Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=C(C)C=1.C(O)(=O)[C:9](O)=[O:10].[CH2:14]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:32]([O:31][C:29]([C@@H:26]1[CH2:25][CH2:24][C@@H:23]2[CH2:28][N:27]1[C:9](=[O:10])[N:22]2[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:30])[CH3:33]
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccnc1
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C

Procedure:
3-picoline (52.6 ml, 543 mmol, 4 eq) was added to a slurry of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (50 g, 136 mmol, 1 eq) in dichloromethane (1000 ml) at 0° C., followed by a solution of triphosgene (36.4 g, 122.4 mmol, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0° C. until the reaction was deemed to be complete. The reaction was quenched with a solution of sodium bicarbonate (28.6 g, 340 mmol, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in dichloromethane (solution yield: 35 g, 116 mmol, 85%). Acetonitrile was added and the solution was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in acetonitrile. This solution was diluted with acetonitrile to 700 ml. To this was added ammonium carbamate (11.3 g, 145 mmol, 1.25 eq) and Novozyme 435 (35 g, immobilized Candida antarctica lipase B). The mixture was stirred at 40° C. until the reaction was deemed to be complete. The reaction mixture was filtered and concentrated in vacuo. The solution was diluted with dichloromethane, washed with aqueous ammonium chloride, and concentrated in vacuo. Chlorobutane was added and the solution was concentrated in vacuo. The precipitate was isolated by filtration, washed with chlorobutane and dried to give 2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a white solid (24.3 g, 88 mmol, 65% from ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate).
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][CH:15]([OH:19])[CH:14]1[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O>[CH2:1]([NH:8][C:9]([O:11][CH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][CH:15]([OH:19])[CH:14]1[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=S)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCC=CCC1C(O)CC(O)C1COC(=S)NCc1ccccc1
Yield: 16.8 %

Procedure:
According to the procedures described for 4a the reaction of ester 3c (60 mg, 0.142 mmol) and lithium hydroxide (0.57 mL of a 0.5 N solution in H2O, 0.29 mmol) afforded 9.7 mg (17%) of the title compound after purification by flash column chromatography (silica gel, 100% EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][CH:25]([N:24]([CH3:31])[CH3:23])[CH2:26][CH2:27]3)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)c1cc(I)ccc1Nc1ccnc2cc(Cl)ccc12
Product: CN(C)C1CCN(C(=O)c2cc(I)ccc2Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-(7-Chloro-4-quinolylamino)-5-iodo benzoic acid is converted to the acid chloride which is reacted with 4-dimethylamino piperidine as in Example 1 to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:16][CH2:15]1)=[O:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a solution of cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid (L) (20 mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg, 0.14 mmol), HOBt (18 mg, 0.14 mmol), triethylamine (0.019 mL, 0.14 mmol) and benzyl amine (0.007 mL, 0.7mmol). The reaction mixture was stirred at room temperature for lh followed by quenching with aqueous NaHCO3 and EtOAc. The layers were separated and the organic was washed twice with water, dried over Na2SO4, filtered and concentrated. Purification of the crude oil by preparative reverse-phase HPLC gave cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid benzylamide (Example 10) (12 mg): 1H NMR (300 MHz, CD3OD) δ 7.40-7.20 (m, 9H), 4.39 (s, 2H), 3.81 (m, 1H), 2.45 (m, 1H), 2.02-1.77 (m, 8H); mass spectrum m/z 349 [(M+H)+; calcd for C21H25N4O: 349].
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cccnc1

Procedure:
A mixture of 39 g. of ethyl nicotinate, 33 g. of cyclopropylmethyl ketone and 18 g. of sodium methoxide in 400 ml. of benzene is heated under reflux for 6 hours. The mixture is diluted with 400 ml. of water and the benzene phase is separated. The aqueous phase is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give a solid. This solid is recrystallized from hexane to give colorless crystals, melting point 69°-70°C.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][C@@H:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]1[OH:40]>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[OH:40])=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)NCC2
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: C(O[C:9](=O)[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[CH2:14][CH2:13]1)C)C1C=CC=CC=1>Br>[BrH:23].[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:10][CH3:9])[CH2:17][CH2:16]1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](CCCCCBr)CC1
Agent: Br
Product: CN[C@H]1CC[C@H](CCCCCBr)CC1
Reaction time: 0.33 h

Procedure:
22.55 g (56.89 mmol) of trans-[4-(5-Bromo-pentyl)-cyclohexyl]-methyl-carbamic acid benzyl ester were dissolved at RT in 100 ml HBr (33% in acetic acid). After 20 min, the reaction was evaporated, suspended in toluene (2×) and evaporated again. The suspension was taken up in hexane and filtered to give 17.49 g (90%) of trans-[4-(5-Bromo-pentyl)-cyclohexyl]-methyl-amine hydrobromide, MS: 262 (MH+, 1Br).
Reaction SMILES: [NH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30]([C:33](=O)[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1>>[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30](/[C:33](=[N:2]/[NH:1][C:3]3[O:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)/[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNc1nc2ccccc2o1
Product: C/C(=N\Nc1nc2ccccc2o1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 74 %

Procedure:
The title compound was prepared from 2-hydrazinylbenzo[d]oxazole and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 74% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.5 (m, 1H), 8.87 (dd, 1H), 8.4-7.9 (m, 4), 7.8-7.6 (m, 2H), 7.6-7.1 (m, 5H), 4.58 (s, 2H), 2.49 (s, 3H). LCMS (method C): [MH]+=452, tR=4.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
4-(N-((4-Fluorophenyl)sulfonyl)aminomethyl)-1-tert-butoxycarbonylpiperidine (100 mg, 0.27 mmol, from Example 87, Step A) was added to a slurry of sodium hydride (12 mg, 60% in mineral oil, 0.30 mmol) in 5 mL of dry tetrahydrofuran at 0° C. under nitrogen. Methyl iodide (0.022 mL, 0.35 mmol) was then added. The reaction mixture was then allowed to warm to room temperature overnight. The mixture was diluted with diethyl ether and washed with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to provide 98 mg (94% yield) of the title compound. ESI−MS. M/z; (M+H)=387.0.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)c(C)c1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)cc1C
Yield: 34.7 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (5.0 g, 0.019 mol) and 4-methoxy-2-methylaniline (3.0 g, 0.022 mol) were heated under reflux in 1,4-dioxan (50 ml) for 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium bicarbonate solution, water and brine. The solution was dried and evaporated to an oil, which crystallised on standing. The crystals were triturated with ether and recrytallised from ethyl acetate to give 3-butyryl-4-(4-methoxy-2-methylphenylamino)-8-methoxyquinoline (2.4 g, 34.8%), m.p. 161°-3°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)=[O:2].Cl.[CH3:15][O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][O:16][C:17]([C:19]1([NH:28][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([CH:1]=[O:2])[CH:4]=2)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]
Reactant: COc1ccc(C(=O)O)cc1C=O
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(C=O)c2)Cc2ccccc2C1

Procedure:
3-Formyl-4-methoxy-benzoic acid (F. D. Chattaway and F. Calvet, J. Chem. Soc. (1928), 2913-2918) (1.017 g, 5.65 mmol) was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 4 of example 3. The obtained product (1.895 g) was dissolved in acetic acid (20 ml), sodium acetate (0.57 g, 6.96 mmol) was added and the mixture was stirred under reflux for 24 h. The volatiles were evaporated in vacuo, the residue partitioned between a saturated sodium hydrogencarbonate solution and EA, and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated to dryness to yield 1.52 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4](=[S:8])[O:5]CC)[CH3:2].[CH2:15](N(CCC)C(=S)OCCC)[CH2:16]C>>[CH2:1]([N:3]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[C:4](=[O:8])[S:5][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=S)N(CC)C1CCCCC1
Reactant: CCCOC(=S)N(CCC)CCC
Product: CCSC(=O)N(CC)C1CCCCC1
Yield: 80 %

Procedure:
The procedure described in Example 4 is repeated but an equivalent amount of O-ethyl N-ethyl-N-cyclohexyl-thiocarbamate is substituted for O-propyl N,N-dipropyl-thiocarbamate. The title compound is obtaned with a yield of 80 %; b.p.: 142°-145°C/9 Hgmm., nD30 = 1.5049.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[C:4]([CH3:13])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: COCCOc1cc(C)nc(N)n1
Solvent: ClCCl
Product: COCCOc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Reaction time: 2 h

Procedure:
To a dry stirred solution of 18.3 parts of 2-amino-4-(2-methoxyethoxy)-6-methylpyrimidine in 300 parts of methylene chloride at ambient temperature and pressure was added 22 parts of 2-chlorobenzenesulfonylisocyanate. The mixture was stirred for 2 hours and then the methylene chloride was removed under reduced pressure. The resulting solid was triturated with 1-chlorobutane and filtered to yield 35 parts of N-[[4-(2-methoxyethoxy)-6-methylpyrimidine-2-yl]aminocarbonyl]-2-chlorobenzenesulfonamide, m.p. 130°-140° C. The product showed characteristic absorption bands in the infrared spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH:16]([O:18][C:19](=O)[CH3:20])=[O:17].C(O)(=O)C.[CH:26]([OH:28])=O>>[CH:16]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:17].[C:19]([C:26]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:28])(=[O:18])[CH3:20]
Reactant: O=CO
Reactant: CC(=O)OC=O
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)C(=O)N(c1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C
Product: CC(C)[C@@H](C(=O)O)N(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (1.22 mmole), acetic formic anhydride in acetic acid (23.8 mmole, 2.1 g) and formic acid (1.5 ml) is stirred overnight at RT under nitrogen. The reaction product is concentrated and then subjected to prep. TLC eluting with 20% ethylacetate/hexane to yield the m-phenoxybenzyl ester of N-formyl,N-(4-chlorophenyl)valine, MS m/e 437 (M+, 8.1), 182 (100).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH3:35])C.ClC(C1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1)CCC.ClC(C1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1)C>>[CH3:35][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)Cl
Product: CCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
A] The title compound was prepared in analogy to example 47, via [rac]-(2-methyl-4-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 4B]) instead of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:27])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]=O.[CH2:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:27])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[Cl:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:30]([CH2:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNc1ccccc1
Reactant: O=CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Product: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)c1ccccc1

Procedure:
The product was obtained according to general working method V starting from 0.422 g (0.616 mmol) N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z3d) and 0.094 mL (0.739 mmol) N-ethylaniline.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(F)cc1
Product: CN1CCCn2c1cc(OCc1ccc(F)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-fluorophenyl)methanol.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>CO>[NH:15]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1)[NH2:16]
Reactant: NN
Reactant: COc1cc(S(N)(=O)=O)cnc1Cl
Solvent: O
Solvent: CO
Product: COc1cc(S(N)(=O)=O)cnc1NN

Procedure:
2-Chloro-3-methoxy-5-sulfamoylpyridine (0.3 g, 1.35×10-3 mole) and hydrazine hydrate (0.53 g, approximately 0.01 mole) were added to methanol (20 ml). After refluxing overnight, the reaction mixture was stripped of methanol in vacuo to yield an oil which was cooled in an ice bath and triturated with water (5 ml). The precipitate was collected by filtration and air dried; yield, 0.22 g (75 percent).
Reaction SMILES: C(O[CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)C.[CH2:10]([SH:13])[CH2:11][CH3:12]>>[CH2:10]([S:13][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH2:11][CH3:12]
Reactant: CCCS
Reactant: CCOC1CCC(=O)N1
Product: CCCSC1CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4 g of 5-ethoxy-pyrrolidin-2-one, 30 cm3 of propanethiol and 2 g of Amberlite-15 resin is agitated for 2 hour 45 minutes at ambient temperature. The resin is filtered off, then the excess propanethiol is distillated. 2.8 g of the expected product is obtained, isolated from isopropyl ether. m.p. 40°-42° C.
Reaction SMILES: Br.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[S:12]C=C(C3(C(O)=S)CC=C(C)S3)[N:15]=2)=[CH:5][CH:4]=1.[Br:25][CH2:26][C:27]([C:29]1[CH:30]=[C:31]([C:35]([O:37][CH3:38])=[S:36])[S:32][C:33]=1[CH3:34])=O.CC1C=CC(CNC(N)=S)=CC=1>>[BrH:25].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:11]2[S:12][CH:26]=[C:27]([C:29]3[CH:30]=[C:31]([C:35]([O:37][CH3:38])=[S:36])[S:32][C:33]=3[CH3:34])[N:15]=2)=[CH:7][CH:8]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: CC1=CCC(C(O)=S)(c2csc(NCc3ccc(C)cc3)n2)S1
Agent: Br
Agent: Cc1ccc(CNC(N)=S)cc1
Product: COC(=S)c1cc(-c2csc(NCc3ccc(C)cc3)n2)c(C)s1
Yield: 81 %

Procedure:
Methyl 4-(2-{[(4-methylphenyl)methyl]amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (111 mg, 0.35 mmol) was allowed to react with 4-methylphenylmethylthiourea as described in Example 154, step (a) to give 125 mg (81% yield) of methyl 4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C18H18N2O2S2, 358.5 (M+H), found 359.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13][N:14]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)c1ccc(-c2nccs2)cc1
Agent: O=S(=O)(O)O
Product: CCN(CC)c1ccc(-c2ncc([N+](=O)[O-])s2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To a mixture of N,N-diethyl-4-(thiazol-2-yl)aniline (1.39 g, 6.00 mmol) and concentrated sulfuric acid (10 mL) was added concentrated nitric acid (0.45 mL) at −10° C. The reaction mixture was stirred at 0° C. for 3 h, then poured into ice water and extracted with CH2Cl2 (30 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=1:1) to give the title compound as a yellow solid (0.73 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH2:20][CH3:21])=[O:9])=[O:5]
Reactant: CCO
Reactant: Nc1ccccc1C(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(=O)c1ccccc1N

Procedure:
3-(2-Aminobenzoyl)propionic acid (26.7 g) and concentrated sulphuric acid (25 cc) in absolute ethanol (250 cc) are stirred for 17 hours at room temperature (approximately 20° C.). The ethanol is evaporated off under reduced pressure, water (200 cc) and ethyl acetate (200 cc) are added and potassium carbonate is added until the pH is 8. The mixture is filtered, and the aqueous phase decanted and re-extracted with ethyl acetate (2×100 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl 3-(2-aminobenzoyl)propionate (24.8 g) is obtained in the form of an oil. The proton NMR spectrum in deuterated chloroform shows the following characteristics: