Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:25]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14]3)=[O:8])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1cccc2c1NC(c1ccccc1)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirred solution of 8-diphenylphosphinoyl-2-phenyl-1,2-dihydroquinoline (8) (1.2 g, 2.95 mmol) in EtOAc (40 mL) was added Pd/C (1.2 g, 100 wt %) and the suspension was stirred overnight at room temperature. The mixture was then filtered over celite and evaporated to give 9 (1.19 g) quantitatively as a white solid. 1H NMR (400.13 MHz, CDCl3) δ 8.63 (dd, 1H, J=14.0, 7.2 Hz, C7—H), 8.16 (dd, 1H, J=8.8, 1.2 Hz, C5—H), 7.86 (1H, d, J=8.4 Hz, C3—H), 7.91 (dd, 4H, J=12.4, 7.2 Hz, Ph-H), 7.81 (dd, 1H, J=8.4 Hz, C4—H), 7.65 (td, 1H, J=8.0, 2.0 Hz, C6—H), 7.5-7.2 (m, 11H, Ph-H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 156.2, 147.4 (d, J=6.1 Hz), 138.4, 137.7 (d, J=7.1 Hz), 136.8, 134.3, 133.2, 132.2, 132.1, 131.9, 131.0, 129.3, 128.3, 128.0, 127.8, 127.4, 125.9, 125.7, 118.7 ppm; 31P NMR (161.97 MHz, CDCl3) δ 27.7 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:18][CH3:19])[CH:11]=2)[O:17][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzyloxy-3'-methoxyacetophenone (2.00 g, 7.81 mmol), lithium bis(trimethylsilyl)amide (1.96 g, 11.71 mmol), chlorotrimethylsilane (1.48 mL, 11.71 mmol), THF (80 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 114°-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 3.86 (s, 1 H), 6.75 (s, 1 H), 7.21 (m, 7 H), 7.40 (m, 6 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:38].[N:39]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[C@@H:41]([NH:47][C:48]([C:50]1[O:51][C:52]3[C:58](Br)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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]>[ClH:38].[N:39]12[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46]1)[C@@H:41]([NH:47][C:48]([C:50]1[O:51][C:52]3[C:58]([C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][O:11][CH2:10][C:9]5=[O:14])=[CH:4][CH:3]=4)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2
Reactant: O=C1COCCN1c1ccc(Br)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCOCC4=O)cc3)c2o1

Procedure:
205.4 mg (0.70 mmol) of 4-(4-bromophenyl)-3-morpholinone (Example 16A), 204.4 mg (0.81 mmol) of bis(pinacolato)diboron, 171.2 mg (1.74 mmol) of potassium acetate, 19.6 mg (0.03 mmol) of PdCl2(dppf), 207 mg (0.54 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 1.34 ml of 2 M sodium carbonate solution and a further 19.6 mg (0.03 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 233 mg (85% of theory) of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C@H:24]([CH2:29][CH3:30])[CH2:25][C:26]([OH:28])=O)=[CH:19][CH:18]=1.[OH-].[Na+].C(OCC)(=O)C>CS(O)(=O)=O>[CH2:29]([C@@H:24]1[CH2:25][C:26](=[O:28])[C:19]2[C:20](=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:32])[F:31])[CH:18]=2)[NH:23]1)[CH3:30]
Reactant: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@@H]1CC(=O)c2cc(C(F)(F)F)ccc2N1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 44 %

Procedure:
Phosphorus pentoxide (600 g) was dissolved in methanesulfonic acid (6.0 liter) at below 40° C., the solution was added to the compound (1200 g) obtained in Example 1 (1) above and the mixture was stirred under nitrogen atmosphere at 65-75° C. for 3-4 hours. When the reaction was completed, the reaction mixture was cooled, 12N sodium hydroxide aqueous solution was added dropwise thereto at below 40° C. and the mixture was adjusted to pH 10-12. Ethyl acetate (6.0 liter) was added and the mixture was stirred, filtered and washed with ethyl acetate (6.0 liter). The filtrate was separated and the organic layer was washed with 25% ammonia water (1.8 liter) and water (1.8 liter). The organic layer was further washed with water (3.6 liter) and concentrated in vacuo at 45-55° C. of the bath temperature. The residue was dissolved in ethyl acetate (1.2 liter) and n-hexane (4.8 liter) at 50-70° C. and n-hexane (4.8 liter) was added dropwise at the same temperature. After cooled to below 10° C., the mixture was filtered and the crystalline was washed with chilled ethyl acetate/n-hexane=1/20 (1.2 liter). The wet product was air-dried or dried under reduced pressure at 45-55° C. and the titled compound was obtained (496 g, yield 44%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:21]=1[NH2:22].Cl>C(O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[C:21]([CH:23]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(Cl)cc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 68.2 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (100 mg, 0.385 mmol), 2-methoxy-5-chloroaniline (90 mg, 0.577 mmol) and 2N HCl (150 μl) in 1:1 ethanol/water (5 ml) was refluxed for 48 h. The resulting yellow solid was collected by filtration, washed with water, ethanol/water (1:4) and then dried under vacuum to give the title compound (100 mg, 67%). 1H NMR (CDCl3): 9.66 (d, J=1.8 Hz, 1H), 8.70-8.76 (m, 2H), 7.68 (dd, J=7.5, 1.0 Hz, 1H), 7.44 (dd, J=7.5, 1.0 Hz, 1H), 7.09 (dd, J=8.7, 2.7 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])C(O)=O.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:9][C:10]=1[F:11])[NH2:12]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Nc1ccc(F)c(F)c1

Procedure:
Following the procedure of Example 1B, the 4,5-difluoroanthranilic acid was decarboxylated by reaction with sulfuric acid, to form 3,4-difluoroaniline.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[S:12]1[C:16]2[S:17][CH2:18][CH2:19][C:20](=[O:21])[C:15]=2[CH:14]=[CH:13]1>C1C=CC=CC=1>[OH:21][C:20]1[C:15]2[CH:14]=[CH:13][S:12][C:16]=2[S:17][CH2:18][C:19]=1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=O)OC
Reactant: O=C1CCSc2sccc21
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(=O)C1=C(O)c2ccsc2SC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of sodium methoxide (21.6 g, 0.4 mole) and dimethyloxalate (47.2 g, 0.4 mole) in benzene (300 ml) is refluxed for 5 min. in order to dissolve most of the solid. To the cooled solution is added a solution of 5,6-dihydro-4H-thieno[2,3-b]-thiopyran-4-one (34 g, 0.2 mole) in benzene (300 ml) and the mixture is stirred for 3 hrs. to give a yellow suspension. The mixture is poured into ice-water mixture (1750 ml). After separating the aqueous layer from the benzene layer, the benzene layer is extracted with 1(N) NaOH solution (250 ml), and the combined aqueous solution is washed once with ether (100 ml) and acidified with (N) HCl. The yellow crystalline glyoxalate is filtered off and dried over P2O5 to give 45.8 g (91%) of the desired product; m.p. 53°-56° C.
Reaction SMILES: CO.[F:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]([C:23]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]=2[CH3:32])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:35]([F:38])([F:37])[F:36].[OH-].[Na+]>CCOC(C)=O.Cl>[F:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]([C:23]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]=2[CH3:32])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[CH:6][C:5]=1[C:35]([F:38])([F:36])[F:37]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)c2sc3ccccc3c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 3-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, condenser and thermocouple was charged with MeOH (1.9 L) and N-[4-fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carbomethoxy-benzenesulfonamide (190 g, 0.35 mol) followed by 3M NaOH (412 mL, 1.2 mol) and the resulting mixture refluxed for 2 h. The resulting mixture was then cooled to room temperature, diluted with EtOAc (2 L) and 1N HCl (2 L), the layers separated and the aqueous phase extracted with EtOAc (2 L). The organic extracts were combined, washed with brine (1.5 L), dried over Na2SO4, filtered and evaporated under reduced pressure to yield a yellow solid. The yellow solid was placed in vacuum oven for 18 h at 50° C. to yield N-[4-fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carboxy-benzenesulfonamide as a yellow solid. 1H-NMR (DMSO-d6) δ 13.63 (s, 1H), 8.19 (d, 2H), 8.01 (d, 2H), 7.86-7.83 (m, 1H), 7.71-7.63 (m, 3H), 7.49-7.37 (M, 3H), 4.89 (br s, 1H), 1.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.C(Cl)(Cl)Cl>C(O)C.O.NN>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: NCc1ccc(I)cc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 143.5 %

Procedure:
In a solution of 2.9 g of N-[(2-chloro-4-iodophenyl)methyl]phthalimide in 60 mL of ethanol, 3.0 mL of 80% hydrazine monohydrate aqueous solution was added, and stirred at 70° C. for 30 minutes. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 100 mL of chloroform was added therein and insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The procedure comprising adding 30 mL of chloroform in the residue, filtering off insoluble material and distilling off the solvent under reduced pressure was repeated twice to obtain 2.8 g of the aimed product as yellow oily substance.
Reaction SMILES: C([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28](N)=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)=O.[OH-:43].[Na+].O>CO>[NH:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28]([OH:43])=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(N4CCC5(CCCN5C=O)C4)cc3OC(C)C)nc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1c(C(=O)O)sc2cnc(Nc3ccc(N4CCC5(CCCN5)C4)cc3OC(C)C)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 76 mg of 2-{[4-(1-formyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide and 2 ml of 5N sodium hydroxide in 15 ml of methanol is stirred at ambient temperature for 3 hours, and then maintained at reflux for 1 h 30. The mixture is stirred at AT for 15 h and then again maintained at reflux for 5 h 30. The reaction medium is then run into 20 ml of water and then the methanol is eliminated by concentration under reduced pressure. The resulting aqueous phase is washed several times with dichloromethane (3 times 20 ml) and then acidified so as to obtain a pH with a value of about 7/8, and then the aqueous phase is extracted a further three times with 20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 72 mg of 2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid in the form of a brown solid.
Reaction SMILES: C(OC([NH:11][C:12]([NH:33]C(OCC1C=CC=CC=1)=O)=[N:13][CH:14]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=O)C1C=CC=CC=1>CCO.[Pd]>[C:20]([Si:17]([CH3:19])([CH3:18])[O:16][CH2:15][CH:14]([NH:13][C:12]([NH2:33])=[NH:11])[C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)N=C(NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)NC(=N)N
Yield: 106.1 %

Procedure:
To a solution of N,N′-bis(benzyloxycarbonyl)-N″-[2-(tert-butyl-dimethyl-silanyloxy)-1-(tert-butyl-dimethyl-silanyloxymethyl)-ethyl]-guanidine (12.48 g, 19.8 mmol) in 100 mL EtOH was added 5% Pd/C (0.5 g). The mixture was stirred under H2 at 50 psi. After 2 hours the mixture was filtered through a pad of celite and concentrated in vacuo to give N-[2-(tert-butyl-dimethyl-silanyloxy)-1-(tert-butyl-dimethyl-silanyloxymethyl)-ethyl]-guanidine (7.6 g, 106%) as a white foam: MS (M+H)=362.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:21][C:20]=1[F:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 180 °C

Procedure:
To a mixture of 2-methylindole (6.23 g, 47.5 mmol), 4-benzyloxy-3-fluoro bromobenzene (14.066 g, 50 mmol), potassium carbonate (5.83 g, 55 mmol), and N-methylpyrrolidinone (500 mL) was added copper (I) bromide (1.0 g, 7 mmol). The stirred solution was heated to 180° C. and maintained for 18 hr. The reaction mixture was cooled, poured onto ice and extracted with ethyl acetate. After washing the organic layer with water and brine, and drying over anhydrous MgSO4 the solvent was removed to yield a dark liquid, which was purified by silica gel chromatography (2% ethyl acetate-hexanes) to provide the title compound alley as a white solid (3.45 gr. 22% yd): mp 70-71° C.; 1H NMR (DMSO-d6): δ 2.26 (3H, s), 5.28 (2H, s), 6.39 (1H, s), 6.99-7.05 (3H, m), 7.21-7.24 (2H, m), 7.36-7.54 (7H, m)); MS m/z (M+H)+332: Anal. for C22H18NOF 0.1H2O: Calc'd: C, 79.31; H, 5.51; N, 4.20. Found: C, 79.29; H, 5.39; N, 4.16
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([NH2:17])=[C:9]([N+:18]([O-])=O)[CH:8]=1>[C].[Pd].CO>[NH2:17][C:10]1[C:9]([NH2:18])=[CH:8][CH:7]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccc(N)c1N

Procedure:
A mixture of 5 g 5% palladium-carbon, 2.8 liters of methanol, 59 g of potassium acetate (anhydride), and 138.4 g methyl 5-chloro-3-nitroanthranilate was subjected to hydrogen absorption with stirring and cooling with a water bath. When the hydrogen absorption was completed, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. To the residue were added ice and 1 lit mixture of n-hexane:ethyl acetate (6:4) and separated. The organic solvent layer was washed with saturated sodium bicarbonate solution, then washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated in vacuo to give dark brown crystals, m.p. 59°-61° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC[C@H](N)c3ccccc32)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., acetyl chloride (1 ml, 12 mmol) was added to a solution of the amine (B3) (3.2 g, 10 mmol) in dry acetonitrile (100 ml) followed by the dropwise addition of triethylamine. The reaction mixture was warmed to room temperature, stirred for 1 hour then concentrated. The residue was dissolved in ethyl acetate. The solution washed with saturated NaHCO3 and brine, dried and concentrated. The crude product was further purified by silica gel chromatography (CH2Cl2/CH3CN 9:1 to 7:3) to give (S)-tert-butyl 4-acetamido -3, 4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B4). LC-MS: m/e=359.3 (M+H), 303.3 (M+H−Me3CO). Rt=2.94 min. 1H-NMR (500 MHz, DMSO-d6): 8.17 (d, 1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86 (m, 2H), 2.97 (m, 2H), 2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H), 1.61 (m 2H), 1.48 (d, 1H), 1.42 (s, 9H).
Reaction SMILES: C[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7](OC)=[CH:6][CH:5]=2.[H-].[Na+].BrCCC[C:19](OC(C)(C)C)=[O:20]>>[CH:19]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1c[nH]c2ccccc12

Procedure:
Synthesis of the indoquinone-Naloxone linker involves multiple steps. Starting from 2-methyl-5-methoxyindole, alkylation on nitrogen with sodium hydride and t-butyl 4-bromobutanoate, followed by formylation provides the 3-formyl indole. After the nitration reaction, the 4-NO2 group is reduced to the amino group. Treatment with Fremy's salt produces the indoquinone structure. The 3-formyl group is reduced and converted to 4-NO2-phenyl carbonate compound A. Morphine is converted to the carbamate compound B through an activated carbonate intermediate. Compounds A and B are combined in the presence of an amine in DMF to provide the completed drug-linker unit after an acid catalyzed t-butyl ester hydrolysis (Scheme 9).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.O.[NH3:13]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:13])=[O:9])[N:6]=1
Reactant: N
Reactant: CCOC(=O)c1csc(N)n1
Solvent: O
Product: NC(=O)c1csc(N)n1
Yield: 76 %

Procedure:
3.0 g Ethyl 2-aminothiazol-4-carboxylate was added to 100 ml ammonia water, reacted for 2 hr, concentrated, and placed aside to precipitate a needle crystal, which was filtered, washed with water, and dried to obtain 1.9 g 2-aminothiazol-4-carboxamide (yield 76%) with mp 208-211° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48]([OH:50])=O.[N:55]1([CH2:61][CH2:62][NH2:63])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CC(N(C)C)=O>[Cl:54][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([Cl:44])[N:53]=1)[C:48]([NH:63][CH2:62][CH2:61][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:50]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
HATU (989 mg, 2.6 mmol), HOAT (354 mg, 2.6 mmol) and DIEA (907 μl, 5.21 mmol) were added to a stirred solution of 2,6-dichloroisonicotinic acid (500 mg, 2.60 mmol) in anhydrous DMA (4 ml). The mixture was stirred for 10 minutes after which 2-morpholin-4-yl-ethylamine (420 μl, 2.86 mmol) was added. The mixture was stirred at room temperature for 12 h and the mixture was partitioned between EtOAc and water. The EtOAc layer was washed well with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as an oil (830 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[N:26]=2)[N:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(OC)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 80 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
To N-(3-ethyl-1-((6-methoxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (210 mg, 0.492 mmol) in THF (6 mL) was added hydrochloric acid (4M in dioxane, 2 mL). The reaction vial was sealed, heated to 80° C. and stirred for 24 hours. The reaction was cooled to ambient temperature and saturated NaHCO3 aqueous solution was added until pH=7. THF and H2O were removed under reduced pressure. The resulting solid was washed with H2O (20 mL) and dried under vacuum to provide the desired product (198 mg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:16])=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:3].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]([C:4]1[C:5]([F:16])=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[O:7][CH2:8][C:9]([O:11][CH2:6][CH2:5][CH2:4][CH2:14][CH2:13][CH3:12])=[O:10])=[O:3]
Reactant: NC(=O)c1c(F)ccc(OCC(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 120.8 %

Procedure:
n-Bromohexane (0.077 ml, 0.55 mmol, 1.05 equiv.) was added to a suspension of 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetic acid (120 mg, 0.52 mmol, 1 equiv.) and K2CO3 (215 mg, 1.56 mmol, 3 equiv.) in DMF (3 ml) and the mixture was stirred at 70° C. for 1.5 h. After cooling at r.t., the mixture was poured into water (25 ml) and the precipitant solid was filtered and washed with water (2×20 ml). After drying, the crude solid was triturated by stirring in hexane (10 ml), filtered and washed with hexane (3×10 ml), to give the desired compound as a white solid (99 mg, 60%), mp 108° C. HPLC-MS: m/z 316 [M+H]+, Rt=4.09 min.