Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:26])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:27][C:28]([OH:32])([CH3:31])[C:29]#[CH:30].C(NC(C)C)(C)C>CN(C=O)C>[F:26][C:3]1[C:2]([C:30]#[C:29][C:28]([OH:32])([CH3:31])[CH3:27])=[CH:25][C:6]2[C:7]3[N:8]([C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 23 %

Procedure:
9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 2.5 mg (23% yield). M+1=424.2.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([NH2:14])=[O:13])[S:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:40][C:41]1[N:45]=[CH:44][O:43][N:42]=1.O>CN(C=O)C>[O:43]1[CH:44]=[N:45][C:41]([CH2:40][N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[NH:15][C:4]3[C:5]4[C:10]([CH3:11])=[C:9]([C:12]([NH2:14])=[O:13])[S:8][C:6]=4[N:7]=[CH:2][N:3]=3)[CH2:25][CH2:26]2)=[N:42]1
Reactant: Cc1nc(Nc2ccc(F)cc2OC2CCNCC2)c2c(C)c(C(N)=O)sc2n1
Reactant: ClCc1ncon1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(Cc4ncon4)CC3)c12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a suspension of methyl 4-(4-fluoro-2-(piperidin-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (0.06 g, 0.15 mmol) in DMF (2.0 mL) was added Hünigs base (0.06 mL, 0.35 mmol) and 3-(chloromethyl)-1,2,4-oxadiazole (0.035 g, 0.3 mmol) and the mixture was warmed to 60° C. for 18 hours. After cooling to ambient temperature water (2 mL) was added and the mixture stirred for 0.5 hours. The precipitated solid was collected by filtration and triturated from boiling MeCN. The solid was collected by filtration and dried under vacuum to give beige solid (0.046 g, 63%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[O:22][CH:23]=[CH:24][C:25]=1[C:26](O)=[O:27]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:26]([C:25]3[CH:24]=[CH:23][O:22][C:21]=3[CH3:20])=[O:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1occc1C(=O)O
Product: Cc1occc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-methylfuran-3-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 77% yield.
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[C:20]4[C:12]([C:13]5[C:18]([N:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2)C=CC=1>[Cu](I)I.ClCCl.O>[C:22]1([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=5[NH:19][C:20]4=3)[C:5]3[C:6]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2c(c1)N=c1c-2ccc2c1=Nc1ccccc1-2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5[nH]c4c32)cc1
Temperature: 190 °C
Reaction time: 72 h
Yield: 40.6 %

Procedure:
In a 1,000-ml three-necked flask that had been deaerated and filled with nitrogen were placed 26.0 g (101.4 millimoles) of indolo[2,3-a]carbazole, 122.7 g (601.4 millimoles) of iodobenzene, 54.7 g (287.2 millimoles) of copper iodide, 66.7 g (482.6 millimoles) of potassium carbonate, and 800 ml of quinoline and the mixture was stirred at 190° C. for 72 hours. The mixture was cooled to room temperature, 500 ml of water and 500 ml of dichloromethane were added, and the yellow crystals formed were filtered off. The filtrate was separated into an organic layer and an aqueous layer and the organic layer was washed three times with 500 ml of water. The organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solvent was stripped off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.7 g (41.2 millimoles, 40.6% yield) of 11-phenylindolo[2,3-a]carbazole as a white powder.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([N:10]([CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:13]=2[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[NH2:22][C:20]1[CH:19]=[CH:18][C:14]2[CH2:15][CH2:16][CH2:17][CH:11]([N:10]([CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12][C:13]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Yield: 82.8 %

Procedure:
A suspension of powdered iron (160 mg) and ammonium chloride (15 mg) in a mixture of ethanol (6 ml) and water (2 ml) was refluxed, and to this one was dropwise added (2S)-1-[N-benzyl-N-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (158 mg) in ethanol (3 ml). After being further refluxed for 1 hour, insoluble materials were filtered off. The filtrate was evaporated in vacuo. The residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1) to give (2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (122 mg).
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:8]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2=[N:3][C:4]3[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=4)=[CH:9][C:8]2=3)[CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)C(Cl)=Nc2ccccc2O3)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)C(N2CCOCC2)=Nc2ccccc2O3)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a stirring solution of title compound 69 (285 mg, 0.754 mmol) in toluene (5.0 mL) was added morpholine (1.00 g, 11.48 mmol) and the reaction mixture was stirred at 130° C. for 4 h. It was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography with 10%-30% ethyl acetate in hexanes to afford title compound 70 (223 mg, 69%) as a white solid. LRMS (ESI): (calc) 428.17. (found) 429.5 (MH)+. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.09 (d, J=8.6 Hz, 2H), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.71-7.69 (m, 3H), 7.40 (d, J=8.4 Hz, 1H), 7.17-7.01 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 3.90-3.75 (m, 4H), 3.60-3.48 (m, 4H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH3:16][N:17]1[CH2:21][CH2:20][CH:19](CS([O-])(=O)=O)[CH2:18]1.S([O-])(=O)(=[O:29])C>CN(C)C=O>[CH3:16][N:17]1[CH2:21][CH2:20][CH:19]([O:29][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH2:18]1
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS(=O)(=O)[O-]
Reactant: CN1CCC(CS(=O)(=O)[O-])C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a cooled suspension of sodium hydride (2.42 g of 60% content 0.06 mole) in 50 ml of dimethylformamide under nitrogen was added dropwise a solution of 10 g (0.055 mole) of 2-chloro-5-nitrobenzamide in 20 ml dimethylformamide. The suspension was stirred at room temperature for 1 hr and heated to 60° C. at which time 9.9 g (0.055 mole) of N-methyl-3-pyrrolidinylmesylate (freshly prepared) in 10 ml of dimethylformamide was added. The reaction mixture was heated to 135° C. for 24 hr. Since little product was observed, 9.9 g (0.055 mole) additional N-methyl-3-pyrrolidinylmesylate and 1.21 g (60% in oil, 0.03 mole) of sodium hydride was added. Heating was continued for 24 hr. Another 4 equivalents of the above mesylate was added after cooling the reaction mixture to 100° C. The reaction mixture was maintained at 100° C. for 24 hr. The dimethylformamide was removed by rotary evaporation at 60° C., 0.5 mm Hg. The residue was taken up in 400 ml of methylene chloride and washed with 3×200 ml of 1N sodium hydroxide and 2×200 ml water. The organic layer was extracted with 3×200 ml of 1N hydrochloric acid. The aqueous extracts were combined and washed with ~200 ml chloroform. The aqueous layer was made basic with concentrated sodium hydroxide and extracted with 2×300 ml of methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was crystallized from toluene to give 1.7 g (12%) of crude crystals. One recrystallization from toluene afforded light beige crystals, m.p. 215°-10° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH2:12][C:13](=[CH:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1460) in 2 mL of CDCl3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1461.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 151, step 3, 4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=467.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([C:12](OC)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(F)c2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cc2c(CO)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of methyl 7-fluoro-2-methyl-2H-indazole-4-carboxylate (2.10 g, 10.1 mmol) in tetrahydrofuran (101 mL) was slowly added a solution (1 M, 30.3 mL, 30.3 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (1.80 g, yield 99%).
Reaction SMILES: [C:1]([N:4]1[C@:8]([CH2:15][CH2:16][CH:17]=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:5]1)(=[O:3])[CH3:2].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][C@:8]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([C:1](=[O:3])[CH3:2])[N:5]=[C:6]([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH2:7]2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1N=C(c2cc(Br)ccc2F)C[C@@]1(CCC=O)c1ccccc1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc(Br)ccc3F)=NN2C(C)=O)CC1
Reaction time: 8 h

Procedure:
To a solution of 57 mg (0.137 mmol) 3-6 in 1.0 mL of anhydrous DCE under Ar was added 26.3 mg (0.206 mmol) 1-acetylpiperazine followed by 58.1 mg (0.274 mmol) sodium triacetoxyborohydride. The mixture stirred overnight before quenching with saturated aqueous NaHCO3 solution and adding a small amount of DCM. The aqueous phase was re-extracted with DCM and the organic phases were loaded directly onto silica gel for flash chromatography using a mixture of hexanes, EtOAc, and 20:1:1 EtOH—NH4OH—H2O to give 3-7 as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[OH-:10].[Na+].Br[CH2:13][CH2:14][CH2:15]Br.Cl>O>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:13][CH2:14][CH2:15][O:10][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:6][CH:7]=[CH2:8])=[O:4]
Reactant: BrCCCBr
Reactant: C=CCC(C)(C)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCC(C)(C)C(=O)OCCCOC(=O)C(C)(C)CC=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a mixture of 2.6 g (0.02 mole) of 2,2-dimethyl-4-pentenoic acid (XII) and 50 ml of hexamethylphosporic triamide a solution of 1.2 g (0.03 mole) of sodium hydroxide in 3.6 ml of water is added. The reaction mixture is stirred at room temperature for 1 hour and then 1.2 ml (2.4 g, 0.012 mole) of 1,3-dibromopropane are added. The mixture is stirred at room temperature for 4 hours, then poured onto 100 ml of 5 % aqueous hydrochloric acid and extracted twice with 50 ml of diethyl ether each. The organic phase is washed twice with 25 ml of water each, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The crude product thus obtained is purified by chromatography on a silica gel column eluted with a 7:3 mixture of hexane and diethyl ether. Thus 2.03 g of the desired compound are obtained in the form of a colourless oil. Yield: 68.5%. According to TLC chromatography using the above-specified eluent Rf =0.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[OH:12].[Br:14]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C.ClCCl.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([Br:14])[C:5]=1[OH:12]
Reactant: BrBr
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C=O)cc(Br)c1O
Reaction time: 17 h

Procedure:
To a solution of 5-formyl-2-hydroxy-benzoic acid methyl ester (7.93 g) in acetic acid (50 ml) and dichloromethane (40 ml), cooled to 0° C., was added bromine (2.49 ml). After stirring for 17 h, the mixture was allowed to reach room temperature. Sodium acetate (3.61 g) was added and stirring was continued for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H](C(O)=O)CC(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]1[CH2:26][CH2:25][O:24]CC1.ClC(O[CH2:31][CH:32]([CH3:34])[CH3:33])=O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:25](=[O:24])[C@H:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3 mmol) in THF, cooled to −40° C., was added N-methylmorpholine (3.68 g, 36A4 mmol; 4.0 mL) and isobutyl chloroformate (2.37 g, 17.3 mmol; 2.25 mL). After stirring for 15 min, ammonia was bubbled through the solution for 5 min. The solution was warmed to room temperature, evaporated brine, and the residue was dissolved in ethyl acetate, washed with 0.1 N Hcl, and saturated brine, then dried (MgSO4), filtered and evaporated to dryness to give the title compound as a white solid (4.58 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@H:21]([N:23]=[N+]=[N-])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N=[N+]=[N-])[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](N)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of 80C (410 mg, 1.10 mmol) and 10% Pd/C (100 mg) in MeOH:EtOAc (2:1, 15 mL) was stirred under hydrogen atmosphere for 2 h. The reaction was filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (10 g ISCO silica gel cartridge, 0-20% MeOH/DCM) to the title compound 80D (284 mg): MS (ES) m/z 345 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31].C(=O)([O-])O.[Na+].[ClH:40]>C(#N)C.C(O)C>[ClH:40].[CH2:30]([NH:32][C:33](=[O:34])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1)[CH3:31]
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CCNC(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 51 %

Procedure:
A suspension of 2.00 g (0.0067 mol) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 100 ml of acetonitrile was treated with 1.9 ml (0.013 mol) of triethylamine and 2.1 ml (0.027 mol) of ethyl isocyanate. The mixture was boiled under reflux for 20 hours and then poured into aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. After drying the organic phase with sodium sulphate and distillation of the solvent the residue was chromatographed over silica gel with methylene chloride/methanol 20:1. The oil obtained was dissolved in ethanol and treated with an equimolar amount of ethanolic HCl. After concentration the residue was dissolved in methylene chloride, treated with active charcoal and sodium sulphate, filtered and the solvent was distilled off in a vacuum. The residue was suspended in ethyl acetate, filtered off and dried in a vacuum. There were obtained 1.39 g (51%) of (+)-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl ethylcarbamate hydro-chloride with m.p. 133°-136°.
Reaction SMILES: [OH:1][CH:2]([C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3](N)=[O:4].[CH2:20]([OH:22])[CH3:21]>O>[OH:1][CH:2]([C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([O:22][CH2:20][CH3:21])=[O:4]
Reactant: CC(c1ccccc1)(c1ccccc1)C(O)C(N)=O
Reactant: CCO
Solvent: O
Product: CCOC(=O)C(O)C(C)(c1ccccc1)c1ccccc1

Procedure:
2.15 g (8.4 mmol) of 2-hydroxy-3,3-diphenylbutyramide were dissolved in 15 ml of ethanol, 15 ml of conc. HCI were added and the mixture was refluxed for 40 hours. The solvent was stripped off under reduced pressure, and the residue was taken up in water. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed twice with 10% strength sodium hydroxide solution. Drying with MgSO4 and stripping off the solvent under reduced pressure resulted in 1.75 g (73%) of ethyl 2-hydroxy-3,3-diphenylbutyrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](I)[CH3:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(Cl)ccc1C
Yield: 63.2 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (25.8g) and ethyl iodide (32.0 g) was heated at reflux in ethanol (500 mL) for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and water (300 mL). The organic phase was washed with water, dried over anhydrous MgSO4, then evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration and dried to give the title compound (17.0 g) as a yellow solid, m.p. 137°-139° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N,10.42. Found: C, 53.58; H, 4.74; N, 10.32. Mass spectrum (EI, M.+) m/z 268/270. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.45-7.49 (m, 1 H), 7.40-7.43 (m, 2 H), 4.35 (dd, 2 H), 3.07 (m, 2 H), 2.1 (s, 3 H), and 1.28 ppm (t, 3 H).