Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(C(=O)O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-methoxycarbonylphenyl)carboxamide was dissolved in methanol (3 ml), 33% aqueous potassium hydroxide (1.5 ml) was added, and the admixture was stirred at room temperature for 2 hours. The reaction mixture was washed 2 times with ethyl acetate, and the water layer was neutralized with dilute hydrocholoric acid and extracted 2 times with chloroform. The chloroform layer was dried with sodium sulfate, and the solvent was then removed by reduced-pressure distillation to obtain 34 mg of the title compound (yield: 45%).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[C:19]([CH:24]=[C:25]([Cl:27])[N:26]=2)[C:20](OC)=[O:21])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)(C)C>[Cl:27][C:25]1[N:26]=[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:16][CH2:15]2)[CH:18]=[C:19]([C:20]([NH:1][NH2:2])=[O:21])[CH:24]=1
Reactant: NN
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(=O)NN)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Hydrazine (0.55 ml 17.0 mmol) was added to a solution of methyl 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-chloroisonicotinate (Intermediate 23, 0.15 g, 0.40 mmol) in isopropanol (3 ml). The mixture was stirred at room temperature overnight then the isopropanol was removed in vacuo to give the title product (130 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH2:20]1COCC1.C([Mg]I)C.O>C(OCC)C>[OH:18][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21
Agent: CC[Mg]I
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C(C)(O)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.1 g (12 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid and 50 ml of THF are introduced into a three-necked flask. At 0° C. and under a stream of nitrogen, 16 ml (48 mmol) of a solution of ethylmagnesium iodide in ethyl ether (3M) are added dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (20:80). After evaporation of the solvents, 2.6 g (79%) of the expected product, melting point 168°-169° C., are collected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:34][C:29]4[NH:30][C:31]5[C:27]([CH:28]=4)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:33][CH:32]=5)[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-Pyridin-3-yl-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([CH3:43])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)=[CH:5][C:6]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[C:7]([N:9]([CH3:21])[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH:8]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[C:4]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([CH3:43])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)=[CH:5][C:6]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[C:7]([N:9]([CH3:21])[CH2:10][CH2:11][NH:12][CH3:13])[CH:8]=1
Reactant: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCNC
Yield: 41.2 %

Procedure:
A solution of tert-butyl N-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-(prop-2-enoylamino)phenyl]-methylamino]ethyl]-N-methylcarbamate (Intermediate 170, 321 mg, 0.55 mmol) in CH2Cl2 (10 mL) and TFA (2 mL) was stirred at r.t. for 0.5 h and then concentrated in vacuo. The residue was dissolved in 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (110 mg, 41%) as a pale yellow solid after trituration with diethyl ether; 1H NMR: 2.35 (3H, s), 2.58-2.62 (2H, m), 2.71 (3H, s), 2.85-2.89 (2H, m), 3.86 (3H, s), 3.92 (3H, s), 5.74 (1H, dd), 6.28 (1H, dd), 6.59 (1H, dd), 6.99 (1H, s), 7.15 (1H, t), 7.21-7.27 (2H, m), 7.53 (1H, d), 7.87 (1H, s), 8.24 (1H, d), 8.32 (1H, d), 8.66 (1H, s), 9.16 (1H, s), 10.33 (1H, s); m/z: ES+ MH+ 486.55.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 3-trifluoromethyl-phenylamine (1 eq.) and ethyl 4-bromobutyrate (2 eq.) in DMF were added K2CO3 (3 eq.) and KI (cat.). The mixture was heated at 100° C. for 16 h, water and EtOAc were added, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 70/30) to afford 4-(3-trifluoromethyl-phenylamino)-butyric acid ethyl ester as a yellow oil.
Reaction SMILES: CC1(C)CCC2([C:8](=[O:9])[O:7][C:6](=[O:10])[CH2:5]2)C1.[CH3:14][C:15]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]1=O>>[CH3:14][C:15]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]21[C:8](=[O:9])[O:7][C:6](=[O:10])[CH2:5]2
Reactant: CC1(C)CCC2(CC(=O)OC2=O)C1
Reactant: CC1(C)CCCC1=O
Product: CC1(C)CCCC12CC(=O)OC2=O

Procedure:
The title compound was prepared using methods analogous to 7,7-dimethyl-2-oxaspiro[4.4]nonane-1,3-dione using 2,2-dimethylcyclopentanone in Step A. 1H NMR (500 MHz, DMSO-d6) δ 3.18-2.94 (m, 2H), 2.34-2.18 (m, 1H), 1.98-1.64 (m, 4H), 1.62-1.48 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16](F)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(=O)[NH:27]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.O>[NH2:27][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(F)c(F)cc2F)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(F)cc2F)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(3,5,6-trifluoro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.59 g, 5 mmol, Example 39a), potassium phthalimide (0.93 g, 5 mmol, Aldrich) in DMF (20 mL) was heated at 140° C. with stirring for 16 h. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with EtOAc (2×70 mL). The combined organic extracts were dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 20% EtOAc in hexane to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 315 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[O:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:43]=[C:42]1[CH2:50][NH:51][CH3:52].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:51]([CH2:50][C:42]2[O:41][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH:43]=2)[CH3:52])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CNCc1cc2ccccc2o1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN1CCN(Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4o3)cnc2N)CC1
Yield: 20 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting benzofuran-2-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (158 mg, 20%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.35-8.33 (m, 2H), 7.99 (br s, 2H), 7.62-7.19 (m, 6H), 6.82 (d, J=12.2 Hz, 1H), 5.01-4.80 (m, 2H), 3.62-3.25 (m, 6H), 3.22 (s, 2H), 3.10-2.92 (m, 5H), 2.73 (s, 3H); MS (ESI) m/e 420 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=1.[H-].[Na+]>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:19]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a reaction flask, tert-butyl 4-hydroxypiperidine-1-carboxylate (2.02 g, 10.0 mmol) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (2.18 g, 10.0 mmol) were dissolved in THF (19.7 mL) and cooled to 0° C. Sodium hydride (0.603 g, 15.1 mmol) was added and then the mixture was stirred for 30 minutes at 0° C. and at 25° C. for another 16 hours. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, brine, dried over MgSC4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the product.
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.[F-:19].[K+].[CH:21]1([CH2:24][N:25]2[C:31]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=3[C:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:28][CH:27](OS(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[O:54])[CH2:23][CH2:22]1>C(#N)C>[CH:21]1([CH2:24][N:25]2[C:31]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=3[C:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:28][CH:27]([F:19])[C:26]2=[O:54])[CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OC2N=C(c3ccccc3)c3cc(Cl)ccc3N(CC3CC3)C2=O)cc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=C1C(F)N=C(c2ccccc2)c2cc(Cl)ccc2N1CC1CC1
Reaction time: 0.5 h

Procedure:
To 5.4 g. of 1,4,7,10,13,16-hexaoxacyclooctadecane dissolved in 50 ml. of dry acetonitrile is added, with stirring, 1.4 g. of anhydrous KF. After 30 minutes, 4.95 g. of 1-cyclopropylmethyl-3-p-toluenesulfonyloxy-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, obtainable by tosylation of the 3-hydroxy compound, in 50 ml. of dry acetonitrile are added. The mixture is stirred for 2 hours more and is worked up in the customary manner to give 1-cyclopropylmethyl-3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1>C(O)C.C(OCC)C.[Pd]>[CH3:12][S:9]([NH:8][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
N-[2-(4-{N-Benzylmethanesulphonamido}phenyl)-2-hydroxyethyl]-N-methyl-2-(phthalazin-1-on-2-yl)ethylamine (0.4 g--as solvate from part D) in ethanol (50 ml) containing 5% Pd/C (0.1 g) was stirred under a hydrogen atmosphere (50 p.s.i.) at 50° for 18 hours. The reaction mixture was then filtered and the ethanol removed. The residue was dissolved in methylene chloride and washed three times with sodium bicarbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). The appropriate fractions were combined and evaporated to give an oil which solidified after stirring for 14 hours in diethyl ether, filtration giving the title compound, 0.11 g, m.p. 134°-137°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28].ClCCl>C(#N)C.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:27]([OH:29])=[O:28])[CH:3]=2)[NH:8][N:9]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 62 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (997 mg, 2.30 mmol) in acetonitrile (15 mL) and saturated aqueous NaHCO3 (10 mL) in a microwave vial was added 3-carboxyphenylboronic acid, pinacol ester (625 mg, 2.52 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (94 mg, 0.12 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 90° C. for 1500 seconds. The acetonitrile was removed via rotary evaporation. Ethyl acetate was added and then separated from the aqueous layer. The organic layer was dark brown and LC/MS showed that the product remained in this layer. Concentrated down to a dark brown oil and redissolved in a 5% perchloric acid in acetic acid solution (10 mL). The reaction solution was stirred 4.5 hours at ambient temperature. The perchloric acid was removed via rotary evaporation and then ethyl acetate and H2O were added. Sodium bicarbonate powder was added until pH=3. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to afford a brown powder (580 mg, 62% yield). 1H NMR (500 MHz, d6-DMSO) δ 13.81 (br s, 1H), 8.81 (d, J=2.5 Hz, 1H), 8.31 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.59 (m, 2H), 7.41 (t, J=7.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 3.80 (s, 3H). MS: m/e 346.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.[OH-:17].[Na+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].O>[NH2:16][C:4]1[CH:3]=[CH:2][C:15]([C:15]2[CH:2]=[CH:3][C:4]([NH2:16])=[C:5]([C:6](=[O:17])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=2)=[CH:14][C:5]=1[C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: [Na+]
Solvent: C1=CCCC=CCC1
Solvent: O
Product: Nc1ccc(-c2ccc(N)c(C(=O)c3ccccc3)c2)cc1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
4-Bromo-2-aminobenzophenone (0.55 g, 2.0 mmol) was dissolved in dry and deoxygenated dimethylformamide (10 ml) in an inert atmosphere box. To this was added in portions bis(1,5-cyclooctadiene)nickel (O) (0.55 g, 2.0 mmol). The reaction was moved from the inert atmosphere box to a vacuum-argon manifold using standard Schlenk-wave techniques. The reaction was heated at 5°-55° C. for 4 hrs. and left at room temperature overnight. The mixture was poured into 200 ml of water which was made slightly basic with sodium hydroxide. The water was extracted several times with ethyl acetate which after drying with sodium sulfate and evaporation gave a dark brown liquid (0.48 g). Recrystallization from hexane yielded 100 mg of yellow brown solid mp 180°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.[Na+].[I-]>C(#N)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([O:21][Si:30]([CH3:33])([CH3:32])[CH3:29])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12
Reaction time: 1.5 h

Procedure:
20.3 g (72 mmol) of 3-methoxy-estra-1,3,5(10)-trien-17-one is suspended with exclusion of moisture in 80 ml of acetonitrile (P2O5 and molecular sieve dried) and mixed with 17.4 ml of triethylamine (125 mmol, dried on KOH) as well as with 12.24 ml of trimethylchlorosilane (96 mmol) at an inner temperature of 35° C. Then, an NaI solution, which contains 15 g of NaI (96 mmol) in 100 ml of acetonitrile (NaI dried at 140° C. in a vacuum), is instilled in this suspension, so that the reaction temperature is kept at 35° C. without external heating. The reaction performed under nitrogen is performed with vigorous stirring. It is seen that after the addition has been completed, the amount of undissolved initial product becomes smaller. Later, the crystals completely disappeared. After 1.5 hours, the silyl enol ether begins to crystallize. After 4 hours, the crystal suspension is stirred in ice water, to which some triethylamine was added. Then, it is fritted, rewashed with water, sucked dry and the substance dried on P2O5 in a vacuum. 25.4 g of silyl enol ether, which can be recrystallized from hexane or methanol, is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]3[N:30]=[C:29]([N:31]([CH3:33])[CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:34][C:35]([F:38])([F:37])[F:36])[CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+].[C:47]1(B(O)O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:32][N:31]([CH3:33])[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([NH:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:3][C:4]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:10])=[O:9])[CH2:14][CH2:15]2)[N:30]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(-c4ccccc4)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 130 °C
Reaction time: 10 h

Procedure:
To a solution of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide obtained in step H of example 1 (122 mg, 0.198 mmol) in toluene (2.7 mL) were added MeOH (0.9 mL), 2 M aqueous K2CO3 (0.9 mL), phenylboronic acid (29.0 mg, 0.237 mmol), and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol). The reaction mixture was stirred at 130° C. for 10 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography H-silica gel, 25% EtOAc in hexane and silica gel, 9% MeOH in CHCl3) to give trans-3-trifluoromethoxy-biphenyl-4-sulfonic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide (77 mg, 0.125 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH:6]=[N:5]2.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[N:5]2
Reactant: Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1

Procedure:
A mixture of 3-[N-(6-chloroquinoxalin-2-yl)amino]phenol (10 mmole), ethyl 2-bromopropionate (10 mmole), anhydrous potassium carbonate (2 g) and methyl ethyl ketone (100 ml) was heated under reflux for a period of 12 hours. The reaction mixture was filtered and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over alumina (eluent dichloromethane) to give ethyl 2-{3-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.