Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1>C(O)C.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A suspension of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]acrylic acid (100 mg, 0.30 mmol, 1 eq) and Pd(OH)2 (2.82 mg) in ethanol (1 ml) and THF (0.4 ml) is stirred at RT under a hydrogen atmosphere for 23 h. The reaction mixture is filtered and concentrated in vacuum on a rotary evaporator to obtain the compound in quantitative yield (100 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C=C/CCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC/C=C/C=C/C(=O)O
Temperature: 50 °C
Yield: 87.7 %

Procedure:
To a solution of the above ethyl ester (15) (140 mg, 0.52 mmol) in absolute EtOH (4 mL) was added LiOH—H2O (0.75 mL, 1.5 mmol, 2N solution in water). The reaction was heated at 50° C. for 1 h, then concentrated to remove excess EtOH. After acidification with 5% citric acid (20 mL), the product was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated to give a white solid (16) (110 mg, 88%). 1H NMR (400 MHz, CDCL3) δ 7.31 (dd, J=15.2, 10.8 Hz, 1H), 6.25 (dd, J=15.2, 10.8 Hz, 1H), 6.11 (quintet, J=7.2 Hz, 1H), 5.81 (d, J=15.2 Hz, 1H), 4.58 (br s, 1H), 3.24 (m, 2H), 2.37 (m, 2H), 1.44 (s, 9H); MS (ESI−) m/z 240.11 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)C[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 78.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-L-asparagine (0.020 g, 0.031 mmol) was dissolved in methanol (2 ml). NaBH4 (0.004 g, 0.106 mmol) was added and when the reaction was complete according to LC-MS a few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.016 g (80%) of the title product was obtained. NMR (400 MHz, CD3COOD) 2.62 (dd 1H), 2.73 (dd, 1H), 2.90-3.07 (m, 2H), 3.89-4.08 (m, 3H), 4.55 (dd, 1H), 4.60 (ABq, 2H), 4.78-4.85 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.09 (m, 6H), 7.24-7.38 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2(Cl)[CH2:13][CH2:12]2)=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=[O:8].[F:15]C1(C2C=C(C(OCC)=O)N(C)N=2)CC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:11]2([F:15])[CH2:13][CH2:12]2)=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C2(F)CC2)nn1C
Reactant: Cn1nc(C2(Cl)CC2)c(Cl)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C2(F)CC2)c(Cl)c1C(=O)O

Procedure:
The preparation was carried out analogously to the preparation of 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylic acid using ethyl 3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate and 5.0 eq of sodium hydroxide in methanol.
Reaction SMILES: [C:1]([CH:3]([Cl:17])[CH2:4][C:5](Cl)([Cl:15])[C:6](OC1C=CC=CC=1)=[O:7])#[N:2].[ClH:18]>S1(CCCC1)(=O)=O>[Cl:15][C:5]1[C:6]([OH:7])=[N:2][C:1]([Cl:18])=[C:3]([Cl:17])[CH:4]=1
Reactant: Cl
Reactant: N#CC(Cl)CC(Cl)(Cl)C(=O)Oc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: Oc1nc(Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A solution of 40.0 g (0.137 mole) of phenyl 4-cyano-2,2,4-trichlorobutyrate and 190 ml of anhydrous sulfolane in a glass lined pressure reactor was cooled to 0° C. in an ice-water bath, and charged with dry HCl gas (28 g) at 5° C. by passing dry HCl gas therethrough. The reactor was closed and the reaction mixture heated with stirring at 125° C. for 5 hours. After cooling to ambient temperature, the HCl gas was vented off and a clear brown solution was obtained. GLC analysis of the resulting solution indicated a yield of 78% (±1%) of 3,5,6-trichloropyridin-2-ol. The solution was poured into water and extracted with several portions of methyl t-butyl ether. The combined extract was washed with water and then stirred for 1 hour with 150 ml of aqueous 13% sodium carbonate solution. A white solid formed in the aqueous phase and was filtered off, washed with methyl t-butyl ether and dried to give 23.0 g of 3,5,6-trichloropyridin-2-ol sodium salt. By acidifying the above sodium salt with dilute aqueous HCl, it was quantitatively converted into a white powder consisting of 3,5,6-trichloropyridin-2-ol, m.p. 170°-171° C. This substance was found to be identical in all respects with an authentic sample of the material.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (2-methylpropanoyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (29a) (11 g, 22 mmol) dissolved in 120 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 3.9 g (60 mmol) of sodium azide (NaN3). After work-up, the crude material (29b) was used in the next step without further purification. MS (ESI) m/z 522.08 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17](C)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]([CH3:26])[C:13](=[N:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:37]I>O1CCCC1>[CH2:18]([N:17]=[C:15]1[N:14]([CH3:26])[C:13](=[N:27][C:28]2[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]1[CH3:37])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CI
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N(C)Cc3ccccc3)n2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=NCc3ccccc3)n2C)cc1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(N-methyl-N-benzylamino)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in tetrahydrofuran (20 ml) was added methyl iodide (2.58 ml). The solution was refluxed for 10 hours and cooled to ambient temperature. The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform to give 2-benzylimino-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.62 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)#[CH:37]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:37]#[C:36][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: C#Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C#Cc4ccc(F)cc4)cn3)c2CC1
Temperature: 65 °C
Yield: 94.2 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 2.07 mmol), tetrakistriphenylphosphine palladium(0) (120 mg, 0.104 mmol), cuprous iodide-(20 mg, 0.105 mmol), triethylamine (2.60 mL) and 1-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). Degas the mixture, purge with nitrogen, and heat at 65° C. for 3 days. Dilute the mixture with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (50:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a tan foam (1.02 g, 95%). MS (APCI+) m/z: 523 (M+H)+, 423 (M+H−Boc)+. Use a method similar to the General Procedure 14 to give the title compound as a tan powder. MS (APCI+) m/z: 423 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 94.9 %

Procedure:
To a solution of ethyl-3-aminobenzoate (50 mL, 333 mmol) and 2,6-difluorobenzenesulfonyl chloride (44.2 mL, 333 mmol) in DCM (300 mL) at 0° C. was added pyridine (32.2 mL, 400 mmol). The reaction mixture was warmed to rt, stirred for 36 h, and quenched with 2 mL NH3 (7 M in MeOH). The suspension washed with 10% NaHSO4 and the organic extracts combined and passed through a short column of silica gel. Residual material was flushed from the column with 10% MeOH/EtOAc. The organic extracts were combined and the solvent removed under reduced pressure to provide 107.9 g (95%) of the title compound of Step A. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.20 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.35-7.49 (m, 2H), 7.29 (t, J=9.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), and 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:10]([NH2:23])[CH:9]=2)=[O:5])C.O.[OH-].[K+]>C(O)C>[NH2:23][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][C:11]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
6-Amino-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (65, step E) (500 mg) is suspended in ethanol (15 mL). Water (10 mL) is added, followed by KOH (1M, 5 mL). The suspension is stirred at 75° C. for 2.5 h. The solvent is evaporated to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid.
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C1(C)C=CC=CC=1.C(=O)([O-])O.[K+].[CH2:30]([O:52]C(Cl)=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>CC(N(C)C)=O.C(Cl)(Cl)Cl.CO>[CH2:30]([O:52][NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCCCCCONc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
to a solution of 2.43 g of arabinofuranosylcytosine dissolved in 40 ml of dimethylacetamide, there is added 10 ml of a toluene solution containing 3.0 g of potassium hydrogen carbonate and 5.8 g of behenyloxycarbonyl chloride. The reaction is carried out at room temperature with stirring of the mixture for 4 hours. After completion of the reaction, the mixture is poured into ice-water and the precipitated solids are collected by filtration, followed by washing successively with acetone and with chloroform. The white solids obtained are dissolved in a mixture of chloroform-methanol and the resultant insolubles are filtered off. After removal of the solvent, the rersidue is subjected to precipitation from chloroform to obtain 2.0 g of N4 -behenyloxy-1-β-D-arabino-furanosylcytosine (Yield:35%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22](OC)=[O:23])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][OH:23])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCO)c2CC1
Temperature: -30 °C
Yield: 93.8 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (750 mg, 1.94 mmol) in THF (25 mL) at −78° C. under nitrogen, add 1M DIBAL in toluene (5.0 mL, 5.0 mmol) dropwise with stirring. Warm to −30° C. over 1 h and quench carefully with water. Extract with EtOAc, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (651 mg, 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[CH3:17][O-:18].[Na+]>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[C:2]([O:18][CH3:17])[CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nnc1Oc1ccccc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
In methanol (60 mL) was dissolved 3.00 g (11.8 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), 1.00 g (17.6 mmol) of 95% sodium methoxide was added to the solution at room temperature and the mixture was stirred at 60° C. for 4 hours. Moreover, 1.00 g (17.6 mmol) of 95% sodium methoxide was further added and after stirring the mixture at 60° C. for 1 hour, it was allowed to stand at room temperature overnight. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was successively washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=4:1) to obtain 2.75 g (11.0 mmol, Yield: 93.2%) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].O1CCCC1.O.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:34][CH2:31][CH:32]=[CH2:33])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid methyl ester (456.0 g, 1.008 mol) in a mixture of methanol (4.5 L), tetrahydrofuran (4.5 L) and water (1.13 L) was treated with allylamine (441.89 ml, 336.25 g, 5.88 mol) and stirred at room temperature for 30 min. (completion of reaction was confirmed by TLC-DCM:MeOH/9:1). The yellow colored suspension was filtered and washed with hexane to remove unreacted allylamine and dried to give the title compound as solid (yellow). Yield: 350g (50.90%), mp. 153–154° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@H:14]([CH2:15][CH2:16][C@H:17]2[CH2:21][OH:22])[C@H:13]2[C@H:4]1[C:5]1[CH2:6][CH:7]=[C:8]([O:23]C)[CH2:9][C:10]=1[CH2:11][CH2:12]2)[CH3:2].Cl.C(=O)([O-])O.[Na+].O>O1CCCC1>[CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@H:14]([CH2:15][CH2:16][C@H:17]2[CH2:21][OH:22])[C@H:13]2[C@H:4]1[C:5]1[CH2:6][CH2:7][C:8](=[O:23])[CH2:9][C:10]=1[CH2:11][CH2:12]2)[CH3:2]
Reactant: CC[C@H]1C[C@]2(C)[C@H](CO)CC[C@@H]2[C@@H]2CCC3=C(CC=C(OC)C3)[C@@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1C[C@]2(C)[C@H](CO)CC[C@@H]2[C@@H]2CCC3=C(CCC(=O)C3)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
xi)—A solution of (11β,14β,17α)-11-ethyl-3-methoxyestra-2,5(10)-diene-17-methanol (3.3 g) in tetrahydrofuran (30 ml) was treated with hydrochloric acid (2 M, 10 ml). The reaction mixture was stirred at room temperature for 30 min. and then neutralized with a saturated aqueous solution of sodium hydrogencarbonate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (11β,14β,17α)-11-ethyl-17-(hydroxymethyl)estr-5(10)-en-3-one (3.3 g). The product was used in the following step without further purification.
Reaction SMILES: [CH:1](=[C:8]1[NH:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]#[N:17])[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[C].[Pd]>[CH2:1]([CH:8]1[NH:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]#[N:17])[NH:10][C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#CCC1NC(=O)C(=Cc2ccccc2)NC1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#CCC1NC(=O)C(Cc2ccccc2)NC1=O
Yield: 91 %

Procedure:
2.91 g (0.0121 mol) of 3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine was dissolved in 80 ml of dimethylformamide and catalytically reduced with hydrogen at room temperature by adding 1.4 g of 10% palladium carbon. After reaction for 4 hours, the catalyst was removed by filtration, and the resulting filtrate was concentrated to obtained 2.68 g of 3-benzyl-6-cyanomethyl-2,5-dioxopiperazine. Yield: 91.5%. 1H NMR (d6 -DMSO) δ2.13 (dd, 1H), δ2.21 (dd, 1H), δ3.00 (dd, 1H), δ3.14 (dd, 1H), δ4.12 (m, 1H), δ4.29 (m, 1H, δ7.29 (m, 5H), δ8.32 (bs, 1H), δ8.41 (bs, 1H) MS (FAB):244 (MH+) mp:255°-256° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[C:34]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=5[O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:59])CC2)CC1>>[OH:59][CH:5]1[CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[C:34]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=5[O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][CH2:3]1
Reactant: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCCCCC6)CC5)cc34)c2c1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c2c1

Procedure:
This compound is synthesized from 4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121, see example 92) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][CH:16]=1)=[O:14]>CO>[NH2:1][C:2]1[N:6]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][CH:16]=2)=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCN(CC)c1ccc(C(=O)CBr)cc1
Solvent: CO
Product: CCN(CC)c1ccc(C(=O)Cn2c(N)nc3ccccc32)cc1
Yield: 36.4 %

Procedure:
A solution of 2-aminobenzimidazole (197 mg, 1.5 mmol) and 2-Bromo-4′-(diethylamino)acetophenone (402 mg, 1.5 mmol) in MeOH (7 mL) was stirred at r.t. for 18 hours. The volatiles were removed in vacuo and NaHCO3 (sat. aq., 30 mL) was added. The aqueous mixture was extracted with EtOAc (3×30 mL). The combined EtOAc extracts were dried with MgSO4 and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient up to 5:95 (MeOH:DCM) to isolate 2-(2-amino-1H-benzo[d]imidazol-1-yl)-1-(4-(diethylamino)phenyl)ethanone (176 mg, 36%) as a beige solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CO>[CH2:15]([N:9]1[C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water are added to a suspension of 83 g (0.5 mol) of 3-methylxanthine in 500 ml of methanol, the mixture is stirred at 70° C. for one hour, 85.5 g (0.5 mol) of benzyl bromide are then added dropwise at the same temperature and the reaction mixture is kept between 70° and 80° C. for 5 hours. It is then cooled and filtered cold with suction, the product on the suction filter is washed with water and dissolved in 1000 ml of 1N sodium hydroxide solution under the influence of heat, the solution is filtered and the pH is brought slowly to 9.5 with 4N hydrochloric acid, while stirring. The crystals are filtered off from the still warm solution, washed with water until free from chloride and dried in vacuo.