Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=O.O>C1(C)C=CC=CC=1>[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=[S:10]
Reactant: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 137.8 %

Procedure:
Lawesson's reagent (40 mg, 0.1 mmol) was added to a solution of (E)-α-methoxy-N-methyl-2-(α-methyl-4-chloro-benzylideneaminooxy)phenylacetamide (73 mg, 0.2 mmol) in toluene (3 ml), and the mixture was heated at 80° C. for 1.5 hours with stirring. The mixture was cooled to room temperature. Water was added, and the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylthioacetamide (50 mg, 66%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][C:2]3[N:7]=[C:6]([NH:15][C:14]4[CH:16]=[CH:17][C:18]5[O:19][CH2:20][CH2:10][O:11][C:12]=5[CH:13]=4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:13][C:12]=2[O:11]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8 Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.7(s, 1H), 6.58 (s, 1H), 4.23 (m, 4H), 4.24(m, 4H); 19F NMR (CDCl3): δ −47445; LCMS: ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][C:19]([O:21]CC)=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
The ethyl 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetate (10.45 g, 27.5 mmol) was dissolved in a mixture of methanol (150 ml), dioxane (40 ml) and aqueous NaOH solution (4 M, 41.3 ml, 165.2 mmol, 6 eq.) and the solution was stirred overnight When the reaction had ended (TLC control, MC/methanol 95:5), the solution was concentrated. The crude product was taken up in ethyl acetate (600 ml) and the mixture was . . . with KHSO4 solution (0.5 M, 600 ml). The aqueous phase was extracted once more with ethyl acetate (100 ml) and the combined organic phases were washed with sat. NaCl solution (500 ml), dried over Na2SO4 and concentrated. Yield: 9.4 g, 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:31][CH2:30][CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1Br
Reactant: NCCN1CCOCC1
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)cc1Br
Yield: 18 %

Procedure:
Following the procedure described above in Example 1, 4-[(3-bromo-4-methylphenyl)amino]-6-fluoro-[1,7]naphthyridine-3-carbonitrile (300 mg, 1.1 mmol, 1 eq) was reacted with 2-morpholin-4-yl-1-ethylamine (3 mL, 20 eq). The crude product was purified via preparative HPLC to obtain 67 mg product (18% yield):
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[CH:27]([NH:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]1)([CH3:29])[CH3:28]>>[CH:27]([N:30]([C:21]([C:14]1[C:15]([C:17]([F:19])([F:20])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:23])[CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32]1)([CH3:29])[CH3:28]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)NC1CCCCN(C(=O)OC(C)(C)C)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)C3CCCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl 3-(isopropylamino)azepane-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)(=[O:16])[CH3:15]>>[CH3:9][O:8][C:6](=[O:7])/[CH:5]=[CH:4]/[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[O:1][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OCCCCCBr
Reactant: COC(=O)C=Cc1ccccc1O
Product: COC(=O)/C=C/c1ccccc1OCCCCCOC(C)=O

Procedure:
Using the procedure of example 63, 1.78 g (10 mmol) of methyl 2-hydroxycinnamate was alkylated with 2.3 g (11 mmol) of 5-bromopentyl acetate giving (E)-3-[2-[[5-(acetyloxy)pentyl]oxy]phenyl]-2-propenoic acid methyl ester, as a pale-yellow oil, in quantitative yield. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O
Product: O=C1CC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)CCN1S(=O)(=O)c1ccccc1Cl

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethyl)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione and 2-chlorobenzenesulfonyl chloride. MS (ESI): 501.08 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Yield: 76.7 %

Procedure:
11.5 g (30.6 mmol) of (S)-8-bromo-9-oxo-11,12, 13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime were treated with 6.02 g (35.2 mmol) of chloroacetic anhydride in 60 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 3 hours. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 10.2 g (76%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of m.p. 242°-244°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:29][CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C=O)C.O>[NH:34]1[CH:35]=[C:31]([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[C:7](=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5]3)[N:32]=[CH:33]1
Reactant: BrCCc1c[nH]cn1
Reactant: CC(=C1CCc2cc(O)ccc2C1=O)c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
The product obtained from Step 2 (0.180 g, 0.68 mmol) was dissolved in 5 mL of dry DMF and treated with K2CO3 (0.376 g, 2.72 mmol) and 4-(2-bromoethyl)imidazole hydrobromide (0.192 g, 0.75 mmol). After stirring overnight at room temperature, the reaction was diluted with water and extracted with EtOAc. The pooled extracts were washed well with aqueous 0.5N KOH, water and brine, and then dried, filtered, and concentrated. Purification of the residue (SiO2, 5% MeOH in DCM) afforded 0.120 g (49%) of the title compound as a light yellow foam. Conversion of this product to its HCl salt according to the method of Example 34 afforded 0.063 g of a light yellow powder, mp 170-172° C.: CI-MS m/e 359 (M+ +1).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][O:6][P:7]([O-:10])[O:8][CH3:9].C[O-].[Na+]>>[OH:3][C:2]([P:7](=[O:10])([O:8][CH3:9])[O:6][CH3:5])([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: COP([O-])OC
Agent: C[O-]
Agent: [Na+]
Product: COP(=O)(OC)C(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
Into a flask fitted with a reflux condenser was placed a mixture of 37 ml (29 g, 0.50 mol) of acetone and 46 ml (55 g, 0.50 ml) of dimethylphosphite followed by 3 ml of saturated methanolic sodium methoxide solution. A vigorous exotherm ensued and the mixture was allowed to stir at RT for about 16 h. A large deposit of crystals formed and were filtered and washed well with ether-hexane (1:1) to give 50 g of dimethyl 1-hydroxy-1-methylethylphosphonate, mp 75°-77° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13]I.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([O:12][CH3:13])[CH3:11])[CH:5]=1
Reactant: CI
Reactant: CC(O)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
To a stirred and ice-cooled mixture of 1.09 g (27.4 mmol) NaH (60% in mineral oil) in 20 mL dry DMF was added a solution of 5.00 g (24.9 mmol) 1-(3-bromo-phenyl)-ethanol in 10 mL dry DMF under argon atmosphere. The mixture was stirred for 30 min at 0° C. 1.70 mL (27.4 mmol) methyl iodide was added and stirring was continued for 4 h at RT. The mixture was worked up by adding water, followed by extraction with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Cyc/EtOAc=9/1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[F:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:45]3[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4ccnc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 2-fluoropyridine-4-boronic acid (40 mg, 0.27 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture, 0.4 ml of aqueous sodium carbonate (1M) was added, followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, and the residue was dissolved in 2.5 ml of methanol. The product was purified with Preparative HPLC to give 70 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]I)=[CH:4][CH:3]=1.[C-:12]#[C-:13].[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:12]#[CH:13])=[CH:4][CH:3]=1
Reactant: [C-]#[C-]
Reactant: Clc1ccc(CCCI)cc1
Agent: [Na+]
Product: C#CCCCc1ccc(Cl)cc1

Procedure:
The title compound was synthesized using 3-(4-chlorophenyl)-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:21][C:20]4[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Product: Clc1ccc(CSc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 89 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-chlorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>O1CCCC1>[F:1][CH:2]([F:13])[C:3]1[C:7]([C:8]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH2:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([CH3:14])[CH:16]=2)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: Cc1cccc(CC2CCCN2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(CC2CCCN2C(=O)c2c(C(F)F)nn(C)c2F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
At ambient temperature, a solution of 267 mg (1.25 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (1.14 mmol) of 2-(3-methylbenzyl)pyrrolidine and 127 mg (1.25 mmol) of triethylamine in 5 ml of tetra-hydrofurane. The reaction mixture is stirred for 1 hour at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and filtered over a Chemelut™ cardridge to yield after concentration 350 mg of a beige oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 300 mg (71% yield) of [3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazol-4-yl][2-(3-methylbenzyl)pyrrolidin-1-yl]-methanone as a colourless oil (M+H=352).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: COc1ccc(Cl)c(Br)c1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with 3-bromo-4-chloroanisole (1.625 ml, 7.34 mmol), (3-fluorophenyl)boronic acid (1.129 g, 8.07 mmol), potassium carbonate (3.04 g, 22.01 mmol), and tetrakistriphenylphosphine palladium (0) (0.424 g, 0.367 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (19.57 ml) and water (4.89 ml) were added. A reflux condenser was attached, and the flask was lowered into a 90° C. heating bath. After 2 h, the mixture was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 0-10% EtOAc/Heptane) to give an oily solid as product that was used directly in the next step. m/z (ESI) 281.1 (M+H)+.
Reaction SMILES: C1C=CC(N)=CC=1.Cl.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:47])([OH:46])[OH:45])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])C)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:45])([OH:47])[OH:46])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])[CH3:17]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: CNCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The aniline salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-tyrosyl-L-alanyl)amino]-ethylphosphonic acid was suspended in acetic acid and 10% palladium-on-carbon was added under argon. Acetic acid was then added. The mixture was stirred overnight at room temperature and then hydrogenated until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate was evaporated. The residual solid was triturated with methanol, filtered off, washed and dried. The solid was purified by reprecipitation from aqueous hydrochloric acid/ethanol with propylene oxide to give (1R)-1-(N-sarcosyl-L-tyrosyl-L-alanylamino)-ethylphosphonic acid of melting point 275°-277° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1cccs1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(-c2cccs2)c1

Procedure:
3-Methoxybromobenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-methoxyphenyl)thiophene as a yellow liquid. APCI-Mass m/Z 191 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Br:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]([N:1]=[CH:16][N:17]([CH3:19])[CH3:18])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Br)c([N+](=O)[O-])cc1N
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc([N+](=O)[O-])c(Br)cc1C#N
Reaction time: 0.33 h
Yield: 86 %

Procedure:
2-Amino-5-bromo-4-nitrobenzonitrile (815 mg, 3.37 mmol) is admixed with N,N-dimethylformamide dimethyl acetal (1.65 mL, 12.5 mmol). After 20 minutes in an ultrasonic bath, excess N,N-dimethylformamide dimethyl acetal is removed on a rotary evaporator to leave, after chromatographic purification of the residue (silica gel, n-hexane/ethyl acetate: 0→60% ethyl acetate) the product in 86% yield (863 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=1)=[O:43]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(F)cc21
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
A solution of triphenylphosphine (771 mg, 2.94 mmol) in methylene chloride (7 mL) cooled to 0° C. was treated with N-bromosuccinimide (523 mg, 2.94 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (500 mg, 2.26 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 15 min. The reaction was then treated with 2-aminothiazole (521 mg, 5.20 mmol) and stirred at 25° C. for 18 h. At this time, the mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was then washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (160 mg, 23%) as pink solid: mp 203-204° C.; EI-HRMS m/e calcd for C15H14FN3OS (M+) 303.0842, found 303.0844.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[N:9]([CH3:13])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C(=O)COc2ncc(Br)cc21
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a suspension of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (500 mg, 2.183 mmol) in acetone (8 mL) at RT was added potassium carbonate (905 mg, 6.55 mmol) followed by methyl iodide (0.341 mL, 5.46 mmol). This was heated to 60° C. under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to RT, solvent removed in vacuo. The residue was partitioned between water/ethyl acetate (ca. 25 mL each). The aqueous layer was extracted with ethyl acetate (ca. 25 mL twice). The combined organic layers were dried over MgSO4 and solvent removed in vacuo. The residue was purified on silica gel (eluted with 20-60% ethyl acetate/cyclohexane) to afford the title compound (334 mg). LCMS (A): m/z (M+H)+ 243/245, C8H7BrN2O2 requires 242/244 (acidic).