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](O)=[O:23])([CH3:16])([CH3:15])[CH3:14].[C:51]([O:70][NH2:71])([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O.C1COCC1>[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][CH:42]=1)[CH2:35][CH3:36])[CH:21]([C:22](=[O:23])[NH:71][O:70][C:51]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
WSC.HCl (683 mg, 3.49 mmol) was dissolved in water (1 mL) and the pH was adjusted to 4.8. The compound of Example 55 (300 mg, 0.582 mmol) was dissolved in the same amount of THF and added to the former solution. O-Trityl hydroxylamine (505 mg, 1.746 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The water phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, a saturated sodium hydrogen carbonate solution, and brine. The solvent was evaporated, following drying over sodium sulfate, and the crude was flashed with 30% ethyl acetate in hexanes. 1H NMR(CDCl3, 400 MH: 1.32(s, 9H); 1.50(m, 1H); 1.74(m, 1H); 2.32(m, 6H); 2.53(m, 2H); 3.46(m, 2H); 7.00(m, 1H); 7.16–7.57(m, 30H); FAB: 774(MH+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(SCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 63.7 %

Procedure:
A solution of ethyl 2-ethylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.35 g) in a methanol (7 ml) solution containing 1N NaOH (2.2 ml) was heated under reflux for 2 hours. After evaporation of the solvent, the aqueous residue was adjusted to about pH 3-4 with 1N—HCl to give crystals. The crystals were collected by filtration. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.21 g, 64%), m.p. 209-210° C. (decamp.).