Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:15][CH:16]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2nc(N)sc2-c2ccc(SC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(-c2sc(N)nc2-c2ccc(CO)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}benzoate (100 mg) in tetrahydrofuran (4 ml) was added portionwise lithium aluminium hydride (21.3 mg), and the mixture was stirred for 1 h at 20° C. To the reaction mixture were added ethyl acetate (10 ml) and water (3 ml). The resulting precipitate was removed by filtration, and the filtrate was washed with brine, dried over sodium sulfate and evaporated to give (4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}phenyl)methanol as a yellow solid, that was used as crude in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:30])[CH:20]=[CH:19][C:18](C2C=CC=CC=2B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=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>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([CH3:30])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2ccccc2B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)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: Cc1ccccc1
Product: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of tert-butyl-4-bromobenzoate (48 g, 0.186 mol), 4-tolyl-benzeneboronic acid (25.3 g, 0.186 mol), Na2CO3 (200 g in 500 mL of water) in toluene (750 mL) under N2 was added Pd (PPh3)4 (10.7 g, 0.009 mol) and reaction mixture was refluxed for 10 h. After cooling to rt, organic layer was separated and aqueous layer was extracted with EtOAc (2×200 mL). The combined layer was washed with brine and concentrated. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 4:1) to give tert-butyl-4-(4-tolyl)benzoate (40 g, 800%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:27])[NH:16][C:17]2[S:18][C:19]3[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=3[N:25]=2)[CH:10]=1)(C)(C)C.[ClH:29]>C(Cl)Cl.CCOCC.CCCCCC>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=2[N:25]=1)=[O:27].[ClH:29].[ClH:29].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=2[N:25]=1)=[O:27]
Reactant: CN1CCc2nc(NC(=O)c3cccc(CNC(=O)OC(C)(C)C)c3)sc2C1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCc2nc(NC(=O)c3cccc(CN)c3)sc2C1

Procedure:
To a solution of [3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (3.56 g, 8.76 mmol) in anhydrous DCM (175 mL) at rt add HCl (44 mL 4M solution in 1,4-dioxane, 175 mmol) and stir the reaction at rt for 24 h. Dilute the solid suspension with Et2O (300 mL) and hexane (500 mL), stir vigorously for 20 min Filter and wash with Et2O and hexane to afford the desired product 3-aminomethyl-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-benzamide dihydrochloride as a solid (3.28 g, 8.64 mmol).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N+:10]2[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1.BrCC(C1C=CC=CC=1)=O.CC1C=C2C([CH:37]=[CH:38][CH:39]=[N:40]2)=CC=1>C(#N)C>[C:14]([C:13]1[N:10]2[C:11]3[C:6]([CH:7]=[CH:8][C:9]2=[C:38]([C:39]#[N:40])[CH:37]=1)=[CH:5][CH:4]=[C:3]([CH3:2])[CH:12]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: Cc1ccc2ccc[n+](CC(=O)c3ccccc3)c2c1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccccc4)n3c2c1

Procedure:
7-Methyl-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (490 mg, 2.46 mmol), 7-methyl-quinoline (302 mg, 2.11 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 499 mg (69%) as a light tan solid: 1H NMR (CD3OD) 9.28–9.25 (m, 2H), 8.37 (d, J=8.4 Hz, 1H), 8.23–8.19 (m, 2H), 8.13–8.08 (m, 2H), 7.91 (dd, J=0.9, 8.7 Hz, 1H), 7.83–7.78 (m, 1H), 7.70–7.64 (m, 2H), 2.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:11])=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.BrN1C(=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]=[O:18])=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(Cl)nc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2ccc(Cl)nc12
Temperature: 100 °C
Yield: 28.1 %

Procedure:
A mixture of 5-chloro-3-methyl-thieno[3,2-b]pyridine (0.5 g, 2.7 mmol), N-bromosuccinimide (0.48 g, 2.7 mmol) and benzoyl peroxide (50 mg) in carbon tetrachloride (3 mL) was heated at 100° C. in a microwave reactor for 15 minutes. The supernatant was decanted and evaporated under reduced pressure, the residue was suspended in toluene (3 mL) and pyridine-N-oxide (0.5 g) was added, followed by sodium bicarbonate (0.4 g) and diisopropylethylamine (3 drops). The reaction mixture was heated at 150° C. in a microwave reactor for 5 minutes, was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 20/80) to give 150 mg of 5-chloro-thieno[3,2-b]pyridine-3-carbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Br)c1
Reactant: NNc1ccccc1
Product: Cc1ccn(-c2cccc(Br)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-bromophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide; HRMS(M+H)+ calc. 511.043949; found: 511.043295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]#1.[F-].[Cs+]>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[C:10]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: c1ccccc#1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The present invention further provides one pot process for C-arylation of ethyl 3-(4-chlorophenylamino)-3-oxo-propanoate (2) using benzyne precursor (1) in presence of CsF and CH3CN to obtain ethyl 3-(4-chlorophenylamino)-3-oxo-2,2-diphenylpropanoate (4) with more than 85% yield (cf scheme 3).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:22][C@@H:23]1[C@@H:36]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[O:35][C@@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:25](O)[C@H:24]1[O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49].[N-:53]=[N+:54]=[N-:55].[Na+].[Cl-].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Cl-].[Cl-]>ClCCl>[N:53]([C@H:25]1[C@@H:24]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@H:23]([F:22])[C@@H:36]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[O:35][C@H:26]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N+:54]=[N-:55]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@@H](N=[N+]=[N-])[C@@H](OC(=O)C(C)(C)C)[C@@H]1F

Procedure:
To a solution of pyridine (22.2 μl, 0.274 mmol) in dichloromethane (370 μl) was added dropwise trifluoromethane-sulfonic anhydride (46 μl, 0.274 mmol) at 0° C., and 15 minutes later, a solution of Compound (21) in dichloromethane (1 ml) was added dropwise to the mixture at 0° C. Disappearance of the material was continued by TLC, and the reaction mixture was diluted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, saturated sodium chloride aqueous solution and water, dried over anhydrous magnesium sulfate and thereafter concentrated. The residue was further dried by a vacuum pump, and then dissolved in benzene (1 ml). Sodium azide (13 mg, 0.206 mmol) and tetraammonium chloride (57 mg, 0.206 mmol) were added to the solution under an argon stream at room temperature, and the mixture was reacted at 40° C. The disappearance of the material was confirmed by TLC, and the reaction mixture was thereafter concentrated in a vacuum. The residue was subjected to extraction with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution and water, dried over anhydrous magnesium sulfate and thereafter concentrated. The residue was purified by silica gel column chromatography (ethyl acetatae:hexane=1:4), affording Compound (22) (in an amount of 30.4 mg, 95% in yield).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:7].C([O-])(=O)C.[Na+].[BH4-].[Na+]>O.C(O)(=O)C>[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:18][CH:19]=1)[CH3:7]
Reactant: CCNC(=O)OCCOc1ccc(N)cc1
Reactant: CCC(C)=O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCNC(=O)OCCOc1ccc(NC(C)CC)cc1

Procedure:
To a mixture of 2-butanone (5 ml), 2-(4-aminophenoxy)ethyl N-ethylcarbamate (1.00 g) and sodium acetate (2.50 g) in a solution of 5 ml of acetic acid and 10 ml of water, cooled to -5°, is added sodium borohydride (4.00 g) in portions. After addition is complete, the reaction mixture is adjusted to alkaline pH and is extracted with ether. The combined organic extracts are concentrated and the crude product is purified by column chromatography to give 2-[4-(1-methylpropylamino)phenoxy]ethyl N-ethylcarbamate (compound 35, Table B).
Reaction SMILES: N[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[NH2:9][CH2:10][CH2:11][SH:12].[ClH:13]>C(O)(=O)C>[ClH:13].[ClH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]cnc1CN
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN

Procedure:
Sodium amide (0.39 g., 0.01 mole) was dissolved in 40 ml. of liquid ammonia and 4.11 g. (0.01 mole) of [(5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide was added. The suspension was stirred at -40° C. for one hour and then allowed to warm to room temperature as the ammonia evaporated. The triphenyl phosphine was extracted from the residue with benzene and the remaining solids were taken up in water and extracted with chloroform. The chloroform extracts were dried and evaporated to give 4-aminomethyl-5-methylimidazole in 70% yield. This amine was refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=3)[C:19](OC)=[O:20])[CH:12]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[C:17]([CH2:25][OH:26])[CH:16]=3)[CH:12]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(c2cc(CCc3ccc(C(=O)OC)c(C(=O)OC)c3)cs2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(c2cc(CCc3ccc(CO)c(CO)c3)cs2)OCCO1

Procedure:
In a manner similar to that of Example 6(f), by reaction of 6.7 g (18 mmol) of dimethyl 4-{2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-4-thienyl]ethyl}phthalate with 1.6 g (43 mmol) of lithium aluminium hydride, the desired product is obtained in the form of a colourless oil (m=5.3 g; Y=85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:27][C:8]2=[C:9]3[C:14](=[C:15]([O:17]C)[CH:16]=[C:7]2[CH:6]=1)[N:13]=[C:12]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[C:10]3[C:23]([O:25][CH3:26])=[O:24])=[O:4].[OH2:28]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[NH:27][C:8]2[C:9]3[C:10]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:12]([C:19]([O:21][CH3:22])=[O:20])=[N:13][C:14]=3[C:15](=[O:17])[C:16](=[O:28])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O
Reactant: COC(=O)c1cc(C(=O)OC)c2c(n1)c(OC)cc1cc(C(=O)OC)[nH]c12
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C(=O)c1cc(C(=O)OC)[nH]c1-2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (about 250 g, 0.67 mol) in acetonitrile (ACN) (about 7.5 L), a solution of ceric ammonium nitrate (about 1.83 kg, 3.35 mol) in about 2.25 L of water is added over a period of about 30 minutes at about −5° C. The reaction mixture is stirred at about −5° C. over a period of about 1.5 hours. Thereafter, resulting reaction mass is filtered, washed with water and dried to obtain the product [4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester] as a bright orange solid (about 145 g, 58%). 1H NMR (DMSO-d6, 300 MHz): 3.90 (s, 3H), 3.97 (s, 3H), 4.05 (s, 3H), 7.29 (d, J=1.8 Hz, 1H), 8.56 (s, 1H), 12.52 (s, 1H); LC-MS (ESI): 373.0 (M-H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[F:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([F:20])=[C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a suspension of iron powder (28.75 g) in 5 % aqueous acetic acid (57.5 ml) heated at 80° C., a solution of 3-chloro-2-(2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (30.45 g) in acetic acid (103 ml) and ethyl acetate (103 ml) was added, and the resultant mixture was heated at a temperature of 60° to 80° C. under reflux for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture. The residue was removed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-(5-amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g). m.p., 120.9° C.
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.CC(C)CCN.[CH2:27]([O:29][C@@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C@@H:42]([C:44](=[O:61])[NH:45][CH2:46][CH2:47][C:48]2[CH:53]=CC(OC3C=CC=CC=3)=C[CH:49]=2)C)=[CH:37][CH:36]=1)[C:31]([OH:33])=[O:32])C>>[CH3:27][O:29][C@@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:44](=[O:61])[NH:45][CH2:46][CH2:47][CH:48]([CH3:49])[CH3:53])=[CH:37][CH:36]=1)[C:31]([OH:33])=[O:32]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CC(C)CCN
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCC(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3-methyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C17H25NO5 [M−H]−: 322.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([O:10]CC)=[O:9])[N:6]=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:15]([O:14][N:13]=[C:7]([C:5]1[N:6]=[C:2]([NH:1][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:3][CH:4]=1)[C:8]([OH:10])=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCON=C(C(=O)OCC)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 58.6 %

Procedure:
Stages 4 and 5: 35.2 g (0.13 mole) of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate are tritylated with 44.6 g (0.155 mole) of trityl chloride (97% pure) analogously to Example 4, stage 4, and the product is split, without further purification, as described in Example 4, stage 5, to give 37 g of 2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([O:29]C4CCCCO4)[CH2:26][O:27][CH3:28])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:48][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]([OH:29])[CH2:26][O:27][CH3:28])=[CH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-{5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridin-2-yl}-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.70 g), ammonium acetate (0.42 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.39 g, yield 69%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 511 (MH+).
Reaction SMILES: [Si]([N:8]1[C@@H:11]([CH2:12][S:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][C:9]1=[O:20])(C(C)(C)C)(C)C.[F-].[Cs+]>CO>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[S:13][CH2:12][C@@H:11]1[NH:8][C:9](=[O:20])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CSc1ncccn1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: O=C1C[C@H](CSc2ncccn2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.1 %

Procedure:
To a solution of 1-(tert-butyldimethylsilyl)-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidin-2-one (280 mg, 0.905 mmol) in MeOH (4.5 mL) was added cesium fluoride (206 mg, 1.36 mmol). The reaction mixture was stirred 1.5 h at room temperature, then concentrated under vacuum. The residue was dissolved in CH2Cl2, washed with H2O and brine, dried (MgSO4), filtered and evaporated to give 4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidin-2-one (184 mg) which was used as such. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 2H), 7.02 (t, J=5.1 Hz, 1H), 6.13-5.93 (m,1H), 4.04-3.99 (m,1H), 3.54 (dd, J=14.0, 5.4 Hz, 1H), 3.27 (dd, J=14.0, 7.0, 1H), 3.14 (ddd, J=15.0, 5.1, 1.9 Hz, 1H), 2.78 (ddd, J=15.0, 2.2, 1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][NH:44][CH2:45][C:46]([NH2:48])=[O:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:44]([CH2:45][C:46]([NH2:48])=[O:47])[CH3:43])=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CNCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(N)=O)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methylamino-acetic acid amide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C@H:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl>[Br:8][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26]
Reactant: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A suspension of 6.1 g (34.4 mmol) of NBS and 4 g of silica gel in 125 ml of dry dichloromethane was stirred under argon for 30 min. Then a solution of 4.56 g (17.2 mmol) of (S)-4-(1-methylheptyloxy)-2-nitro-toluene in 150 ml of dichloromethane was added via syringe. The reaction mixture was stirred at room temperature for 72 h. The resulting suspension was filtered through a short silica gel pad and the pad was washed several times with dichloromethane. The solvent was evaporated and the crude product extracted with a mixture of hexanes/ethyl acetate [95/5]. The suspension was filtered, the solvent removed and the residue was purified by flash chromatography using hexanes as eluent, affording 4.6 g (78%) of (S)-α-Bromo-4-(1-methylheptyloxy)-2-nitrotoluene (Compound 35, Scheme VI, R1 =(S)--OCH(CH3)C6H13) as a yellow liquid; Rf [hexanes/ethyl acetate 98/2]: 0.26; 1H NMR (300 MHz, CDCl3): δ0.86(t, 3H, J =6.7 Hz), 1.18-1.48(m, 8H), 1.30(d, 3H, J=6.1 Hz), 1.58(m 1H), 1.70(m, 1H), 4.40(m, 1H), 4.77(s, 2H), 7.06(dd, 1H, J=2.7 Hz, J=8.5 Hz), 7.40(d, 1H, J=8.5 Hz), 7.50(d, 1H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ13.98, 19.36, 22.50, 25.28, 29.10, 29.25, 31.67, 36.12, 75.00, 111.93, 121.08, 124.14, 133.61, 148.69, 158.92; IR (CHCl3): 3020, 2930, 2850, 1625, 1525, 1500, 1350, 1320, 1250, 1100, 975, 850, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 345(M+ +1.38), 43(M+ -1 1.35), 264(37), 152(100), 112(28), 71(59), 57(93), 55(38), 43(93), 41(70).