Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:32][C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:36]([F:39])([F:38])[F:37])[C:34]=1[CH3:35])#[N:29]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:36]([F:39])([F:37])[F:38])[O:32][C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 540 mg (1.48 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 500 mg (1.59 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 50° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 160 mg of a black powder (yield: 17.7%; mp: 176-178° C.)
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:5][CH:4]=1.[CH:16](=[O:18])[CH3:17]>O1CCCC1>[CH3:17][CH:16]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:5][CH:4]=1)[OH:18]
Reactant: CN1CCC(C)(C)c2ccc(Br)cc21
Reactant: CC=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
2 g of Magnesium shavings were covered with 20 ml of tetrahydrofuran. A solution of 20.8 g of 7-bromo-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline in 80 ml of tetrahydrofuran was added dropwise thereto at 55°-60° C. using an ultrasonics bath. Thereafter, the mixture was boiled at reflux for an additional 2 hours, cooled to 0° C. and a solution of 10 g of acetaldehyde in 80 ml of tetrahydrofuran was added dropwise thereto. After stirring at room temperature for 1 hour, the mixture was poured on to ice/saturated ammonium chloride solution and extracted with ether. The oil obtained after drying and evaporation of the solvent was filtered over a silica gel column (eluting agent hexane/ethyl acetate 9:1) and gave 14.5 g of 1,2,3,4-tetrahydro-α,1,4,4-tetramethyl-7-quinolinemethanol as a yellowish oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19](=[O:35])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:13][CH:12]=1)[N:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1.[Li+].[OH-]>CO>[C:31]([O:30][C:28]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:19](/[CH:18]=[CH:17]/[C:14]1[CH:13]=[CH:12][C:11]([CH:4]([N:5]2[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6]2)[C:3]([OH:36])=[O:2])=[CH:16][CH:15]=1)=[O:35])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)C(c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CCC(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(C(=O)O)N2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-(3-hydroxy-pyrrolidin-1-yl)-acetic acid methyl ester (1.23 g, 2.5 mmol) in MeOH (30 mL) was added aqueous LiOH (1 N, 10 mL), This mixture was stirred for about 5 h at room temperature, and then evaporated to remove most of the MeOH. The aqueous layer was acidified with concentrated HCl to pH 5-6. The acidified aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 0.85 g (81%) of a yellow solid product. MS: calc'd 482 (MH+), exp 482 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:12]=[C:11]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:30]=2)[CH:10]=1.P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=2)[N:12]=[C:11]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([OH:34])=[O:33])[CH:30]=2)[CH:10]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(=O)OC(C)(C)C)c2)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(=O)O)c2)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
TFA (1.17 ml, 15.2 mmol) was added to a stirred solution of tert-butyl [4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]acetate (330 mg, 0.76 mmol) in DCM (3.8 ml) at room temperature. The reaction mixture was stirred at 40° C. overnight. Upon cooling, the reaction mixture was poured into phosphate buffer pH 4 and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in Et2O to afford [4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-pyrazol-1-yl]acetic acid as a pale yellow solid. [M+H]+ 378. found, 378
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][S:5]2.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH:20][C:11](=[O:13])[CH2:10][C:7]2[N:8]3[CH:9]=[C:2]([CH3:1])[N:3]=[C:4]3[S:5][CH:6]=2)[S:18][CH:19]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: Cc1cn2c(CC(=O)O)csc2n1
Product: Cc1cn2c(CC(=O)Nc3scc(Br)c3-c3ncn[nH]3)csc2n1

Procedure:
The title compound was synthesized from 2-(6-methylimidazo[2,1-b]thiazol-3-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=8.520, method [6], MS (ESI) 423.0 (M+H); 1F1 NMR (300 MHz, CD3Cl) δ 8.12 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.0 (s, 1H), 4.15 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[NH2:17]>C(OCC)(=O)C>[CH3:24][O:23][C:19]1[CH:18]=[C:16]([NH:17][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:15]=[C:14]([O:13][CH3:12])[C:20]=1[O:21][CH3:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cc(O)ccc2[N+](=O)[O-])cc(OC)c1OC
Temperature: 100 °C
Reaction time: 10 h

Procedure:
3.7 g of 3-fluoro-4-nitrophenol and 4.76 g of 3,4,5-trimethoxyaniline were mixed and stirred for 10 hours at 100° C. After cooling, it was taken up in ethyl acetate and water and extracted three times with ethyl acetate. The combined organic phases were extracted three times with 1N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation to a very large extent in a vacuum. The product was digested with diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.C(OCC)(=O)C.Br[CH2:41][F:42]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:41][F:42])=[N:10]2)=[CH:7][CH:8]=1
Reactant: FCBr
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(OCF)nn2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol) and potassium carbonate (418 mg, 3.03 mmol) in bromofluoromethane (1 mL)-dimethylformamide (3 mL) was heated at 100° C. with stirring for 3.5 hours. After cooling, ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The desired product was triturated with hexane, isolated by filtration, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(fluoromethoxy)-1H-1,2,4-triazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:28]([C:25]1([NH:24][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:23])([CH3:22])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[CH:7][CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:27][CH2:26]1)([OH:30])=[O:29]
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cccc21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (374 mg, 1.0 mmol), copper(I) iodide (57 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309 mg, 3.0 mmol) and potassium carbonate (415 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (228 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 381.0.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].C(OCC)C>OS(O)(=O)=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(=O)[nH]c(N)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixture of 2-amino-6-methylpyrimidin-4(3H)-one (50 g, 0.4 mol) in 250 mL of H2SO4 at 0° C. was added 40 mL of HNO3 with an additional funnel. After being stirred at room temperature for 3 h, the reaction mixture was slowly poured into 3.6 L of diethyl ether and stirred for 15 min. Decant the ether solution and added 1.0 L of ethyl acetate to the solid and stirred for 10 h. The solid (54.8 g, 81% yield) was filtered and used for next step without any further purification.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)[O-])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)[N:19]=2)=[CH:22][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 150 mL) was added to a solution of N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate(4.75 g, 8.85 mmol) in dichloromethane (100 mL) at 0° C. 2 hours later, the ice-bath was removed and the solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The solid formed upon removal of organic solvent was collect by filtration to give trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.85 g, 100%). 1H NMR (DMSO-d6) δ 1.44(m, 2H), 1.96 (m, 6H), 2.21 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.83 (s, 3H), 4.60 (m, 1H), 5.03 (bs, 2H), 6.76 (d, J=7.91 Hz, 1H), 6.98 (d, J=7.89 Hz, 1H), 7.03 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]#[N:14])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:27])[NH2:14])=[N:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2c1CCC2
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 3.600 g (14.92 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile were dissolved in 37 ml of absolute methanol. 1.306 (24.17 mmol) of sodium methoxide were added and the mixture was stirred at RT for 4 h. 1.452 g (24.17 mmol) of acetic acid and 1.197 g (22.38 mmol) of ammonium chloride were added and the suspension was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was suspended in 100 ml of water and 25 ml of 1N hydrochloric acid. The mixture was extracted with dichloromethane. The aqueous phase was basified (pH=12) with 2N sodium hydroxide solution and extracted three times with a mixture of dichloromethane/methanol (v/v=8:2). The combined organic phases were dried with sodium sulphate and concentrated, toluene was added and the mixture was again concentrated to dryness. 1.94 g (50% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:33](O)[CH2:34][OH:35].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:35][CH2:34][CH2:33][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
A solution of 63.9 g of 3-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one in 460 ml of dichloromethane is stirred with 460 ml of ethylene glycol, 155 ml of trimethyl orthoformate and 1.2 g of para-toluenesulfonic acid for 3 hours at a bath temperature of 50° C. Then, it is diluted with dichloromethane, washed with sodium bicarbonate and common salt solution and dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene is obtained as oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)[CH3:28].[BH3-]C#N.[Na+].C(Cl)(Cl)Cl.CO>CCO>[CH3:12][C:10]1[CH:11]=[C:3]([CH2:2][NH:1][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[CH:4]=[C:5]2[C:9]=1[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cc(CN)cc2c1C(=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(CNC(C)c2ccccc2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 6 h
Yield: 44 %

Procedure:
A mixture of 5-aminomethyl-7-methyl-2-(4-trifluoromethoxybenzoyl)-2,3-dihydro-isoindol-1-one (0.053 g, 0.15 mmol), acetophenone (0.036 g, 0.30 mmol), Ti(i-OPr)4 (1 mL), and NaBH3CN (0.1 g, 1.6 mmol) in EtOH (2 mL) was stirred for 6 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-5-[(1-phenyl-ethylamino)-methyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.38 (d, 3H), 1.64 (bs, 1H), 2.73 (s, 3H), 3.62 (dd, 2H), 3.82 (q, 1H), 4.21 (s, 2H), 4.75 (s, 2H), 7.08-7.39 (m, 11H). GC-MS: m/z 439 (M-15)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:12]2[C:17]3[S:18][C:19]([C:21]4[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][N:31]5[CH2:35][CH2:34][NH:33][C:32]5=[O:36])[N:22]=4)=[CH:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+]=[N-].C(O)=O.NN.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Ni]>[NH2:1][CH2:4][C:5]1[C:6]([C:12]2[C:17]3[S:18][C:19]([C:21]4[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][N:31]5[CH2:35][CH2:34][NH:33][C:32]5=[O:36])[N:22]=4)=[CH:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Agent: [Ni]
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O=CO
Product: NCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.3 %

Procedure:
To a solution of 1-(2-{4-[7-(5-azidomethyl-2-fluoro-pyridin-4-yl)-benzo[b]thiophen-2-yl]-5-fluoro-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (105 mg, 0.3 mmol) in ethanol (10 mL) in a round bottom flask add 2 g hydrazine formic acid salt (1:1) and 0.5 g of Raney Nickel. Stir the mixture for 3 hours at room temperature. Pour the reaction mixture diluted sodium carbonate solution. Abstract the product into chloroform, and wash with water and saturated aqueous sodium chloride. Separate organic layer from aqueous layer and dry over Na2SO4. After filtration, evaporate the organic solvent in vacuo to give a crude product. Purify the crude with flash column chromatography (chloroform/methanol/ammonium hydroxide, 7/3/0.05) to give the title compound as a yellow solid (0.50 mg, 53%). MS (ES) m/z 482 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20]=2[CH2:21][O:22][CH3:23])=[C:17]([O:24][C:25]2[N:30]=[CH:29][CH:28]=CN=2)[CH:16]=[CH:15][CH:14]=4)[O:5][N:4]=1)[CH3:2].ClC1C=C[C:35](OC2C=CC=C3C=2C2C(COC)=C(C4ON=C(CC)N=4)N=CC=2N3)=[N:36]C=1.C(OC(C)C)(C)C>CCO>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20]=2[CH2:21][O:22][CH3:23])=[C:17]([O:24][C:25]2[CH:35]=[N:36][CH:28]=[CH:29][N:30]=2)[CH:16]=[CH:15][CH:14]=4)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ncccn5)c4c3c2COC)n1
Reactant: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cn5)c4c3c2COC)n1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCc1noc(-c2ncc3[nH]c4cccc(Oc5cnccn5)c4c3c2COC)n1

Procedure:
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methoxymethyl-5-(2-pyrimidinyloxy)-β-carboline, mp 175°-176° C. (EtOH), 5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-3-(3-ethyl1,2,4-oxadiazol-5-yl)-β-carboline, mp 144°-146° C. (diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25])[C:19]([Cl:30])=[CH:18][N:17]=1>>[Cl:30][C:19]1[C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CC(C)[C@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Product: CC(C)[C@H](Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl)C(N)=O

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and (S)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide were converted to (S)-2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methyl-butyramide, HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.51 (dd, 1H), 7.39 (m, 2H), 4.52 (m, 3H), 3.41 (s, 3H), 3.11 (t, 2H), 2.32 (m, 1H), 1.08 (d, 3H), 1.02 (d, 3H); MS (m/e) 419 (M+1).