Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].C([O:6][CH:7]([C:16]1C(C)=C(OC)[C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[C:17]=1[O:29][CH3:30])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)(=O)C.[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>[N+]([O-])([O-])=O.[Ag+]>[OH:6][CH:7]([C:16]1[C:31]([CH3:32])=[C:35]([O:34][CH3:33])[C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[C:17]=1[O:29][CH3:30])[C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:13])=[O:1])=[CH:14][CH:15]=1
Reactant: COc1c(C)c(C(OC(C)=O)c2ccc(C=O)cc2)c(OC)c(OC)c1OC
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COc1c(C)c(C(O)c2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
After adding dropwise an aqueous solution (20 ml) of silver nitrate (3.06 g, 18.00 mmol) to an aqueous solution of 1 N sodium hydroxide (36 ml), a solution of 4-[acetoxy-(2,3,4,5-tetramethoxy-6-methylphenyl)methyl]benzaldehyde (2.34 g, 6.00 mmol) obtained in Step 2 of Example 1 in THF (30 ml) was added dropwise and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and the solid was washed with hot water. The filtrate and the wash solution were combined, which was then acidified with concentrated hydrochloric acid and then was extracted with ether. The extract was dried and the solvent was distilled off to yield the title compound (2.3 g, 6.37 mmol, yield 100%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[N:15]=2)[CH2:10][CH:9]1[C:34](=[O:46])[NH:35][C:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:7])(C)(C)C.O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:44]([O:43][C:41]([C:36]1([NH:35][C:34]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:46])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:42])[CH3:45]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Compound 155 (0.896 g, 1.41 mmol) was dissolved in a mixture of DCM (30 mL), TFA (10 mL), a few drops of TES and a drop of H2O. The reaction was stirred for 30 minutes followed by removal of solvent by evaporation. The crude residue was partitioned between CHCl3 and saturated NaHCO3 (aq). The organic phase was dried (Na2SO4) and evaporated which gave the compound (0.81 g, 99%) as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(O[N:41]1N=N[C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1N>CN(C=O)C>[N:47]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:41][C:17]([C:15]1[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]2[CH2:12][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][C:10]=2[CH:16]=1)=[O:18]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)Nc2ccccn2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A mixture of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.9 mmol), DIPEA (0.37 g, 2.85 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (15 mL) was stirred at room temperature for 1 hr, and then pyridin-2-amine (0.18 g, 1.94 mmol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The mixture was concentrated. The residue was purified by prep. HPLC to give the title compound (73 mg, 21% yield, TFA salt) as a white solid. 1H NMR (400 MHz, CDCl3): δ 11.71 (br, 1H), 8.76 (d, 1H), 8.27 (d, 1H), 8.14 (t, 1H), 7.17-7.46 (m, 9H), 4.96 (d, 1H), 4.78 (t, 1H), 2.82 (m, H), 2.67 (m, 1H), 2.19 (m, 1H), 1.96 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:49]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(Cl)cc1
Yield: 36 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (60 mg, 0.26 mmol), triethyl orthoformate (0.5 ml), 4-chloroaniline (61 mg, 0.48 mmol), and acetic acid (0.06 ml) were used to give 31.6 mg (0.093 mmol, 36% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=4)[CH2:41][CH2:40]3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: NC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)NC3(c4cccc(C(F)(F)F)c4)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 6.7 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[3-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-44, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.17-1.37 (m, 4H), 1.51 (s, 6H), 3.06 (s, 2H), 7.34-7.51 (m, 8H), 8.39 (s, 1H), 11.00 (2H); MS [M+H]+: 559.16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[NH:30][C:29]2[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:28]=2[N:27]=1.Cl.[OH-].[Na+]>C(O)CCC.O1CCCC1>[F:36][C:32]1[C:33]([F:35])=[CH:34][C:28]2[NH:27][C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:30][C:29]=2[CH:31]=1
Reactant: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Methyl 2-[(4′-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate (264 mg, 0.02 mmol) was dissolved in n-butanol (8 mL), 2-chloro-5,6-difluoro-1H-benzimidazole (185 mg, 0.98 mmol) and 4 N HCl (0.2 mL) were then added, and the resulting mixture was heated at 90° C. for 5 h. The mixture was then cooled to rt, and solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and then treated with I N aqueous sodium hydroxide (2.45 mL, 2.45 mmol). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (9.1 mg, 3%). LC-MS m/z 462.3 (MH+), ret. time 3.23 min; 1H NMR (300 MHz, DMSO-d6) δ 1.69-1.81 (m, 4H), 1.98-2.18 (m, 2H), 3.14-3.22 (m, 1H), 4.04-4.09 (m, 1H), 7.38 (t, 2H), 7.77-7.84 (m, 6H), 8.05 (d, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11][CH3:12])(=[O:9])[CH3:8].[OH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>C(#N)C>[C:7]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])(=[O:9])[CH3:8]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCOc1ccccc1C#N
Reaction time: 8 h

Procedure:
Potassium carbonate (30 mmol) and then ethyl acetate (11 mmol) are added to a solution of 2-hydroxybenzonitrile (10 mmol) in acetonitrile. After stirring overnight, the solution is filtered and evaporated, the residue is taken up in ethyl acetate, and the organic phase is washed, dried and then evaporated to yield the expected product.
Reaction SMILES: COC1C=CC(C2CCCOC2[N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[N:28]=[C:27]([CH2:29][N:30]([CH3:32])[CH3:31])[NH:26][N:25]=4)=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=CC=1.[C:33]1(C)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O:40]1CCOC[CH2:41]1.Cl>>[CH3:41][O:40][C:33]1[CH:38]=[CH:37][C:36]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([C:24]4[N:28]=[C:27]([CH2:29][N:30]([CH3:31])[CH3:32])[NH:26][N:25]=4)[CH:19]=3)[NH:15][N:16]=2)=[CH:35][CH:34]=1
Reactant: C1COCCO1
Reactant: COc1ccc(C2CCCOC2n2ncc3cc(-c4n[nH]c(CN(C)C)n4)ccc32)cc1
Reactant: Cc1ccccc1
Agent: Cl
Product: COc1ccc(-c2n[nH]c3ccc(-c4n[nH]c(CN(C)C)n4)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
({3-[3-(4-Methoxyphenyl)-1-perhydro-2H-pyran-2-yl(1H-indazol-5-yl)](1H-1,2,4-triazol-5-yl)}methyl)dimethylamine (0.57 g, 1.32 mmol) was suspended in 10 mL of 4 M in HCl dioxane solution. Toluene (10 mL) was added and the suspension was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 solution and then concentrated under reduced pressure. The residue was taken up in DMSO and filtered. Purification by preparative HPLC (15–80% acetonitrile in water) furnished 92 mg (20% yield) of the title compound. 1H NMR (DMSOd6) δ 14.0 (s, 1H), 13.2 (s, 1H), 8.6 (s, 1H), 8.05 (dd, 1H), 7.95 (m, 2H), 7.65 (d, 1H), 7.14 (m, 2H), 3.8 (s, 3H), 3.6 (s, 2H), 2.2 (s, 6H); ES-MS (m/z) 349 [M+H]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7](=[C:16]([F:18])[F:17])[CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1.[CH3:19][O:20][CH2:21]Br.[Cl-].[NH4+]>CCOCC>[CH3:19][O:20][CH2:21][C:13]1[O:12][C:11]([S:10][CH2:9][CH2:8][C:7]([F:6])=[C:16]([F:17])[F:18])=[N:15][CH:14]=1
Reactant: COCBr
Reactant: FC(F)=C(F)CCSc1ncco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COCc1cnc(SCCC(F)=C(F)F)o1
Reaction time: 1 h
Yield: 13.2 %

Procedure:
10.40 ml of n-butyl lithium (1.6 M n-hexane solution) were slowly added dropwise to a solution of 3.14 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole in 40 ml of ether at −70° C. After stirring for 1 hour, a solution of 2.06 g bromomethyl methyl ether in 10 ml ether was added dropwise. After bringing the mixture back to room temperature and stirring for 1 hour, 50 ml of saturated solution of ammonium chloride was added to separate it into an ether layer and an aqueous layer. The aqueous layer was further extracted with ether and together with the separated ether layer it was washed with a saturated sodium chloride water and dried with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was treated by column chromatography to obtain 0.5 g of 5-methoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 13%). n20D=1.4705.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10](=[NH:16])[NH:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.[O-]CC.[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:16]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: COCCNC(=N)c1cc(F)cc(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cc(F)cc(F)c2)n(CCOC)c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 3,5-difluoro-N-(2-methoxyethyl)benzenecarboximidamide hydrochloride (1:1 (i.e. the product from Example 9, Step B) (24.3 mmol) in ethanol (25 mL) was added diethyl ethoxymethylenemalonate (5.25 g, 24.3 mmol) followed by sodium ethoxide (21% soln) (9.1 mL, 24.3 mmol). The reaction mixture was heated and stirred at reflux for 24 h. The reaction mixture was cooled to room temperature concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (6.1 g).
Reaction SMILES: P(Cl)(Cl)Cl.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:14]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:18]=1[OH:31])([OH:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[OH:31][C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:24]=2[N:25]([CH2:26][CH2:27][O:28]3)[C:29](=[O:30])[C:17]=1[C:14](=[O:16])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH3:5]
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)c1c(O)c2cccc3c2n(c1=O)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Phosphorus trichloride (0.353 ml) was added dropwise to a water-cooled solution of N-methyl-4-fluoroaniline (3.04 g) in toluene (18 ml). The mixture was stirred at room temperature for 30 minutes. 6-Carboxy-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2 g) was added thereto, and the resulting mixture was stirred at 100° C. for 2 hours. Water (20 ml) and 4N sodium hydroxide (15 ml) were added thereto. The insoluble material was filtered and the filtrate was separated. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The extract was dried over magnesium sulfate, filtered, and concentrated. The residue was recrystallized from a mixture of ethanol and isopropyl ether to give pale brown crystals of 2,3-dihydro-7-hydroxy-6-[N-(4-fluorophenyl)-N-methylcarbamoyl]-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH:24][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1c(Cl)cccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,6-dichloro-aniline (63 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 43% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.76 (1H, s), 8.99 (2H, s), 8.68 (1H, s), 7.60 (2H, m), 7.41 (1H, m). MS m/z: 492.00, 493.99, 495.96 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=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.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:4]2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[C:3]=2[CH:14]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Reactant: COc1ccc(B(O)O)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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude (E)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (30 g, 0.124 mol) was dissolved into 300 mL of DME. To this was added a solution of Na2CO3 (21 g, 0.2 mol in 200 mL of H2O) followed by addition of 4-methoxyphenyl boronic acid (22 g, 0.145 mol) and Pd(PPh3)4 (1.2 g, 8.3 mmol). The reaction mixture was heated in a 85° C. oil bath, under N2, for 2 h and then cool to room temp. To this was added 200 mL of EtOAc and the mixture stirred for 5 min. The organic layer was separated and washed with H2O (200 mL) and brine (200 mL). Organic layer was dried over MgSO4 and then concentrated to dryness to give 53 g of crude product. This was subjected to silica chromatography using 210 g of silica gel and EtOAc/hepatene (12:88 to 30:70 to 50:50 to 70:30; total of 8 L mobile phase). Fractions containing pure product were combined and concentrated to dryness to give 42.7 g of pure product (quantitative). 1H NMR (300 MHz, CDCl3) δ 3.38 (s, 3H), 3.73 (d, 1H), 3.85 (s, 3H), 4.75 (d, 1H), 6.9 (m, 2H), 7.31 (m, 2H), 7.48-7.58 (m, 3H).
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:27][NH2:28]>C(O)C>[CH3:27][NH:28][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Reactant: CN
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 2.10 g (31.0%) of a colorless oil, bp 90–100° C. at 0.5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#N)[C:9]1=[O:17].[OH2:18].S(=O)(=O)(O)[OH:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:20])=[O:18])[C:9]1=[O:17]
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccccc1F
Reactant: O
Reactant: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccccc1F
Temperature: 25 °C
Yield: 72 %

Procedure:
An aqueous solution (98% sulfuric acid 3 mL, water 3 mL) of 1-(2-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (660 mg, 3.08 mmol) in sulfuric acid was stirred at 130° C. for 6 hr. The reaction solution was cooled to room temperature, water was added, and the precipitated solid was collected by filtration. The obtained solid was washed with ethyl acetate to give the title compound (550 mg, 72%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([CH2:31][OH:32])[CH:28]([OH:33])[CH:27]3[OH:34])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.N1C=CN=C1.[C:49]([Si:53](Cl)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([CH3:52])([CH3:51])[CH3:50].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:35]1[CH2:37][CH:36]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]([OH:34])[CH:28]([OH:33])[CH:29]([CH2:31][O:32][Si:53]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO)C(O)C3O)c2n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(O)C3O)c2n1

Procedure:
A solution of the product of step (a) (1.11 g), imidazole (417 mg) and tert-butylchorodiphenylsilane (0.75 ml) in dry DMF (4 ml) was stirred for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were dried, concentrated and purified (SiO2, petrol:acetone 3:1 as eluant) to give the subtitle compound (1.16 g).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:6][C:5]1([NH:16][C:17](=[O:20])[O:18][CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)#N.S(Cl)(Cl)=O.C([O-])(O)=[O:26].[Na+].[CH2:30]([OH:32])[CH3:31]>>[CH3:19][O:18][C:17]([NH:16][C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:6][CH:4]1[CH2:3][C:1]([O:32][CH2:30][CH3:31])=[O:26])=[O:20]
Reactant: CCO
Reactant: O=C([O-])O
Reactant: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CC#N
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC1CC1(NC(=O)OC)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of methyl (1SR,2SR)-2-(cyanomethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (intermediate B9a) (2.1 g, 7.63 mmol, Eq: 1.00) in ethanol (40 ml) was added dropwise thionyl chloride (13.6 g, 8.35 ml, 114 mmol, Eq: 15) ant the light brown solution was stirred at 80° C. for 1 hour. Poured cautiously into sat NaHCO3 solution, extracted with dichloromethane, washed the organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the ethyl 2-((1SR,2SR)-2-(methoxycarbonylamino)-2-(3-nitrophenyl)cyclopropyl)acetate (2.54 g, 7.49 mmol, 98.1% yield) as a light brown oil. MS (ISP): m/z=323.2 [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C[C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1.Cl[C:15]1[S:16][C:17]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:18]([CH3:20])[N:19]=1.C(OCC)(=O)C.CO>CC(N(C)C)=O>[CH3:20][C:18]1[N:19]=[C:15]([NH:13][C:11]2[S:12][CH:8]=[N:9][N:10]=2)[S:16][C:17]=1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Cc1nc(Cl)sc1-c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nnc(N)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Cc1nc(Nc2nncs2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Caesium carbonate (0.08 g, 0.24 mmol) and 5-methyl-[1,3,4]thiadiazol-2-ylamine (0.031 g, 0.27 mmol) are added to a solution of 4-(2-chloro-4-methyl-thiazol-5-yl)-benzenesulfonamide (25d) (0.07 g, 0.24 mmol) in dimethylacetamide (2 ml). The mixture is heated with stirring at 110° C. for 18 hours. After adding more 5-methyl-[1,3,4]thiadiazol-2-ylamine (0.056 g, 0.49 mmol) heating is continued at 130° C. for an additional 8 hours. The solvent is removed and the product is purified by chromatography on silica eluting with ethyl acetate to give an orange solid. Trituration with ethyl acetate-methanol affords the title compound as a yellow solid (0.0081 g)