Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.Br[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[O:31])[CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC.O>[C:38]1([C:36]2[CH:37]=[C:32]([C:30]([NH:29][C:18]3[CH:17]=[C:16]([C:9]4[CH:10]=[CH:11][S:7][CH:8]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:31])[CH:33]=[N:34][CH:35]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccsc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Water (0.6 mL), sodium carbonate (47 mg), 3-thiopheneboronic acid (27 mg), and bis(triphenylphosphine)palladium(II) dichloride (2.5 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (80 mg), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 10 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-3-yl)benzoate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@H:36]4[OH:48])=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([NH:6][C:7](=[N:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([Cl:29])=[CH:21][CH:20]=2)=[C:13]([Cl:30])[C:12]=1[CH3:31])SC)=[O:5].O1CCCC1.C(O)C.[CH3:44][NH:45][CH3:46]>O>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]=[C:7]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([Cl:29])=[CH:21][CH:20]=2)=[C:13]([Cl:30])[C:12]=1[CH3:31])[N:45]([CH3:46])[CH3:44])=[O:5]
Reactant: CSC(=Nc1cc(C)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1C)NC(=O)c1ccccc1Cl
Reactant: CNC
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=NC(=O)c2ccccc2Cl)N(C)C)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture containing 5.0 grams of 1-(2-chlorobenzoyl)-3-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-S-methylisothiourea prepared in Part A, 25 milliliters of tetrahydrofuran, 10 milliliters of ethanol and 50 milliliters of a 40% aqueous dimethylamine solution was refluxed in a nitrogen atmosphere for 5 hours. An additional 25 milliliters of 40% aqueous dimethylamine solution was added and reflux was continued for an additional 16 hours. After cooling to room temperature, the mixture was poured into 200 milliliters of water. This aqueous mixture was extracted twice with methylene chloride and twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate. Removal of the solvents afforded 3.97 grams of a crude material. Chromatography of the crude material on silica gel using 9:1 ethyl acetate:methanol for elution afforded 1.87 grams of 2-(2-chlorobenzoyl)-3-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-1, 1-dimethylguanidine as an amphomorous solid having a melting point of 85° C.-97° C. Elemental analysis of the amphomorous solid indicated the following:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:48][C:49]3[S:50][CH:51]=[CH:52][N:53]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.25 h

Procedure:
2-(4-Cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4; (1 equi.) and HATU (1.5 equi) was dissolved in DCM. To this solution was added D1PEA (2 equi.) and stirred for 15 minutes followed by addition of 2-aminothiazole (1 equi.) and continued to stir over night at room temperature. Reaction mixture was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH3:13])[C:3]#[N:4]>O1CCCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:2][C:3]#[N:4])=[C:7]([CH3:13])[CH:8]=1
Reactant: Cc1cc(F)ccc1CC(Cl)C#N
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C=CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 195.2 %

Procedure:
at room temperature, to 21.7 g (0.11 mole) of 2-chloro-3-(4-fluoro-2-methylphenyl)-propionitrile in 100 ml of tetrahydrofuran, and when the addition is complete, the mixture is stirred at room temperature for 15 hours and filtered, the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate, washed consecutively with 1-normal hydrochloric acid and water and dried over sodium sulphate, and the solvent is removed in vacuo. 34.6 g (96% of theory) of 3-(4-fluoro-2-methylphenyl)-acrylonitrile of melting point 86° C. -87° C. are obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([OH:20])=O)[NH:5][C:6](=[O:16])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3].[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[CH2:1]([N:4]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])=[O:20])[NH:5][C:6]([NH:7][C@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: C=CCN(CC(=O)O)NC(=O)N[C@@H](C)c1ccccc1
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC)NC(=O)N[C@@H](C)c1ccccc1
Yield: 81.5 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, (S)-2-(1-allyl-2-(1-phenylethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-5) 133 mg (0.48 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 203 mg (0.4 mmol) and purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 250 mg (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[O:15])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C([NH+](CC)CC)C.[N-:45]=[N+:46]=[N-:47].[Na+].Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[NH:47][N:46]=[N:45][N:24]=4)=[CH:21][CH:22]=3)=[O:15])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
The suspension of 0.13 g (0.25 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-N-(4-cyano-phenyl)-2-cyclohexyl-acetamide, 0.17 g (1.26 mmol) triethylammonium hydrochloride and 82 mg (1.26 mmol) sodium azide in 3 mL ortho-xylene was stirred at 145° C. for 2.5 hrs. The brown suspension was poured on 1M aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in acetonitrile and a few drops of water were added upon which precipitation started. The formed suspension was filtered and the solid was washed with acetonitrile containing a few drops of water to give the desired compound as a white solid (68%). MS (ES+): 548.3 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:37])[C@H:17]([NH:27][C@H:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]1[CH:19]=[CH:20][C:21]2[O:25][CH:24]=[CH:23][C:22]=2[CH:26]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[O:25]1[C:21]2[CH:20]=[CH:19][C:18]([C@@H:17]([NH:27][C@H:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])[C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])=[O:37])=[CH:26][C:22]=2[CH:23]=[CH:24]1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1OCc1ccccc1)c1ccc2occc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc2occc2c1
Reaction time: 5 h
Yield: 82 %

Procedure:
A mixture of palladium on carbon (10%, 500 mg), methyl N-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate (5.1 g) and ethyl acetate (60 ml) was stirred under a hydrogen atmosphere for 5 hours. The reaction was then filtered through Celite and the filter pad was washed with further portions of ethyl acetate. The combined organic fractions were evaporated to give methyl N-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (3.429 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+].CC[O:18][CH2:19][CH3:20]>>[CH:2]1([C@@H:19]([OH:18])[CH2:20][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H](CNCc1ccccc1)C1CCCCC1
Yield: 74 %

Procedure:
Following removal of the solvent under reduced pressure, the β-aminosulfate from the reaction of 1-(R)-cyclohexyl-1,2-cyclic sulfate (0.206 g, 1 mmol) and benzylamine (0.214 g, 2 mmol) was stirred with 20% H2SO4 (5 mL) and ether (5 mL) at room temperature (refluxing of the two phase mixture expedites the hydrolysis) for 12 hours. The organic phase was discarded and the aqueous phase was adjusted to pH 10 with 20% aq. NaOH and extracted with ether (3×20 mL). The combined organic phases were washed with brine (20 mL) and dried over Na2SO4. Concentration gave 1(R)-cyclohexyl-2-benzylaminoethanol (0.117 g, 74%), mp. 56°-58° C., [α]22D=-1.2° (c 1, CHCI3 ; 1H NMR (CDCI3) δ 7.3 (S, 5 H), 3.75 (d, J 5.77 Hz, 2 H), 3.35 (m, 1 H), 2.75 (dd, J=2.5, 9.6 Hz, 2 H), 2.5 (dd, J 9.6, 13 Hz, 1 H), 1.9-1.5 (m, 5 H), 1.3-0.9 (m, 7 H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[N:6]=1)([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][N:28]([C:12](=[O:14])[CH:11]([N:7]4[C:8]([CH3:10])=[CH:9][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[N:6]4)[CH2:15][CH3:16])[C:27]=3[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CCC(C(=O)O)n1nc(C(C)(C)O)cc1C
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(C)(C)O)cc1C

Procedure:
The title compound was prepared from 2-(3-(2-hydroxypropan-2-yl)-5-methyl-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 3.7 mg of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.44 (m, 2H), 7.15 (t, J=8.6 Hz, 2H), 5.92 (s, 1H), 5.17 (dd, J=7.4, 7.4 Hz, 1H), 3.73 (m, 1H), 3.48 (m, 1H), 2.75 (m, 2H), 2.33 (m, 1H), 2.23 (s, 3H), 2.17 (s, 1H), 2.14 (m, 1H), 1.87 (m, 1H), 1.73 (m, 1H), 1.52 (s, 6H), 0.96 (t, J=7.4 Hz, 3H); MS: (ES) m/z calculated for C23H29FN5O2 [M+H]+ 426.2, found 426.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:27][C:28]([CH3:33])([CH3:32])[C:29](O)=O>>[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:29][C:28]([F:27])([CH3:33])[CH3:32])[CH2:15][CH2:16]1
Reactant: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)c(F)c2)CC1
Reactant: CC(C)(F)C(=O)O
Agent: Cl
Product: CC(C)(F)CN1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1

Procedure:
Prepared essentially as Example 2 starting from 4-[3-fluoro-4-(piperidin-4-ylmethoxy)-phenyl]-1-methanesulfonyl-1,2,3,6-tetrahydro-pyridine hydrochloride salt and 2-fluoro-2-methyl-propionic acid. MS (m/z) 443 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[Br-].C([NH3+])CCC.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(OCC)C.O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[NH3+]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
4-bromotoluene, 171 mg (1 mmol), 2-methoxyphenylboronic acid, 152 mg (1 mmol), palladium diacetate, 1 mg (4 μmol), N-butylammonium bromide, 322 mg (1 mmol), and 2 M aqueous Na2CO3, 1.9 mL (3.8 mmol), were placed in a microwaveable pressure vial and heated to 150 C for 5 minutes. After cooling to room temperature, the product was poured into a separatory funnel and 30 mL each of water and diethyl ether were added. After extraction, the layers were separated and the aqueous layer washed with another 30 mL diethyl ether. The ether extracts were combined, dried over MgSO4, and the solvent removed by rotary evaporation under vacuum. 2-methoxy-4′-methylbiphenyl, 160 mg (81% yield) was obtained as a solid product, 95% purity by NMR.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:16]1[CH:17]=[C:18]([CH:22]([CH3:43])[C:23]([NH:25][CH2:26][CH:27]([OH:42])[CH2:28][NH:29][C:30](=[O:41])[C@H:31]([CH3:40])[NH:32]C(OC(C)(C)C)=O)=[O:24])[CH:19]=[CH:20][CH:21]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:16]1[CH:17]=[C:18]([CH:22]([CH3:43])[C:23]([NH:25][CH2:26][CH:27]([OH:42])[CH2:28][NH:29][C:30](=[O:41])[C@H:31]([CH3:40])[NH2:32])=[O:24])[CH:19]=[CH:20][CH:21]=1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C(=O)NCC(O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NCC(O)CNC(=O)[C@H](C)N)c1cccc(C(=O)c2ccccc2)c1

Procedure:
While stirring at 0°, 6.4 ml (83.6 mmol) of trifluoroacetic acid (density=1.49) are added to a solution of 1.59 g (3.17 mmol) of N-tert.-butoxycarbonyl-L-alanine-3-[2-(3-benzoylphenyl)-propionylamino]-2-hydroxypropylamide, containing 0.21 mol of water, in 25 ml of absolute methylene chloride and the resulting solution is stirred for 3 hours at 0°. 60 ml of diethyl ether are then added to the clear colourless solution and the resulting suspension is stirred for 15 minutes at 0°. The colourless crystals formed are filtered off with suction and washed with diethyl ether. 1.45 g of crude product are obtained; this is suspended again in 50 ml of hot diethyl ether. After cooling, the suspension is stirred for a further one hour at room temperature and the resulting crystals are filtered off with suction and washed with diethyl ether. L-alanine-3-[2-(3-benzoylphenyl)-propionylamino]-2-hydroxypropylamide trifluoroacetate is obtained in the form of colourless crystals that decompose at 92° and above and contain 0.25 mol of water; [α]D20 =+10.9°±0.9° (c= 1.054; methylene chloride), Rf =0.12 (chloroform:methanol=4:1), Rf =0.17 (chloroform:methanol=7:3), Rf =0.23 (chloroform:methanol:water=70:30:5).
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1COCC1>[CH:1]1([NH:4][C:5](=[S:39])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)NC2CC2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 150 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-morpholinophthalazin-6-yl)benzamide (85 mg, 0.22 mmol) and Lawesson's reagent (97 mg, 0.24 mmol) in 1 mL THF was heated at 150° C. for 10 min in a microwave oven. Volatile solvents were removed under reduced pressure and the brown residue was purified on an ISCO column (12 g, eluted with 1-10% MeOH in ethyl acetate) to provide N-cyclopropyl-4-methyl-3-(l-morpholinophthalazin-6-yl)benzothioamide as a yellow solid. Found MS (ESI+) m/z: 405.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.C([Li])(CC)C.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH:12]1([CH2:11][O:10][C:4]2[CH:3]=[C:2]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: COc1ccc(Br)cc1OCC1CC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
To 60 ml of dehydrated tetrahydrofuran solution containing 3.64 g (14.2 mmol) of 4-bromo-2-cyclopropylmethoxy-1-methoxybenzene was added dropwise 18.0 ml of tetrahydrofuran solution containing 0.97M sec-butyl lithium at −70° C. under argon atmosphere, and the mixture was stirred at the same temperature for 50 minutes. Then, 3.70 ml (19.2 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane was added to the mixture, and the resulting mixture was raised to room temperature. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and after adjusting a pH thereof to 2 with 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure to obtain 4.78 g (purity: 84.7%) of the title compound as a slightly yellowish oil. (Yield: 94%)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 166.9 %

Procedure:
To a solution of diethyl 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)malonate (6 g, 5.42 mmol) in ethanol (60 mL) was added potassium hydroxide (3.04 g, 54.2 mmol). The reaction mixture was stirred at 80° C. for 1 hr., and then concentrated under reduced pressure. The reaction mixture was adjusted to pH 7 with 10% aqueous HCl solution. The reaction mixture was extracted with 100 mL of EtOAc, and the organic layer was separated, dried over Na2SO4, and then concentrated under reduced pressure to provide 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetic acid (3 g, 100%).