Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].O.[C:10]1(C)C=CC(S(O)(=O)=[O:17])=CC=1.C(OCC)(OCC)OCC.[ClH:31]>O.CC(O)C>[OH2:4].[OH2:17].[ClH:31].[OH:4][C:3]1[NH:5][CH:10]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1nc[nH]c1O
Temperature: 82 °C
Reaction time: 3 h

Procedure:
Under the nitrogen atmosphere, 10.0 g of 2-aminomalonamide and 81.2 mg of p-toluene sulfonic acid monohydrate were added to 200 mL of 2-propanol. After heating to 82° C., 35.4 mL of triethyl orthoformate was added dropwise to the mixture over 5 minutes. Subsequently, the reaction mixture was stirred for 3 hours at 80° C. Color of the reaction liquid was deep blue when the reaction was completed. Subsequently, after cooling to 57° C., the reaction mixture was added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 15.6 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([CH2:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20]([C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH:10]([CH2:16][O:17][C:27]2[N:26]=[N:25][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 4,4-difluoro-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.8 mmol, 0.2 g) in 5 mL of THF was added 60% NaH (4.0 mmol, 96 mg). The mixture was stirred at room temperature for 10 min, then a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.4 mmol, 0.14 g) was added. The mixture was refluxed for 1 h, quenched with water, extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, brine, dried, evaporated, the resulting residue was chromatographed with 20:1 DCM/MeOH to afford 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (150 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([OH:19])[CH2:3]1.Cl.CC[O:23]CC>>[NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([OH:19])[C:3]1=[O:23]
Reactant: CCOCC
Reactant: N[C@H]1Cc2cc(Oc3ccccc3)cnc2N(O)C1
Agent: Cl
Product: N[C@H]1Cc2cc(Oc3ccccc3)cnc2N(O)C1=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 61 %

Procedure:
(3S)-3-Amino-1-hydroxy-6-phenoxy-3,4-dihydro-1,8-naphthyridin-2(1H-one (67) tert-Butyl {(3S)-1-[(tert-butoxycarbonyl)oxy]-2-oxo-6-phenoxy-1,2,3,4-tetrahydro-1,8-naphthyridin-3-yl}carbamate (66) (240 mg, 0.509 mmol) was treated with a solution of HCl in Et2O (2 M, 2 mL) and allowed to stir at RT for 66 h. The solvent was removed under reduced pressure, and the residue was dissolved in a solution of 1:4 (1:9 NH4OH: CH3OH): dichloromethane (0.5 mL). This solution was subjected to silica gel chromatography (Eluant: 1:4 (1:9 NH4OH: CH3OH): dichloromethane) to provide the product as a white solid (83 mg, 61%). LCMS m/z 272.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.98 (br dd, J=15, 14 Hz, 1H), 3.18 (dd, J=15.3, 6.2 Hz, 1H), 4.01 (dd, J=13.8, 6.1 Hz, 1H), 7.03-7.07 (m, 2H), 7.17 (br t, J=7.4 Hz, 1H), 7.40 (dd, J=8.5, 7.5 Hz, 2H), 7.44-7.46 (m, 1H), 8.00 (br d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>N1C=CC=CC=1.O1CCCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccc(Cl)cc2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 1.7 g of 5-chloroanthranilic acid in 40 ml of pyridine is added a solution of 2.6 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under cooling, and the mixture is stirred at room temperature for 2 hours and then heated to 80° C. for 30 minutes. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from acetone to obtain 1.4 g of N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid as colorless needles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(O)C>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(3-Aminopropyl)imidazole (2.39 ml, 0.02 mol) was added to a solution of 4-bromobenzoyl chloride (4.0 g, 0.018 mol) in ethanol (250 ml). The mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was purified by chromatography eluting with hexane/dichloromethane (50:50) increasing in polarity to dichloromethane/methanol (80:20) to give the title compound. NMR: 1.95 (m, 2H), 3.20 (q, 2H), 4.0 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.64 (d, 2H), 7.68 (s, 1H), 7.78 (d, 2H), 8.58 (t, 1H); m/z: 308 [MH]+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17]4[C:22]([CH:23]=[CH:24][C:12]=3[C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=4>C(Cl)Cl.CCCCCC>[CH3:5][N:10]1[C:11]2[C:12]3[CH:24]=[CH:23][C:22]4[C:17]([C:13]=3[CH:14]=[CH:15][C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:19]=[CH:20][CH:21]=4
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2n1C
Yield: 74.5 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[1,2-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 74.5% yield of ethyl 3-methyl-3H-naphth[1,2-g]indol-2-carboxylate, mp 136°-138°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([OH:20])[CH:14]([N+:17]([O-:19])=[O:18])[CH2:15][OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22].[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([O:20][C:28](=[O:30])[CH3:29])[CH:14]([N+:17]([O-:19])=[O:18])[CH2:15][O:16][C:21](=[O:23])[CH3:22])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(O)C(CO)[N+](=O)[O-])cc(OC)c1OC
Product: COc1cc(C(OC(C)=O)C(COC(C)=O)[N+](=O)[O-])cc(OC)c1OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
A mixture of 9.7 g (0.0337 moles) of 1-(3,4,5-trimethoxyphenyl)-2-nitro-1,3-propanediol, 13.78 g (0.135 moles) of acetic anhydride and 2.6 g of acetyl chloride is stirred at 60° C. for 4 hours. Thereafter the mixture is cooled to 20° C. and poured onto 50 g of ice. Crystallization sets in immediately. The separated product is filtered off, washed thrice with 15 ml of ice-cold water, each, and then with a small amount (about 3 ml) of isporopanol, and dried. 11.3 g (90.12%) of the title compound are obtained; m.p.: 107°-109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9])[CH2:27][CH2:28][CH3:29]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1C(F)(F)F
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 10.0 g of 2-bromotrifluoromethylbenzene under nitrogen in 100 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 30.6 ml of a 1.6M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture is added dropwise 15.9 g of tributyltin chloride in 30 ml of tetrahydrofuran. Stirred ? additional hours. The reaction mixture is quenched with 20 ml of water and after stirring for 20 minutes, extracted with chloroform (3×100 ml). The organic layer is filtered through diatomaceous earth and the filtrate washed with saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and evaporated in vacuo to give 16.8 g of the desired product. MS 379.1
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]([N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:30]=1)[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CN=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N=Cc1ccccc1

Procedure:
A solution of potassium bis(trimethylsilyl)amide (11.34 g, 54 mmol) in THF (100 ml) was added dropwise to a mixture of (benzylidene-amino)-acetic acid methyl ester (3.83 g, 21.63 mmol) and 4-chloromethyl-1-trityl-1H-imidazole (21.6 g, 60.18 mmol) in THF (200 ml) at −78° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([S:28](F)(=[O:30])=[O:29])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[S:20](F)(=[O:22])=[O:21].C(N(CC)CC)C.[F:40][C:41]([F:47])([F:46])[S:42]([NH2:45])(=[O:44])=[O:43]>C1COCC1.C(OCC)(=O)C>[F:40][C:41]([F:47])([F:46])[S:42]([NH:45][S:20]([C:19]([F:25])([F:24])[C:18]([F:27])([F:26])[C:17]([F:32])([F:16])[S:28]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])=[CH:14][CH:15]=1)(=[O:30])=[O:29])(=[O:22])=[O:21])(=[O:44])=[O:43]
Reactant: C=C(C)C(=O)NCCc1ccc(O)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Reactant: NS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCCc1ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.95 Gram of N-(4-hydroxyphenethyl)methacrylamide and 10.7 g of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyldifluoride were dissolved in 80 mL of THF, and 80 mL of triethylamine was added thereto. The resulting mixture was stirred at 50° C. for 2 hours, and 5.56 g of trifluoromethanesulfonamide was added thereto. The mixture was further stirred at 80° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with dilute hydrochloric acid and twice with water and dried over sodium sulfate. The solvent was concentrated, and the brown oil as residue was dissolved in 200 ml of methanol. Thereto, 10 g of sodium hydrogencarbonate as solid was added, and the mixture was stirred at 50° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with saturated brine and twice with water and dried over sodium sulfate to obtain 12.2 g of N-(trifluoromethanesulfonyl)-1,1,2,2,3,3-hexafluoro-3-((4-(2-(methacrylamido)ethyl)phenoxy)sulfonyl)-1-propanesulfonamide solution salt as a brown oil. Thereafter, 12.2 g of this brown oil was dissolved in 100 mL of methanol, and 6.43 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, and the solvent was concentrated, as a result, 14.0 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 2.87 (t, 2H), 3.50 (quartet, 2H), 5.28 (s, 1H), 5.66 (s, 1H), 6.05 (bs, 1H), 7.20 (d, 2H), 7.27 (d, 2H), 7.63-7.77 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −78.65 (s, 3F), −107.8 (m, 2F), −112.4 (t, 2F), −118.0 (m, 2F).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:9]=1)[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:47][O:48][NH2:49]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17]([NH:49][O:48][CH3:47])=[O:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:9]=1)[CH3:2]
Reactant: CCOCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Reactant: CON
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)NOC)cc12

Procedure:
The title compound was prepared as in example 116, step 3, using 3-[(2-ethoxyethoxy)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine, and O-methyl hydroxylamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07 (t, J=6.95 Hz, 3H) 3.40 (q, J=6.99 Hz, 2H) 3.47-3.51 (m, 2H) 3.53-3.57 (m, 2H) 3.68 (s, 3H) 4.67 (s, 2H) 5.56 (s, 2H) 7.16 (t, J=8.97 Hz, 2H) 7.31-7.40 (m, 2H) 7.83 (s, 1H) 8.26 (s, 1H) 8.84 (s, 1H) 11.73 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: Cc1cc(=O)[nH]cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cc1cc(=O)n(C)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (124 mg, 0.872 mmol) in DMSO (3 mL) was added potassium carbonate (121 mg, 0.872 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](N2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Na].C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:3]1[C:2]([CH3:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c[nH]c(=O)nc1OCc1ccccc1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are added to a solution of 2.34 g (18 mmol) of sodium benzylate in 25 ml of dry benzyl alcohol and 25 ml of dry dimethylformamide are added. The mixture is heated for 2 hours with stirring to 100° C. The cooled solution is neutralized with acetic acid, concentrated and chromatographed on silica gel using ethylacetate/methanol 9/1. 880 mg (67.9% of theory) of 4-benzyloxy-5-methylpyrimidin-2(1H)-one are obtained with melting point 181°-182°C. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 11.14 (s, 1H), 7.56 (d, 1H), 7.41 (m, 5H), 5.35 (s, 2H), 1.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(Cl)nn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)ccc1=O
Temperature: 25 °C

Procedure:
A mixture of potassium trifluoro(2-methyl-4-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-5-yl)borate (60 mg, 0.20 mmol), 6-chloro-2,4-dimethylpyridazin-3(2H)-one (made according to US2012/108578 A1, 40 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (14 mg, 0.02 mmol) and cesium carbonate (163 mg, 0.5 mmol) in THF (0.8 mL) and H2O (0.2 mL) was stirred at reflux for 15 h. The mixture was cooled to ambient temperature, diluted with EtOAc (5 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Waters Sunfire C18 OBD 5˜80% methanol in water with 0.1% NH3. H2O modifer) to give the title compound as a white solid LC/MS m/z=378.1 [M+H]+; 1H NMR (400 MHz, MeOD) δ 8.53 (s, 1 H), 8.09 (s, 1 H), 7.65 (s, 1 H), 7.41 (dd, 1 H), 7.04 (d, 1 H), 4.66-4.51 (m, 1 H), 4.25 (dd, 1 H), 3.71 (s, 3 H), 2.51 (s, 3H), 2.18 (s, 3 H), 2.11-2.02 (m, 1 H), 1.92 (s, 3 H), 1.85-1.73 (m, 1 H), 1.22-1.13 (m, 1 H), 1.09-1.00 (m, 1 H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
To a solution of 2-phenylindole (0.17 g, 0.86 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 35 mg, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.25 g, 0.78 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (0.17 g, yield 46%) as a colorless oil. 1H NMR (CDCl3) δ: 2.59 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 3.66 (3H, s), 4.98 (2H, s), 5.38 (2H, s), 6.66 (1H, s), 6.88 (2H, d, J=8.7 Hz), 7.00-7.20 (7H, m), 7.29-7.47 (7H, m), 7.67 (1H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]2[S:20][N:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])=[CH:7]3)=[C:36]([O:43][CH3:44])[CH:35]=1)#[N:33]
Reactant: COc1cc(C#N)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
A vial was charged with 5-bromo-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE D, 82.49 mg, 0.168 mmol), (4-cyano-2-methoxyphenyl)boronic acid (59.5 mg, 0.336 mmol), Pd(AmPhos)2Cl2 (5.96 mg, 8.41 μmol), potassium phosphate (107 mg, 0.505 mmol), 1,4-dioxane (631 μl), and water (210 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 40 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give a light-yellow solid. The material was concentrated from DCM, and then taken up in DCM. The solvent was mostly removed via pipette, then the solid was again concentrated from DCM to give 5-(4-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (35.5 mg, 0.084 mmol, 50.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.54 (d, J=1.9 Hz, 1H), 8.46 (s, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.78-7.67 (m, 3H), 7.61-7.50 (m, 3H), 7.46 (d, J=7.6 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.C(N(C(C)C)CC)(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:53]1([CH2:59][C:60]2[S:68][C:67]3[CH2:66][CH2:65][NH:64][CH2:63][C:62]=3[CH:61]=2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:22])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][CH2:16][O:17][CH2:18][C:19](=[O:21])[N:64]2[CH2:65][CH2:66][C:67]3[S:68][C:60]([CH2:59][N:53]4[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]4)=[CH:61][C:62]=3[CH2:63]2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: c1c(CN2CCCCC2)sc2c1CNCC2
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCc3sc(CN4CCCCC4)cc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(4-Methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetic acid (AC6) (353 mg, 1.06 mmol), diisopropylethylamine (372 μl, 2.13 mmol), HOAt (15 mg, 107 μmol) and EDCI (306 mg, 1.60 mmol) were added to a solution of 2-(piperidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (TP10) (277 mg, max. 425 μm) in MC (25 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue obtained was purified by chromatography on silica gel (MC/(7 M NH3 in MeOH), 98:2 and 99:1). The product fractions were combined and evaporated to dryness. The residue was dissolved in dry acetonitrile (5 ml), the solution was dried by freeze drying and the solid was then dissolved in methylene chloride (10 ml). Solid NaHCO3 (approx. 500 mg) was added to this solution and the mixture was stirred for 1 hour. The mixture was then filtered and the filtrate was concentrated in vacuo. The yield was 105 mg (45% over 2 stages). MS, Rt=3.0 min, m/z=550.1 [MH]+