Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:21]3[C:29]4[C:24](=[C:25]([CH2:30][S:31][CH3:32])[CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:11]3C(=O)O[C:14](C)([CH3:18])[O:13][C:12]3=[O:20])=[CH:9][C:4]=2[CH:3]=[CH:2]1.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CC(OCC)=O)=CC=1>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:21]3[C:29]4[C:24](=[C:25]([CH2:30][S:31][CH3:32])[CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:11][C:12]([O:13][CH2:14][CH3:18])=[O:20])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2c(C(c3ccc4sccc4c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)c(F)ccc12
Product: CCOC(=O)CC(c1ccc2sccc2c1)c1c[nH]c2c(CSC)cccc12

Procedure:
The title compound was prepared starting from 1.73 g (71% purity, 3.72 mmol) of the compound from Example 23A in analogy to the synthesis of the compound from Example 47A. 1.23 g (81% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-:30])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]

Procedure:
5 g of 5-acetyl-8-benzyloxyquinoline are dissolved in 50 ml of chloroform. The solution is ice-cooled and 3.12 g of 80% m-chloroperbenzoic acid are added thereto under stirring. The mixture is stirred at room temperature for 24 hours and at 50° C. for 7.5 hours. The mixture is then stirred at room temperature for 64 hours. 2 g of 80% m-chloroperbenzoic acid are further added to the mixture during the reaction. After the reaction, chloroform is added to the mixture. The mixture is washed with water, a 4% sodium bicarbonate solution and a saturated sodium chloride solution, dried and then evaporated under reduced pressure to remove chloroform. 5-Acetyl-8-benzyloxyquinoline-N-oxide is obtained as yellow solid.
Reaction SMILES: CO[CH:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1.C[Si]([C:20]#[C:21][CH3:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH:20]([C@@H:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1)=[CH:21][CH3:22]
Reactant: CC#C[Si](C)(C)C
Reactant: COC(=O)[C@@H]1CCC(OC)N1C(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC=C[C@H]1CC[C@@H](C(=O)OC)N1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cold −45° C. solution of dimethyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10 g, 46.08 mmol, Example 1B) and trimethylsilylpropyne (14.24 ml, 92.16 mmol, 2.0 equiv) in methylene chloride (180 mL) was added a solution of tin (IV) chloride (1 Min methylene chloride, 60.0 mL, 60.0 mmol, 1.3 equiv) dropwise via an addition funnel over 30 minutes. To the dark yellow solution was added solid aluminum chloride (8.58 g, 64.52 mmol, 1.4 equiv) in one portion. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture was carefully quenched by saturated aqueous NH4OH (100 mL) with ice cooling. A white precipitate formed and was removed by filtration. The crude product was obtained after concentration. The residue was chromatographed on a Biotage flash 40 M eluting with 70% hexane/30% ethyl acetate to afford the titled compound. MS (DCI/NH3) m/e 226 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li].[NH:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][OH:27]>>[OH:27][CH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: OC[C@H]1CCCN1
Agent: [Li]
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CO

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ from 4′-trifluoromethyl-biphenyl-4-carboxylic acid, lithium salt using (R)-2-pyrrolidine methanol as the amine. MS (ES+) 350.2
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[S:28][C:27]([C:29]([O:31]C)=[O:30])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[Na+]>>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 61.5 %

Procedure:
From methyl 5-{[2-(1-{4-hydroxy-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}-2-thiophenecarboxylate (150 mg, 0.32 mmol) and 1 M sodium hydroxide aqueous solution (1.60 mL, 1.60 mmol), 89.0 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a pale yellow solid (yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:33]([CH3:35])[CH3:34])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:33]([CH3:34])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C(=O)Nc2ccc(C(=O)O)cc2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
95 mg (177 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: 0.1% aqueous ammonium formate solution and acetonitrile, gradient 30% acetonitrile to 70% acetonitrile). Yield: 28 mg (33% of theory)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:24])[C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=1)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:24])[C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:9]
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)N1CCCC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)N1CCCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the above ester in DCM (26 mL) was added TFA (8.7 mL) and stirred at room temperature. After 3 hours, the reaction mixture was concentrated and treated with Et2O. The solid formed was then filtered and washed with ether and dried to give 4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13](=[O:15])[CH2:14][N:6]1[CH2:5]2.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:15]=[C:13]1[CH2:14][N:6]2[C:7](=[N:8][C:9]3[C:4]([CH2:5]2)=[CH:3][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=3)[NH:12]1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CN2Cc3cc(O)ccc3N=C2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)CN1CC(=O)NC1=N2
Temperature: 100 °C

Procedure:
To a solution of 7-hydroxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (2.6 g) made as per U.S. Pat. No. 3,932,407 and ethyl 4-bromobutyrate (1.72 ml) in 100 ml dimethylformamide was added 1.86 g potassium carbonate. The reaction mixture was sealed under a blanket of nitrogen and heated to 100° C. for 4 hours. The reaction mixture was cooled, poured into 100 ml of water, and the resulting precipitate collected by filtration. Recrystallization from dimethylformamide-water gave ethyl 4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyrate, m.p. 243°-244° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7].II>C(#N)C>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C/C=C/C(=O)O
Agent: II
Solvent: CC#N
Product: O=C(O)/C=C\C=C\C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture containing cis, trans muconic acid (1.00 g), a catalytic amount of iodine (53 mg, 3.0 mole percent), and acetonitrile (35 ml) is heated to reflux for 11 hours. The reaction is performed in the presence of ambient light in the laboratory. After cooling to room temperature, the precipitated solid is filtered off and washed with acetonitrile. After drying under high vacuum, 0.80 g (80 percent yield) of pure trans, trans muconic acid are present as a tan-colored powder. The material obtained by this procedure from cis,trans muconic acid is identical to the material obtained from cis,cis muconic acid by the previous procedure.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:33](=[O:34])[C:29]2([CH2:32][CH2:31][CH2:30]2)[NH:28][C:27]1=[O:35])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1.C(OC([C@H]([C@@H](CC(C)C)C(NN)=O)CCCC1C=CC=CC=1)=O)(C)(C)C.N(C1(C(OCC)=O)CCC1)=C=O>>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:33](=[O:34])[C:29]2([CH2:30][CH2:31][CH2:32]2)[NH:28][C:27]1=[O:35])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCOC(=O)C1(N=C=O)CCC1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)NO

Procedure:
The 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(6,8-dioxo-5,7-diazaspiro[3.4]oct-7-yl)valeramide used as the starting material was prepared in a manner analogous to that described in Example 7, parts (ii) and (iii) starting from 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide and ethyl 1-isocyanato-1-cyclobutane carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].CC(C)([O-])C.[K+].Br[CH2:35][C:36]#[N:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:35][C:36]#[N:37])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: N#CCBr
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCC#N)cccc4c3nc12
Temperature: 100 °C

Procedure:
To a suspension of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (230 mg) in dry N,N-dimethylformamide (3 mL) was added potassium tert-butoxide (175 mg) and then bromoacetonitrile (47 μL). The reaction mixture was heated to 100° C. for 1 hour. The reaction mixture was then cooled, diluted with ethyl acetate, washed with sodium carbonate solution and brine, dried (MgSO4) and the solvent removed in vacuo to provide crude product. This was purified using flash chromatography (silica, 25% MeOH in ethyl acetate) to yield the title compound as a yellow solid (74 mg).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC=1.C(O)C>C(OC(C)C)(C)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1
Reactant: Cn1ccc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: CC(C)OC(C)C
Product: Cn1ccc2ccc(O)cc21

Procedure:
The mixture consisting of 0.24 mole (57 g) of 6-benzyloxy-1-methylindole, 5.7 g of 10% palladium-on-charcoal, 114 ml of cyclohexene and 170 ml of 96% ethanol is heated for 30 minutes under reflux. The mixture is filtered hot to remove the catalyst. After evaporation of the filtrate under vacuum, an oil is obtained which, dissolved in isopropyl ether, gives the desired product after evaporation to dryness. It melts at 74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33](O)=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2cccc(C)c2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2cccc(C)c2)c1

Procedure:
327 mg of compound 32 was obtained in a similar manner to those described in the Examples 1 and 2 using 566 mg of ethyl 4-(2-aminophenoxy)butyrate and 387 mg of 3-[1-(3-methylbenzyl)indole-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10]C2C=CC(F)=C([C@]34OCC[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)C=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 228.6 %

Procedure:
To a solution of tert-butyl (4aR,7aR)-7a-(5-(5-bromopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (12 mg) in dichloromethane (0.43 mL) was added TFA (67 μL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was subjected directly to preparative TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give N-(3- (4aS,7aS)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-bromopicolinamide as a white foam (10 mg). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.70 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.5 Hz), 8.06 (1H, dd, J=2.0, 8.06 Hz), 8.0 (1H, m), 7.75 (1H, m), 7.09 (1H, m), 4.13 (2H, m), 3.22 (1H, m), 3.02 (1H, m), 2.89 (1H, m), and 2.22 (2H, q, J=7.5 Hz). MS: 453.3 (M+H)+. Retention time: 22.49 chiralcel OJ-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol); Retention time: 12.54 chiralcel OD-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:11]([CH3:13])[CH3:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]([N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1[CH:8]=[C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:23]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(C(=O)c1ccc(Cl)cc1Cl)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (3) (345 mg, 0.77 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (30 mL) and then 4.6 ml of LiOH 1N was added to it. After 120 min of stirring at room temperature; solvant was removed and then partitioned between 25 ml of H2O, 4 ml of KHSO4 5% and 25 ml of EtOAc. The organic, layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 175 mg (53%) as a white solid of 3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): Rotamer 95/05: 7.82 ppm (m, Haro, minor rotamer); 7.69 ppm (d, 2H, Haro); 7.61 ppm (d, 1H, Haro); 7.51-7.37 ppm (m, 4H, Haro); 7.35-7.28 ppm (m, 2H, Haro), 4.89 ppm (hex, 1H, N—CH(CH3), major rotamer); 3.84 ppm (hex, N—CH(CH3), minor rotamer); 1.36 ppm (d, 3H, N—CH(CH3), major rotamer); 1.25 ppm (d, N—CH(CH3), minor rotamer); 1.03 ppm (d, 3H, N—CH(CH3), major rotamer); 0.93 ppm (d, N—CH(CH3), minor rotamere).
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][NH:29][CH3:30])=[CH:20]1)[CH3:18].C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:29]([CH2:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([CH2:17][CH3:18])[CH:20]=2)[CH3:30])=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CCn1cc(CNC)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(CN(C)C(=O)/C=C/c2ccc(N)nc2)c2ccccc21
Reaction time: 8 h
Yield: 51.7 %

Procedure:
EDC (0.56 g, 2.93 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.48 g, 2.93 mmole), 1-ethyl-3-(methylaminomethyl)-1H-indole (0.50 g. 2.66 mmole), HOBt H2O (0.40 g, 2.93 mmole) and diisopropylethylamine (0.93 mL, 5.32 mmole) in DMF (30 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (10% MeOH/CHCl3) gave title compound (0.46 g, 52%) as a yellow solid after drying in vacuo: MS (ES) m/e 335 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:28]=5)=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5ccc(OC)c(C(F)(F)F)c5)o4)cc23)cc1
Yield: 91 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 91%) was obtained as colorless crystals.
Reaction SMILES: [NH3:1].[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]1[O:5][CH2:4]1>>[Si:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:2][CH:3]([OH:5])[CH2:4][NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)CCCOCC1CO1
Reactant: N
Product: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanolic ammonia (7 mol of ammonia in methanol, 100 mL, 0.7 mol,) was charged to a 500 mL, one-neck, round-bottom flask placed in an ice bath. To the above solution 3-t-butyldimethylsilylpropyl glycidyl ether (23.04 g, 0.1 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for three days. The reaction solution was then warmed up to 40-50° C. to remove excess ammonia. Methanol was stripped off under reduced pressure. Crude 3-(t-butyldimethylsilylpropyloxy)-2-hydroxypropylamine was obtained as a clear and colorless oil (24 g, 98% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([CH:15]([N:20]=[C:21]=[S:22])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])=[S:22])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCCCC(CC)N=C=S
Agent: Cl
Product: CCCCC(CC)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Yield: 36 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1-ethylpentyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 36%), 1H-NMR (DMSO-d6): δ0.8 (2 q, 6H, 2×CH3), 1.2 (m, 4H), 1.5 (m, 4H), 4.20 (sextet, 1H, CH), 6.55 (br, 2H, NH2), 6.65 (s, 1H, H4), 7.85 (br d, 1H, NH), 11.3 (br s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[CH2:16][N:17](C(=O)C(F)(F)F)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([NH:8][S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)CNCc1cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
To tert-butyl N-(3-{[(tert-butoxycarbonyl)sulfamoyl]amino}benzyl)-N-(trifluoroacetyl)glycinate (2.19 g) were added a 50% aqueous methanol solution (43.9 mL) and potassium carbonate (1.19 g), followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in water, followed by neutralization with 1 M hydrochloric acid. The mixture was extracted with a mixed solvent of n-butanol and ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-chloroform) to obtain tert-butyl N-(3-{[(tert-butoxycarbonyl)sulfamoyl]amino}benzyl)glycinate (1.38 g).