Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[Cl:18].ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:18][C:11]1[CH:12]=[C:13]([CH:14]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:15])[CH:16]=[CH:17][C:10]=1[F:9]
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared starting from 5.00 g (26.12 mmol) of 4-chlorobromobenzene and 4.97 g (31.34 mmol) of 4-fluoro-3-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 5.57 g (77% of theory) of the title compound were obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.Cl.[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][N:43]([C:1](=[O:3])[CH3:2])[CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)cs2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Added acetic anhydride (0.0169 g, 0.165 mmol) to a mixture of 3-phenoxy-N-(4-(piperidin-4-ylmethyl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.100 g, 0.165 mmol), triethylamine (0.0837 g, 0.827 mmol), and THF (5 mL) at 0° C. Warmed to ambient temperature and stirred for 4 hours. Partitioned between ethyl acetate and 2N NaOH, washed with water, brine, dried, and concentrated. The residue was dissolved in dichloromethane (2 mL) and 1N HCl in ether was added. Diluted in hexanes, and concentrated, added hexanes again and concentrated to afford the title compound ((Mixture of rotamers; 0.092 g, 91.2% yield) as a light yellow powder: 1H NMR (d6-DMSO) δ 8.65 (d, 1H); 8.47 (d, 1H), 8.46 (s, 1H), 7.77 (d, 1H), 7.41 (s, 1H), 7.41 (d, 2H), 7.15-7.20 (m, 4H), 6.84 (s, 1H), 0.95-4.36 (m, 1H), 1.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14](O)=[O:15]>>[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Yield: 92.9 %

Procedure:
Using p-anisidine (738 mg, 6.0 mmol) and 3-methyl-4-nitrobenzoic acid (906 mg, 5.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.33 g (93.0%) of the title compound in the form of yellow powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:3][OH:2])[CH:10]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(Cl)c(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=252.0 ([M−H]−) was obtained as a light brown oil (94% yield) by the reaction of 4-(3,4-dichloro-phenyl)-pyridine-2-carboxylic acid methyl ester with 1M lithium aluminum hydride/THF solution in THF at 20° C. for 1 h followed by chromatographic purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:25]([CH2:34][CH2:35][CH3:36])[CH2:24][N:23](C(OCC[Si](C)(C)C)=O)[CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][O:20][CH:21]2[CH:26]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:25]([CH2:34][CH2:35][CH3:36])[CH2:24][NH:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC1CN(C(=O)OCC[Si](C)(C)C)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCCC1CNCC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 5, by treating 2-trimethylsilanylethyl (3RS,4RS, 5SR)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine-1-carboxylate with tetrabutylammonium fluoride solution there was obtained (3RS,4RS,5SR)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine as an almost colourless solid, MS: 484 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O (7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-methylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (dd, J=7.9, 0.8, 1H), 8.04-8.02 (m, 1H), 8.01-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.26 (d, J=8.0, 2H), 7.16 (d, J=7.9, 2H), 3.87-3.78 (m, 4H), 3.61 (s, 2H), 3.13-3.05 (m, 4H), 2.30 (s, 3H); MS (ESI+) M/Z 379 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)C(N)=O.[C:8](N)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(=O)[NH:21][C:20](=O)[C:19]2=CC=CC=[C:18]12>>[OH:15][CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]([NH2:21])[CH2:19][CH2:18]1
Reactant: NC(=O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NC(=O)C(Cl)(Cl)Cl
Product: NC1CCC(O)c2ccccc21

Procedure:
Similarly, the corresponding trichloroacetamide, benzamide and phthalimide are hydrolyzed to afford the title compound.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=O)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(COC)OC>[CH2:1]1[CH:13]2[CH:4]([C:5](=[S:24])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: S=C1Nc2ccccc2C2CCCC12
Reaction time: 3 h

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinolin-4-one (153 mg, 0.82 mmol) and Lawesson's reagent (363 mg, 0.9 mmol) are stirred in dimethoxyethane (20 ml) at room temperature. After 3 hours, another portion of Lawesson's reagent (363 mg, 0.9 mmol) is added to it. After 3 hours, the batch is concentrated by evaporation, and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH:10](C)[NH:9]2)=[CH:4][CH:3]=1.ClC1C=CC(N2C(=O)C(=O)C(C3C=CC=CC=3)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C3C=CC(C)=CC=3)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C3C=CC=C(OC)C=3)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C3C=CC(OC)=CC=3)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C3C=CC=C([N+]([O-])=O)C=3)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(OC)N2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH2:10][NH:9]2)=[CH:6][CH:7]=1
Reactant: CC1NN(c2ccc(Cl)cc2)C(=O)C1=O
Agent: COC1NN(c2ccc(Cl)cc2)C(=O)C1=O
Agent: COc1ccc(C2NN(c3ccc(Cl)cc3)C(=O)C2=O)cc1
Agent: COc1cccc(C2NN(c3ccc(Cl)cc3)C(=O)C2=O)c1
Product: O=C1CNN(c2ccc(Cl)cc2)C1=O

Procedure:
1-(4′-chlorophenyl)-3-methyl-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-phenyl-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-methoxy-4,5-pyrazolinedione;
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccccc3)CC2)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 125.2 %

Procedure:
A mixture of 3.72 g (0.02 mol) of ethyl 6-chloronicotinate and 6.44 g (0.04 mol) of N-phenylpiperazine was stirred at 100° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was stirred with isopropanol. 7.8 g of a yellow solid were obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9][C:10]1[C:15]([NH2:16])=[C:14]([S:17][CH3:18])[N:13]=[CH:12][N:11]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1.O>[CH3:18][S:17][C:14]1[C:15]([NH:16][C:21](=[O:22])[CH2:20][Br:19])=[C:10]([S:9][CH3:8])[N:11]=[CH:12][N:13]=1
Reactant: O=C(Br)CBr
Reactant: CSc1ncnc(SC)c1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ncnc(SC)c1NC(=O)CBr
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Triethylamine (78 mg, 0.8 mmol) was added to a solution of 4,6-bis(methylthio)-5-aminopyrimidine (120 mg, 0.7 mmol) in THF (2 ml) at room temperature, then bromoacetyl bromide (141 mg, 0.7 mmol) was dropped thereinto and the mixture was stirred for 1 hour. Then the same amounts of triethylamine and bromoacetyl bromide were added followed by stirring for 1 hour. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, hexane:acetone=5:1) to provide 78 mg (yield 40%) of N-[4,6-bis(methylthio)-5-pyrimidyl]-2-bromoacetamide as pale yellow crystals.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2.C([O:19][B:20](OCC)[O:21]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:13]1[C:14]2[C:10](=[CH:9][C:8]([B:20]([OH:21])[OH:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc2c(c1)CCC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butylithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallised from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:12].C(=O)(O)[O-].[Na+].[C:23](Cl)(Cl)=[S:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:23]=[S:24])=[CH:7][C:6]=1[F:12]
Reactant: Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(N=C=S)ccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-(2,5-Dichloro-phenoxy)-3-fluoro-phenylamine (1.36 g, 5 mmol) was dissolved in 150 ml of chloroform and 100 ml of saturated aqueous sodium bicarbonate was added. To this biphasic mixture was added dropwise a solution of thiophosgene (0.39 ml, 5 mmol) in 30 ml of chloroform at room temperature with vigorous stirring. The mixture was stirred vigorously for 1 hour at room temperature. The bottom layer of the mixture was separated, and the aqueous layer was extracted twice with CHCl3. The combined organic solution was washed with water, dried over Mg2SO4 and evaporated to give 1.53 g (97.4%) of crude product used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Clc1cc2cc[nH]c2cc1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
To a mixture of 5,6-dichloro-1H-indole (1.0 g, 5.37 mmol), Cu(OTf)2 (194 mg, 0.537 mmol) in DCM (15 mL) at RT, ethyl 2-diazoacetate (918 mg, 8.05 mmol) was added dropwise. The resulting mixture was stirred at RT for 16 h, quenched with water, and then extracted dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the desired product (120 mg, 8.2% yield) as light yellow solid. ESI-MS m/z: 272.1[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH:19][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)aniline (10.6 g) and pyridine (8 ml) in dichloromethane (75 ml) was added dropwise ethanesulfonyl chloride (4.1 ml) in an ice bath and the mixture was stirred at room temperature for 5 hours. After addition of methanol (1 ml), the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (11.7 g, yield 84%) as a pale pink solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)(=[O:7])=[O:6].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(O[K])(C)(C)C.Cl>C1(C)C=CC=CC=1.CN(C=O)C.O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:9]([NH:8][S:5]([NH:4][CH2:3][CH2:2][CH3:1])(=[O:6])=[O:7])=[N:14][CH:13]=[N:12][C:11]=2[O:15][CH2:16][CH2:17][O:18][C:30]2[N:31]=[CH:32][C:27]([Br:26])=[CH:28][N:29]=2)=[CH:24][CH:23]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCNS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50° C. and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0° C. and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20° C. for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HCl. The mixture was heated to 50° C. and the layers were separated. The org. phase was treated with charcoal at 50° C. and filtered over Celite. The filter cake was rinsed with toluene. At 50° C., water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0° C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50° C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0° C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]#[N:23])[N:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:10]=1[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])C1C=CC=CC=1>CO.[Pd]>[C:22]([C:12]1[N:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:10]([C:32]([N:34]([CH3:35])[CH3:36])=[O:33])=[C:9]([OH:8])[C:13]=1[OH:14])#[N:23]
Reactant: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C#N)c(O)c(O)c2C(=O)N(C)C)cc1
Yield: 21.5 %

Procedure:
4-Bis(benzyloxy)-5-cyano-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (12) (85 mg, 0.17 mmol) in methanol (2 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1.5 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford 5-cyano-3,4-dihydroxy-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (UL1-031) (11 mg, 21%) as a yellow solid: m/z 302 (M+H)+ (ES+); 300 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 8.80 (s, 1H), 7.21-7.11 (m, 2H), 7.03-6.93 (m, 2H), 3.79 (s, 3H), 2.88 (br s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][CH:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[OH:32])[CH2:23]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:38]([O:37][C:35]([CH2:34][O:32][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][CH2:31][CH:22]([CH2:21][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=1)[CH3:20])[CH2:23]2)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(CC1CCc2c(O)cccc2C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC1CCc2c(cccc2OCC(=O)OC(C)(C)C)C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 80.6 %

Procedure:
To a solution of 413 mg of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-methyl(aminomethyl)]-5-hydroxy-1,2,3,4-tetrahydronaphthalene and 210 mg of tert-butyl bromoacetate in 10 ml of acetonitrile, a catalytic amount of potassium iodide and 163 mg of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 423 mg of the desired compound as a pale orange oily substance.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][C:11]=2[CH3:15])[N:6]=1)(=O)C.[CH3:17][O-:18].[Na+]>CO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([O:18][CH3:17])=[CH:10][C:11]=2[CH3:15])[N:6]=1
Reactant: CC(=O)Nc1ccc2c(C)cc(Cl)nc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(N)nc2n1

Procedure:
To a suspension of 2-acetamido-5-methyl-7-chloro-1,8-naphthyridine (23.5 g., 0.10 mole) in 250 ml. of methanol is added sodium methoxide (16.2 g., 0.30 mole). The resulting solution is stirred at reflux under nitrogen atmosphere for 18 hours. The methanol is removed in vacuo and the residue is taken up in chloroform (250 ml.) and water (100 ml.). The chloroform layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is recrystallized from ethanol to yield 2-amino-5-methyl-7-methoxy-1,8-naphthyridine melting at 233°-236° C.