Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Reactant: Cc1cc(C)c(C(N)=O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc2c1
Temperature: 110 °C

Procedure:
To a solution of 2-amino-4,6-dimethyl-benzamide (0.20 g, 1.22 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.36 g, 1.46 mmol) in N,N-dimethylacetamide (10 mL) was added NaHSO3 (58.5 wt %, 0.55 g, 3.05 mmol) and p-TSA (0.46 g, 2.44 mmol). The reaction mixture was heated to 110° C. for 2 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 6% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.145 g (30%). MP 181-182° C. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 7.75 (s, 2H), 7.44 (s, 1H), 7.03 (s, 1H), 3.95 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.85 (s, 3H), 2.65 (s, 4H), 2.44 (s, 3H), 2.39 (s, 6H), 1.84 (s, 4H). MS (ES+) m/z: 392.13 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[NH2:14][C:15](N)=[S:16].O>N1C=CC=CC=1>[NH2:14][C:15]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 3 h
Yield: 118.8 %

Procedure:
A solution of 10.13 g of 2,4-dinitrochlorobenzene and 15.2 g of thiourea in 50 ml of pyridine is boiled, with stirring, under a reflux condenser for 3 hours. After cooling, the mixture is thoroughly stirred with 500 ml of water, and the solid is filtered off with suction, washed with water and dried. 11.6 g of 2-amino-5-nitrobenzothiazole having a purity of 66% by HPLC analysis, corresponding to a yield of 78.5% of theory, are obtained.
Reaction SMILES: [Br-:1].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)([CH2:25][CH2:26]2)[CH2:23]1.[CH:40]1([C:45]([OH:55])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](O)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[Br-:1].[CH:40]1([C:45]([OH:55])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:46]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared using an method analogous to Example 4 by replacing (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and 2,2′-diphenylpropionic acid with cyclopentyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: [C:1](=O)([O:5]CC)[O:2][CH2:3][CH3:4].CCOCC.[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]1>C(O)C>[CH2:3]([O:2][C:1](=[O:5])[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][C:15]1([CH3:14])[O:16][CH2:17][CH2:18][O:19]1)[CH3:4]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)CCCC1(C)OCCO1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CCCC1(C)OCCO1

Procedure:
11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrous ether was added to 4.55 g. (0.1 moles) of a 53 percent dispersion of sodium hydride in mineral oil which was washed with anhydrous hexane and dried under nitrogen. This mixture was stirred under nitrogen and 8.6 g. (0.05 mole) of the ketal ketone, 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over a period of 2 hours. A gentle reflux was maintained throughout the addition and the refluxing was continued for an additional period of approximately 11/2 hours. The solution was then cooled with an ice bath, 20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was added and it was stirred for 45 minutes to destroy any unreacted sodium hydride. The suspension was diluted with an equal volume of ether and the ice cold suspension was then added to a rapidly agitated mixture of 6 ml. of glacial acetic acid and 200 ml. of ice water. The etheral layer was separated, and the aqueous layer was additionally extracted twice with ether. The extract was washed with saturated sodium bicarbonate and with a saturated sodium chloride, dried with sodium sulfate, filtered and evaporated in vacuo to give the crude β-keto ester, 6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p. 110°-112° C at 0.2 mm., Analysis calculated for C12H20O5 : C, 59.00; H, 8.25. Found: C, 58.92; H, 8.38.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][OH:14])[CH:10]=[CH:11][C:4]1=2.Cl.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][O:14][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:10]=[CH:11][C:4]1=2
Reactant: CCN(CC)CCCl
Reactant: OCCc1ccc2sccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCOCCc1ccc2sccc2c1
Yield: 99.6 %

Procedure:
In a mixture of 10 mL of 50% (W/V) aqueous solution of sodium hydroxide and 2 mL of toluene is suspended 2.00 g of 2-benzo[b]thiophen-5-yl-1-ethanol. To the suspension are added 2.51 g of N-(2-chloroethyl)-N,N-diethylamine hydrochloride and 0.38 g of tetra-n-butylammonium hydrogen sulfate, and the resulting mixture is heated under reflux for one hour. Water and toluene are added to the reaction mixture, and the organic layer is separated. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=10:1) to obtain 3.10 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N,N-diethylamine as an oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH:6]=[C:5]2[C:20]([O:22][CH3:23])=[O:21].[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=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>[CH:24]1([NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:6]=[C:5]4[C:20]([O:22][CH3:23])=[O:21])[CH:30]=2)=[O:45])[CH2:25][CH2:26]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(Br)cc12
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of the product of step i) (0.7 g), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.565 g) and potassium carbonate (0.518 g) in degassed N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (0.25 g) and the mixture heated at 80° C. under nitrogen for 40 hours. The reaction mixture was concentrated to dryness and the residue purified (SiO2, 5% methanol in dichloromethane as eluent) to give the sub-title compound (0.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2OCc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Yield: 93 %

Procedure:
A solution of 4.2 g (7.57 mmol) of methyl 4-[({2-[2-(4-bromobenzyloxy)phenyl]ethyl}-tert-butoxycarbonylamino)methyl]benzoate from Example 4A in 15 ml of dichloromethane is stirred with 15 ml of trifluoroacetic acid at room temperature for 4 hours. The reaction solution is then neutralized with aqueous sodium bicarbonate solution, and the organic phase is separated off and dried over sodium sulfate. Filtration is followed by removal of the solvent in vacuo. 3.2 g (7.04 mmol, 92% yield) of a colorless oil are obtained which are employed in the next stage without further purification.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2C(=O)CNC2=O)=CC=1.[CH3:40][C:41]1[C:42]([N:48]2[CH2:53][CH2:52][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[CH2:66][C:65](=[O:67])[N:64](CC5C=CC(OC)=CC=5)[C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:50][CH2:49]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[C:42]([N:48]2[CH2:49][CH2:50][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[CH2:66][C:65](=[O:67])[NH:64][C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:52][CH2:53]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)CNC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)NC4=O)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (300 mg) described in Preparation Example 127 and 3-(4-methoxybenzyl)imidazolidine-2,4-dione (176 mg) described in Preparation Example 213 and by the reaction and treatment in the same manner as in Example 508, the title compound (165 mg) was obtained via 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](O)=[O:27])(=[O:19])=[O:18])=[O:15])[N:6]=1.Cl>CCOCC.O1CCCC1>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[O:27])[CH3:1])(=[O:19])=[O:18])=[O:15])[N:8]=1
Reactant: [Li]C
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reaction time: 4 h

Procedure:
A methyllithium solution in ether (1.4 M, 40 ml) was added to a solution of 1.0 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of dry tetrahydrofuran at room temperature. The resulting yellow slurry was stirred for 4 hours and the dilute hydrochloric acid was added. The mixture was then extracted with methylene chloride. The organic extracts were washed, dried, and evaporated in vacuo to dryness. The crude product was purified by preparative TLC, eluted with ethyl acetate/hexane (1:1), m.p. 126°-128° C.
Reaction SMILES: N1C=CC=CC=1.[S:7]([NH:11][C:12]([NH2:14])=[O:13])([CH3:10])(=[O:9])=[O:8].[C:15](Cl)([Cl:17])=[O:16]>ClCCl>[S:7]([NH:11][C:12]([NH:14][C:15]([Cl:17])=[O:16])=[O:13])([CH3:10])(=[O:9])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)(=O)NC(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)NC(=O)Cl

Procedure:
6.1 parts by volume of pyridine were added dropwise, while cooling, to a mixture of 10.5 parts by weight of N-mesylurea, 60 parts. by volume of dichloromethane and 15.0 parts by weight of phosgene, while cooling, and after some hours at 0°C the excess of the phosgene was removed, the precipitate present was filtered off and the filtrate was completely concentrated in vacuo. A viscous oil remained, which had an absorption at 1800 cm-1 in the carbonyl region of the IR-spectrum. The substance was used without further purification for the production of the penicillin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13].O.Cl>CS(C)=O.C(O)C.[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1CCO
Temperature: 25 °C
Reaction time: 144 h
Yield: 62.5 %

Procedure:
To a solution of 4-chloro-1-methyl-2-nitro-benzene (171.6 g, 0.5 mole) in DMSO (150 mL) was added paraformaldehyde (30.0 g, 1.0 mole), followed by potassium hydroxide (1.5 g, 0.027 mol) in ethanol (10 mL). The resulting reaction mixture was stirred at room temperature for six days and water (2 L) was added and the mixture neutralized with hydrochloric acid (2 N). The mixture was extracted with ethyl ether (2×1 L) and the combined organic layers were washed with water (1 L), saturated sodium chloride (1 L), dried (sodium sulfate) and concentrated to a yellow solid. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:2) provided 63.0 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): 7.90 δ (s, 1H); 7.50 δ (d, 1H); 7.36 δ (d, 1H); 3.90 δ (t, 2H); 3.15 δ (t, 2H); 1.50 δ (broad, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:26]([C:27]([OH:29])=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:26]([C:27]([O:29][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCOC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
A mixture comprising 0.40 g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-3-ethoxycarbonyl-2-methylbenzofuran-4-carboxylic acid, 0.26 g of chloromethyl pivalate and 0.21 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was stirred at room temperature for 6 hours, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 0.43 g (yield: 84%) of the desired compound.
Reaction SMILES: [CH:1]1([C:5]([NH:7][NH:8][C:9](=S)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH:1]1([C:5]2[O:6][C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])([CH2:27][CH2:28]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(NC(=S)NNC(=O)C5CCC5)cc4)cc3)(CC1)CO2
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a reaction vial containing methyl 2-(4-(4′-(2-(cyclobutanecarbonyl)hydrazinecarbothioamido) biphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (300 mg, 0.59 mmol) was added DCM (6 ml) at room temperature. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (204 mg, 1.06 mmol) was added and the mixture was stirred at room temperature for overnight. The reaction mixture was purified directly via column chromatography affording the title compound as off-white solid after drying (252 mg, 90% yield). LC/MS, ESI-MS(+): 474.4, RT: 1.40 (Condition E).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[N:18]O)[CH:13]=[C:12]2[Cl:20])[C:9]#[N:10])=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Fe].CC1C=CC=CC=1>[NH2:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])=[C:12]([Cl:20])[CH:13]=1
Reactant: CC1=CC(=C(C#N)c2ccc(Cl)cc2)C(Cl)=CC1=NO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(C#N)c2ccc(Cl)cc2)c(Cl)cc1N

Procedure:
A mixture of 40 parts of 4-chloro-α-[2-chloro-4-(hydroxyimino)-5-methyl-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile, 50 parts of iron-powder, 1500 parts of ammonium chloride solution 0.78N and 270 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is filtered over hyflo and the filter-cake is washed with 4-methyl-2-pentanone. The filtrate is dried, filtered and evaporated. The solid residue is crystallized from methylbenzene. The product is filtered off and recrystallized from methylbenzene, yielding 4-amino-2-chloro-α-(4-chlorophenyl)-5-methylbenzeneacetonitrile; mp. 152.6° C.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5]I)[CH3:2].[Li].[CH3:21][CH2:22][C:23](=[O:29])[CH2:24][C:25](=[O:28])[CH2:26][CH3:27]>CN(C)C=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:24]([C:23](=[O:29])[CH2:22][CH3:21])[C:25](=[O:28])[CH2:26][CH3:27])[CH3:2]
Reactant: CCC(=O)CC(=O)CC
Reactant: CCC(=CCCc1ccc(C(=O)OC)cc1)CCI
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC(=CCCc1ccc(C(=O)OC)cc1)CC)C(=O)CC

Procedure:
[I; Ar is 4-CH3O2CC6H4, R0 is H, R' and R" are CH3CH2CO, Y is C(C2H5)=CHCH2CH2 ] was prepared from 14 g. of 3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl iodide (Preparation D10) and 14 g. of the lithium salt of 3,5-heptanedione in 200 ml. of dimethylformamide according to the procedure described above in Example 2. The product was chromatographed on silica gel and eluted with the pentane-benzene-ether solvent series. Benzene containing 2% ether brought out the desired product, 2.6 g. of 4-[3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:28]=[CH:27][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[C:23]([F:24])([F:25])[F:26])=[C:12]([O:29][CH3:30])[CH:11]=2)[S:1]1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 130 °C

Procedure:
Thiazolidine-2,4-dione (2.55 g, 21.79 mmol) and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile (21.79 mmol) were dissolved in toluene (150 mL) and treated with benzoic acid (3.27 mmol) and piperidine (2.83 mmol). The flask was equipped with a Dean-Stark trap, and the reaction was refluxed in a 130° C. oil bath for 12 h. After cooling to RT, the product was collected by filtration and triturated with hexanes to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 12.68 (NH), 8.32 (d, 1H), 8.00 (dd, 1H), 7.83 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.26 (dd, 1H), 6.90 (d, 1H), 3.77 (s, 3H); LC/MS (m/z) [M+1]+ 421.0 (calculated for C19H12F3N2O4S, 421.04).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]3=[O:39])[C:28]=2[O:40][CH:41]([F:43])[F:42])(=[O:26])=[O:25])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]2)=[O:13])=[O:8])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=[N:79][C:78]2[N:81](O)N=N[C:77]=2C=1.ONC(=N)C>CN(C=O)C>[F:42][CH:41]([F:43])[O:40][C:28]1[C:29]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]2=[O:39])=[CH:30][CH:31]=[CH:32][C:27]=1[S:24]([NH:23][C@H:11]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][N:81]=[C:78]([CH3:77])[N:79]=2)[CH2:16][CH2:15]1)=[O:13])[CH2:10][NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])(=[O:26])=[O:25]
Reactant: On1nnc2cccnc21
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)N1CCC(C(=O)O)CC1)c1ccc(Cl)s1
Agent: CC(=N)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C2CCN(C(=O)[C@H](CNC(=O)c3ccc(Cl)s3)NS(=O)(=O)c3cccc(N4CCCCC4=O)c3OC(F)F)CC2)n1
Temperature: 110 °C
Reaction time: 1.25 h

Procedure:
1-{(S)-3-[(5-Chloro-thiophene-2-carbonyl)-amino]-2-[2-difluoromethoxy-3-(2-oxo-piperidin-1-yl)-benzenesulfonylamino]-propionyl}-piperidine-4-carboxylic acid (69 mg, 0.104 mmol) from Example 10 in DMF (1 ml) and DIPEA (91 μl, 0.52 mmol) was treated with TBTU (35 mg, 0.109 mmol) and HOAT (3 mg, 0.021 mmol) and stirred for 2 min before N-hydroxy-acetamidine (9 mg, 0.115 mmol) was added. Stirring was continued for 1.25 h at RT. After that the reaction mixture was heated at 110° C. for 2 h. The mixture was purified by prep. HPLC. Yield after lyophilization: 44 mg, 60%, colorless, amorphous solid. MS (ES+): m/e=701.2/703.2, chloro pattern.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.[NH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:42]2[CH:43]=[CH:44][N:45]=[CH:46][C:47]=2[CH:48]=[CH:49][CH:50]=1)(=[O:40])=[O:39]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:34][CH2:35][CH2:36][NH:37][S:38]([C:41]2[C:42]3[CH:43]=[CH:44][N:45]=[CH:46][C:47]=3[CH:48]=[CH:49][CH:50]=2)(=[O:40])=[O:39])=[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: COC(=O)COc1ccc(Cl)cc1Cc1cccc(C(F)(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1Cc1cccc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of [4-chloro-2-(3-trifluoromethyl-benzyl)-phenyloxy]-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a clear gum. ESIMS: m/z 564 [(M+H)+, 35Cl], 566 [(M+H)+, 37Cl].