Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([Br:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:7][C:6]1[C:2]([Br:1])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[Br:10]
Reactant: CCOC(=O)c1sc(Br)c([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(Br)c(N)c1Br
Temperature: 60 °C
Yield: 65.5 %

Procedure:
To the solution of Ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate (compound 34a, 10.0 g, 27.85 mmol) in acetic acid (100 ml) was added iron powder (7.77 g, 139.27 mmol). The reaction mixture was then heated at 60° C. for 35 min under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. Acetic acid from the reaction mixture was then evaporated under reduced pressure. The pH of the resulting reaction mass was brought to between 8 and 9 by adding to it saturated sodium bicarbonate solution. To the mixture so obtained was added ethyl acetate (150 ml), the resulting emulsion was filtered and then the organic layer was separated. The aqueous layer remaining behind was re-extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (6.00 g, 65.50%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1>CO.O>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[OH:20])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C)cc(C)c2c1C(O)C1CCCCC21
Yield: 106.5 %

Procedure:
6.0 Grams of sodium borohydride was added to a solution prepared by dissolving 15.0 g of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 300 ml of methanol and 50 ml of water and reaction was effected under ice-cooling for 4 hours. The solvent was distilled off and the residue was extracted with dichloromethane and then the extract was washed twice with saturated sodium chloride solution. Then, this was dried with magnesium sulfate and the solvent was distilled off to obtain 16.1 g of 5,7-dimethyl-8-methoxy-9-hydroxy-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[CH:9][N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CSC(=S)NN=Cc1nc[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncn2c(=S)[nH]ncc12

Procedure:
A suspension of 14.39 gm. of 3-(5-methyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in 100 ml. of diphenyl ether is reacted as described in Example 23 giving the desired product as yellow crystals, m.p. 262°-268° C.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[F:30][C:31]1[CH:42]=[CH:41][C:34]2[S:35][C:36]([CH:38]([NH2:40])[CH3:39])=[CH:37][C:33]=2[CH:32]=1>ClCCl>[F:30][C:31]1[CH:42]=[CH:41][C:34]2[S:35][C:36]([CH:38]([NH:40][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:39])=[CH:37][C:33]=2[CH:32]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)c1cc2cc(F)ccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1cc2cc(F)ccc2s1)C(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
5.1 g of N-methylpiperidine was added to a solution containing 10.4 g of N-isopropoxycarbonyl-L-valine dissolved in 200 ml of dichloromethane, at -20° C. and then 7.0 g of isobutyl chloroformate was added dropwise to the mixture. After the mixture was stirred at -20° C. for 10 minutes, 10.0 g of 1-(5-fluorobenzo[b]thiophen-2-yl)ethylamine was added to the mixture at -50° C. After stirring at the same temperature, the mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. After the reaction mixture was washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and water, the organic layer was then dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 12.3 g of the desired product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: C#CCN(C)C
Product: CN(C)CC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 49 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (113 mg) was coupled with 1-dimethylamino-2-propyne as in General Procedure 5 to give the title compound as a yellow solid (49% yield). M.p.=168° C., LCMS: m/z=375.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (6H, s), 3.38 (4H, m), 3.61 (2H, t, J=4.0 Hz), 4.40 (2H, s), 5.54 (1H, bs), 6.45 (1H, d, J=1.5 Hz), 7.21 (2H, m), 7.33 (1H, m), 7.61 (1H, d, J=1.5 Hz).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18]O.[OH-].[Na+]>CO>[C:1]1([CH:7]2[O:18][C:8]2([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=Cc1ccccc1)c1ccncc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C1(c2ccncc2)OC1c1ccccc1
Yield: 20 %

Procedure:
Using the procedure of Example A-1, step 2, a solution of 4-phenyl-3-(4-pyridyl)-3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated with 30% aqueous hydrogen peroxide (1 ml) in the presence of sodium hydroxide (230 mg, 5.7 mmol). The crude product was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (270 mg, 20%).
Reaction SMILES: [H-].[Na+].O1CC[CH2:5][CH2:4]1.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(I)C>C(OCC)C.O.CN(C)C=O>[C:8]([O:12][C:13]([N:15]([CH2:4][CH3:5])[C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN(C(=O)OC(C)(C)C)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Reaction time: 0.33 h

Procedure:
Under ice-cooling, 60% sodium hydride (43 mg) was added to a tetrahydrofuran (5.0 mL) solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.30 g), followed by stirring at the same temperature for 20 minutes. Ethyl iodide (0.087 mL) was added to the reaction mixture under ice-cooling, followed by stirring at the same temperature for 30 minutes and then at room temperature for 2 hours and 40 minutes. N,N-Dimethylformamide (3.0 mL) was added to the reaction mixture at room temperature, and then 60% sodium hydride (14 mg) and ethyl iodide (0.058 mL) were sequentially added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. Water and diethyl ether were added to the reaction mixture, and the organic layer was separated, washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 85-60% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:23][C@H:22]([OH:24])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C@H:20]3[CH2:21][C@H:22]([OH:24])[CH2:23]3)=[CH:18][CH:19]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Nc1ccc([C@H]2C[C@H](O)C2)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Nc1ccc([C@H]2C[C@H](O)C2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and trans-3-(4-aminophenyl)cyclobutanol (step 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:7]1[N:6]=[CH:5][C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(Br)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-(5-chloro-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (2.34 g, 7.5 mmol), N-bromosuccinimide (1.34 g, 7.5 mmol) and acetonitrile (75 ml) was stirred for 60 minutes. The crude mixture was evaporated and purified by chromatography on silica gel using ethyl acetate:petroleum (2:1) as solvent. Yield 2.5 g, 85%.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[O:32]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[OH:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[OH:32]
Reactant: COc1cc(CCCCC#CCCCC#CCOC2CCCCO2)c(OC2CCCCO2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCCC#CCCCC#CCO)c(O)c2ccccc12
Temperature: 60 °C
Yield: 125.2 %

Procedure:
The 2-(12-tetrahydropyran-2-yloxydodeca-5,10-diynyl-1-(tetrahydropyran-2-yloxy)-4-methoxynaphthalene (0.396 g) is dissolved in 50% methanol/tetrahydrofuran (5 ml) and para-toluenesulfonic acid monohydrate (39 mg) is added. The mixture is heated to 60° C. for 35 minutes at which time TLC indicates complete reaction. After cooling, solid sodium bicarbonate is added, and the solvent is evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to provide 0.335 g of a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:20][N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH:17]([CH3:18])[CH:16]([CH3:19])[O:15]2)=[CH:10][CH:9]=1>C(OCC)(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@@:14]2([CH2:20][N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[C@@H:17]([CH3:18])[C@@H:16]([CH3:19])[O:15]2)=[CH:12][CH:13]=1
Reactant: CC1OC(Cn2cncn2)(c2ccc(Cl)cc2)C1C
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C[C@H]1O[C@@](Cn2cncn2)(c2ccc(Cl)cc2)[C@H]1C
Yield: 57.7 %

Procedure:
A solution of 97.2 ml of oxalic acid in ethyl acetate was added dropwise to a solution of 300 mg (1.08 mmole) of 2R*, 3S*, 4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxetane (prepared as described in Example 20) in 5 ml of ethyl acetate, and the crystals which precipitated were collected by filtration. After drying, there were obtained 229 mg (yield 57.7%) of the title compound, melting at 135°-144° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH:16]=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+]>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:16][NH:2][CH3:1])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(c2ccc(Cl)cc2)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of methylamine in ethanol (18 ml, 33% in ethanol) and 4-(4-chlorophenyl)-4-formyl-piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.62 mmol) was stirred at room temperature overnight. The solvents were concentrated. The crude material was redissolved in methanol (18 ml) followed by addition of sodium borohydride (49 mg, 1.29 mmol). After stirring for 40 minutes at room temperature, the mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogen carbonate (100 ml). After separation of the two phases the aqueous phase was re-extracted with ethyl acetate (100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 10% methanol in dichloromethane gave 4-(4-chloro-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (142 mg, 0.42 mmol, 68%). GC-MS m/z 239 [(M-Boc)+], Rt 5.18 min. 1H NMR (250 MHz, CDCl3): 1.43 (9H, s), 1.80-1.88 (2, m), 2.15-2.24 (2, m), 2.31 (3H, s), 2.81 (2H, s), 2.98-3.09 (2H, m), 3.72-3.78 (2H, m), 7.32 (2H, d, 9 Hz), 7.38 (2H, d, 9 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45](O)=[O:46])[CH:40]=2)[CH2:35][CH2:34]1.[N+:48]([C:51]1[CH:59]=[CH:58][CH:57]=[C:56]2[C:52]=1[CH2:53][CH2:54][NH:55]2)([O-:50])=[O:49].C(N(CC)CC)C>CN(C=O)C.O>[N+:48]([C:51]1[CH:59]=[CH:58][CH:57]=[C:56]2[C:52]=1[CH2:53][CH2:54][N:55]2[C:45]([C:41]1[N:42]=[CH:43][N:44]=[C:39]([N:36]2[CH2:37][CH2:38][CH:33]([N:25]3[C:26]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[NH:32][C:24]3=[O:23])[CH2:34][CH2:35]2)[CH:40]=1)=[O:46])([O-:50])=[O:49]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: O=[N+]([O-])c1cccc2c1CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.470 mmol) TBTU were added to 150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 75 mg (0.46 mmol) 4-nitro-2,3-dihydro-1H-indole, 100 μL (0.712 mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto 30 mL water. The aqueous phase was extracted with DCM (3×20 mL). The combined organic phases were dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was dissolved in 3 mL DMF, filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C:13](=[O:35])[C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C:28](=[CH:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH2:20][CH2:19]4)[CH2:16][C@H:15]2[CH3:34])(=O)=O)=CC=1.[C:36]12([NH:46][C:47]3[N:52]=[C:51]([N:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:50]=[C:49]([N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)[N:48]=3)[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>>[C:36]12([NH:46][C:47]3[N:52]=[C:51]([N:53]4[CH2:54][CH2:55][N:56]([CH2:12][C:13](=[O:35])[C@@H:14]5[C@:31]6([CH3:32])[C@H:17]([C@H:18]7[C:28](=[CH:29][CH2:30]6)[C@:26]6([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]6)[CH2:20][CH2:19]7)[CH2:16][C@H:15]5[CH3:34])[CH2:57][CH2:58]4)[CH:50]=[C:49]([N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)[N:48]=3)[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2
Reactant: c1c(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(NC34CC5CC(CC(C5)C3)C4)n2)CC1
Yield: 79.94 %

Procedure:
The reaction of 21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione with 2-(1-adamantylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine as described in Example 6 gives the title compound in a yield of 79.94%, m.p.:155°-172° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[F:14])([OH:6])[CH2:4]Cl.C(=O)(O)[O-].[Na+].[CH2:20]([NH2:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[Cl:13][C:9]1[C:8]([F:14])=[C:7]([C:3]2([OH:6])[CH2:4][N:22]([CH2:20][CH3:21])[CH2:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCN
Reactant: OC(CCl)(CCl)c1cccc(Cl)c1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CC(O)(c2cccc(Cl)c2F)C1
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 1,3-dichloro-2-(3-chloro-2-fluorophenyl)propan-2-ol (0.88 g, 3.42 mmol), sodium bicarbonate (0.92 g, 10.95 mmol) and ethylamine in tetrahydrofurane (2.0 M, 1.82 ml, 3.64 mmol) in acetonitrile (15 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional ethylamine in tetrahydrofurane (2.0 M, 0.91 ml, 1.82 mmol was added and the mixture was heated at 120° C. for 30 min under microwave irradiation. Aqueous sodium carbonate (50 ml, 10%) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 ml), the pooled organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:4 to 1:1) to give the title compound (0.28 g, 35%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 172-173° C. MS m/z (relative intensity, 70 eV) 229 (M+, 1), 172 (29), 157 (56), 109 (41), 58 (bp).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2)[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCN1C(=O)CSC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)CSC1c1ccc(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 168 h
Yield: 15.9 %

Procedure:
In acetic acid (5 ml) was dissolved 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one (0.35 g), and 47% hydrobromic acid (5 ml) was added, then the mixture was stirred at room temperature for 7 days. After completion of the reaction, the mixture was poured into an ice-cooled 5% aqueous solution of sodium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 0.05 g (16%) of the title compound as a pale brown oil. NMR (CDCl3) (200 MHz) δ: 1.37 (9H, s), 1.2-1.9 (2H, m), 2.26 (3H, s), 2.1-2.5 (2H, m), 2.71 (2H, t, J=5.7 Hz), 2.6-3.0 (1H, m), 3.4-3.8 (1H, m), 3.67 and 3.80 (2H, ABq, J=16.0 Hz), 3.94 (2H, t, J=5.7 Hz), 5.60 (1H, s), 5.82 (1H, s), 5.88 (2H, s), 6.1-7.0 (5H, m), 7.14 (1H, s)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][CH2:18][C:19]=3[CH:24]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 2,3-dihydro-benzofuran-5-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at refulx over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 4H), 7.07 (m, 2H), 6.73 (d, 1H), 4.54 (t, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.66 (s, 3H), 3.18 (t, 2H), 2.94 (t, 2H), 2.63 (t, 2H); MS 326 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH2:17](I)[CH3:18].[ClH:20]>CN(C=O)C.CCOCC>[ClH:20].[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:17][CH3:18]
Reactant: CCI
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1ccc2c(N)cc(C(=O)OC)cc21
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (900 mg, 4,74 mmol, 1 equiv) in DMF (25 ml) at room temperature was added NaH (60% dispersion in mineral oil, 200 mg, 5 mmol, 1.05 equiv) and after 15 min ethyl iodide (400 μl, 5 mmol, 1.05 equiv). The resulting mixture was stirred for 30 min then most of the solvent was removed in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave an oil which was diluted with Et2O and treated with a 4N HCl solution in Et2O. The precipitate obtained was filtrated off to give methyl 4-amino-1-ethyl-1H-indole-6-carboxylate hydrochloride salt (D202) (800 mg, 66%) as a white solid. [M+H]+=219.0, RT=2.50 min.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>C(#N)C>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions, 50 g of O-benzylhydroxylamine hydrochloride is suspended in 783 ml of acetonitrile. To the suspension is added 50.6 ml of pyridine followed by dropwise addition of 43.15 ml trichloroethyl chloroformate in 235 ml of acetonitrile. The reaction is allowed to stir overnight at room temperature. The mixture is concentrated in vacuo and diluted with ethyl acetate. The organic layer is washed with 0.5N citric acid, water, saturated sodium bicarbonate, saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation (bp 150° C. at 0.5 mmHg.) to give 70 g of the desired product.