Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.N[CH:29]1[CH2:34][C:33](C)(C)[NH:32][C:31](C)(C)[CH2:30]1>CS(C)=O>[C:5]([N:32]1[CH2:31][CH2:30][CH:29]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:10])([CH3:6])[CH3:4]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Solvent: CS(C)=O
Product: CC(C)(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 1 mL of 4-amino-2,2,6,6-tetramethylpiperidine in 0.5 mL of DMSO was stirred at 130° C. for 3 h. The mixture was cooled, filtered, and purified by reverse-phase preparative HPLC (YMC C18 100×50 mm column; 10:90 to 90:10 v/v acetonitrile/water+0.1% TFA over 15 min; 20 mL/min) to yield the title compound. Mass spectrum (ESI) 557 (M+1). 1H NMR (500 MHz, CD3OD): selected peaks δ 1.32-1.58 (m, 14H), 2.05-2.24 (m, 2H), 4.40 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:7](=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[C-:18]#[N:19].[K+].O.O1CCOCC1>C(Cl)Cl>[C:12]1([C:8]2[O:9][N:10]=[C:11]3[C:3]([CH2:2][C:18]#[N:19])=[CH:4][CH:5]=[CH:6][C:7]=23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1cccc2c(-c3ccccc3)onc12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CCc1cccc2c(-c3ccccc3)onc12
Yield: 73.3 %

Procedure:
A mixture of 17.3 g (0.06 mole) of 7-bromomethyl-3-phenyl-2,1-benzisoxazole, 17 g of potassium cyanide, 80 ml of water and 120 ml of dioxane was heated at reflux under a nitrogen atmosphere for 2 hr. The mixture was then cooled and diluted with 300 ml of methylene chloride. The organic layer was separated, washed with water and dried over magnesium sulfate. The solvents were removed under vacuum and the residue was crystallized twice from absolute ethanol to give 10.3 g (74%) of yellow crystals, m.p. 125°-138° C.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N:17]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN1C(=O)CCC1>[N+:14]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:24]=1)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])([O-:16])=[O:15]
Reactant: Nc1cccc(N2CCCCC2)c1
Reactant: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1ccc(Nc2cccc(N3CCCCC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a mixture of isopropyl 4-chloro-3-nitrobenzoate (3.0 g, 12.3 mmol) and 2a (2.16 g, 12.3 mmol) in anhydrous NMP (5 ml) was added triethylamine (1.71 ml, 12.3 mmol) and the mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was extracted with diluted hydrochloric acid (4M). The aqueous extract was rendered alkaline by addition of aqueous sodium hydroxide (12M) and extracted with ethyl acetate. This organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographied on silica gel using a mixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluent to yield isopropyl 3-nitro-4-(3-(1-piperidinyl)anilino)benzoate (2.55 g, 54%) as a red oil. This intermediate product was dissolved in ethanol (50 ml) hydrogenated at ambient pressure. The resulting diamine was treated with formic acid (25 ml) at 80° C. for 1 hour. The reaction mixture was poured into water (100 ml) and rendered alkaline by addition of aqueous sodium hydroxide (10M). The crude product was filtered off, washed with water and dried. Purification was achieved by treatment with activated carbon in refluxing 2-propanol followed by trituration with diethyl ether. Yield of 4e1: 1.27 g (53%). M.p. 160-161° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(O)C>[OH:17][CH2:16][CH2:18][NH:19][C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14]
Reactant: NCCO
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Solvent: CCO
Product: OCCNC(=S)C1(c2ccccn2)CCCS1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (12.8 g) and ethanolamine (3 g) in ethanol (150 cc) is heated under reflux for 1 hour 30 minutes. After concentrating the reaction mixture to dryness (20 mm Hg; 2.7 kPa) at 50° C., the resulting residue (14.8 g) is dissolved in boiling ethanol (80 cc) and the solution, to which decolourising charcoal (0.3 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (30 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 50° C. N-(2-Hydroxyethyl)-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (11.4 g), melting at 132° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.[Fe]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1ccc(CO)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(CO)c(N)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxymethyl-3-nitro-benzoic acid methyl ester (step (b), 5.6 g, 26.5 mmol) in 60 mL EtOH/30 mL H2O was added Fe powder (7.5 g, 134.3 mmol) and NH4Cl (0.75 g, 14.0 mmol). The reaction mixture was stirred at 75° C. for 3 h, then filtered while hot through Celite. The Celite was washed with EtOAc and MeOH. The filtrate was concentrated in vacuo and partitioned between EtOAc/H2O. The EtOAc layers was dried over MgSO4 and concentrated in vacuo to give a yellow solid. MS m/z: 179.9 (M−1).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CCc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CCc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)/[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[CH:21][CH:20]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:3]/[N:4]=[C:5](\[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:38][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N/O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Reaction time: 3 h
Yield: 67.9 %

Procedure:
Sodium hydride (60%, in oil, 153 mg) was added to a solution of ethyl E-2-hydroxyimino-2-(3-pyridyl)acetate (619 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature under nitrogen atmosphere and stirred for 3 hours. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (1.02 g, yield 68%) as a pale-yellow oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40][CH2:39]1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:50][CH2:49]3)=[O:22])[CH:17]=2)(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol) in DCE (4.5 mL). The crude product was purified using Ambersep and PL-MIA resins to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:4]([CH3:29])[N:3]=1.[C:30](Cl)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][C:30](=[O:32])[CH3:31])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])=[C:4]([CH3:29])[N:3]=1
Reactant: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCOC(=O)c1c(C)nc(C)c(C(=O)OC(C)C)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.1 g (50 mmols) of 2-hydroxyethyl isopropyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (Example 1) were dissolved in 75 ml of pyridine. 5.9 g (75 mmoles) of acetyl chloride were added to this. After the exothermic reaction was over, the reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with CH2Cl2. The organic extracts were washed with dilute hydrochloric acid and, after drying over sodium sulphate, evaporated in vacuo. The resulting oil crystallized completely, it was stirred with petroleum ether, filtered off with suction and dried.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[C:41](OCC)(=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
(2R,6S)-4-[6-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 0.5 g, 1.01 mmol) was dissolved in 10 ml of THF and cooled to −78° C. Sec-butyl lithium (1.358 ml, 1.77 mmol) was added drop wise over 5 minutes. The reaction stirred at −78° C. for 1.5 hours. The reaction mixture was cannulated into a −78° C. cooled flask containing diethyl oxalate (1.370 ml, 10.09 mmol) in 10 ml of THF. The reaction was allowed to stir at −78° C. for 30 minutes; quenched cold with 1 ml sat NH4Cl and allowed to warm to room temp. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were combined and washed twice with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (486 mg, 81% yield) contaminated with diethyl oxalate. This material was taken to the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:39]([O:38][C:36]([NH:35][CH:4]([CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:12][CH:13]=1)[C:3]([OH:43])=[O:2])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)C(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution of 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid methyl ester (0.173 g, 0.281 mmol) in 4 mL of THF and 1 mL of methanol was treated with 2 N NaOH (1.5 mL, 2.81 mmol). After stirring at room temperature for 3 hours, the solution was acidified with 2 N HCl to a pH 3. The resulting solution was extracted with ethyl acetate (2×50 mL), dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (5% methanol in dichloromethane) to afford 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid. 1H NMR (DMSO, 300 MHz) δ 7.58-7.49 (m, 4 H), 7.44-7.36 (m, 3 H), 7.21 (d, J=7.8 Hz, 1 H), 7.09 (d, J=7.5 Hz, 1 H), 6.76-6.70 (m, 2 H), 4.62 (s, 2 H), 4.14-4.07 (m, 1 H), 3.79 (s, 2 H), 3.47 (t, J=5.4 Hz, 2 H), 2.81-2.72 (m, 3 H), 1.99-1.91 (m, 1 H), 1.40 (s, 9 H); ESI-LCMS m/z calcd for C32H35F3N2O4S: 600.7; found 601.3 (M+1)+.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:26]([O:28]CC)=[O:27])=[C:23]([CH3:25])[N:24]=3)[CH2:16][C@H:15]2[F:31])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].Cl.O>CO.O1CCCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)[CH2:16][C@H:15]2[F:31])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2F)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.18 mL, 2.37 mmol) was added to a mixed solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (196c) (105 mg, 0.237 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. The reaction solution was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution (2.37 mL, 2.37 mmol) and water were added to the resulting residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 72 mg of the title compound (73%) as a colorless solid.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[C:13]([CH3:20])[N:12]=[CH:11]2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([C:17]([O-:19])=[O:18])=[C:13]([CH3:20])[N:12]=[CH:11]2)=[CH:8][CH:9]=1.[Na+:2]
Reactant: Cc1ncn(-c2ccc(Cl)cc2)c(=O)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncn(-c2ccc(Cl)cc2)c(=O)c1C(=O)[O-]

Procedure:
To 5 ml of 1.0 N aqueous sodium hydroxide solution (5.0 mmoles) diluted with 50 ml of methanol is added one equivalent of 1-(4-chlorophenyl)-1,6-dihydro-4-methyl-6-oxopyrimidine-5-carboxylic acid prepared as in Example 2. After stirring for a short time the resulting slurry (pH 7-8) is evaporated in vacuo. The solid residue is slurried in ether and isolated by vacuum filtration. Drying gives a quantitative yield of sodium 1-(4-chlorophenyl)-1,6-dihydro-4-methyl-6-oxopyrimidine-5-carboxylate, m.p. >250° C.
Reaction SMILES: Br[CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=O.[NH:22]([NH:24][C:25](=[S:33])[O:26]C1C=CC=CC=1)N.C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:20]([CH:2]1[S:33][C:25](=[O:26])[NH:24][N:22]=[C:3]1[C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)[CH3:21]
Reactant: CCC(Br)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: NNNC(=S)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCC1SC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (145 μmol) 2-bromo-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one, 60 mg (293 μmol) O-phenyl hydrazinethiocarbamate, 50 μl (363 μmol) TEA, 2 ml acetonitrile and 200 μl water are stirred together at 80° C. for 1 h. The reaction mixture is extracted with water and DCM. The org. phase is dried and the solv. is eliminated completely in vacuo. The residue is combined with 1 ml acetonitrile and 2 drops of water. 10 mg (53 μmol) para-toluenesulphonic acid monohydrate are added under argon and the mixture is also stirred for 1 h at RT under argon. Then it is left to react for 30 min under argon at 100° C. in the microwave. The reaction mixture is purified by RP-HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:46]=[CH:45][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH:28](C(OCC)=O)[C:29]([O:31]CC)=[O:30])[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:21]2)=[CH:17][CH:16]=1.[OH-].[K+].Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:46]=[CH:45][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:22]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CCCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of diethyl 2-[3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propyl]malonate (1.56 g), 4N aqueous potassium hydroxide solution (5 ml) and ethanol (10 ml) was refluxed for 30 minutes. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. A mixture of the residue and pyridine (10 ml) was stirred at 110° C. for 2 hours. After removal of the solvent under reduced pressure, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 5-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]pentanoic acid (857 mg, yield: 65%). This was recrystallized from ethyl acetate-hexane. Melting point: 109–110° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.CC(O)=O.[Fe]>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-6-nitrobenzoate (715 mg, 3.59 mmol) was dissolved in EtOH/HOAc/(10 mL/10 mL), followed by addition of iron powder (602 mg, 10.8 mmol) at room temperature. The resulting mixture was refluxed under N2 for 2 hrs. After cooling down to room temperature, the brown suspension was partitioned between H2O (30 mL) and Et2O (100 mL). After separation, the aqueous solution was extracted with Et2O (50 mL). The combined organic layers were washed with 1N NaOH (3×50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, methyl 2-amino-6-fluorobenzoate, an colorless oil which became wax-type solid on standing. The crude compound was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3 H), 5.67 (s, 2 H), 6.34 (ddd, J=11.58, 8.06, 1.01 Hz, 1 H), 6.41 (d, J=8.31 Hz, 1 H), 7.13 (td, J=8.18, 5.79 Hz, 1 H); Mass spec. 170.06 (MH+), Calc. for C8H8FNO2 169.05.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCc1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of racemic 1,3-diphenyl-1-propanol (1.26 g; 5.94 mmol) was dissolved in 10 mL of acetone, and Jones reagent was added until persistence of the orange color. After stirring for 30 min, the reaction was quenched by adding 2 mL of 2-propanol. The solvent was decanted away from the precipitated solids, which were washed with ethyl acetate. The combined organic fractions were washed with 2×20 mL of water, dried and concentrated. The crude product was filtered through a plug of silica gel, eluting with 25% ethyl acetate/hexane, to obtain 1.07 g (86%) of 1,3-diphenylpropanone as a white crystalline solid, 1H NMR (360 Mhz; CDCl3): d 3.09 (t, 2H, J=8.1); 3.33 (t, 2H, J8.1); 7.29 (m, 5H); 7.49 (m, 3H); 7.98 (m, 2H).