Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1([C:12](Cl)=[O:13])[CH2:6][CH:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1>ClCCl.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:2](=[O:3])[C:4]3([CH2:6][CH:5]3[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12](=[O:13])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=3)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CC1(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC12C(=O)Nc1ccccc1N(c1ccc(Cl)cc1)C2=O
Temperature: 100 °C
Yield: 15.5 %

Procedure:
Ethyl 2,2-bis(chlorocarbonyl)cyclopropanecarboxylate (2 g, crude product from last step) in dichloromethane (10 mL) was added dropwise to a solution of N1-(4-chlorophenyl)benzene-1,2-diamine (2.2 g, 10 mmol) in toluene (50 mL) and the resulting mixture was heated to 100° C. for 48 h. The solvent was evaporated and the residue was purified by CombiFlash (PE:EA=5:1) to obtained ethyl 1-(4-chlorophenyl)-2,4-dioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (500 mg, 13%). LRMS (M+H)+: 384 m/z. 1H NMR (300 MHz, CDCl3): δ 1.07-1.12 (t, J=7.2 Hz, 3H), 1.72-1.81 (m, 1H), 2.16-2.18 (m, 1H), 2.41-2.43 (br, 1H), 3.92-4.00 (m, 2H), 7.20-7.25 (m, 1H), 7.42-7.49 (m, 4H), 7.52-7.65 (m, 3H), 8.06-8.08 (m, 1H).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[C:11]([CH3:49])[CH:10]=1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[C:11]([CH3:49])[CH:10]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.10 mL, 0.30 mmol) was added to a THF (4 mL) and MeOH (2 mL) solution of ethyl 3-(5-(2-(((4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (60 mg, 0.10 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH:10]([CH3:32])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21](=[O:23])[NH2:22])[CH:20]=1)[N:17]([CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH2:16][CH2:15]2)[CH3:2].[OH-].[Na+:38]>C(O)C>[CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH:10]([CH3:32])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21](=[O:23])[NH2:22])[CH:20]=1)[N:17]([CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH2:16][CH2:15]2)[CH3:2].[Na+:38]
Reactant: CCOC(=O)CCCN1CCc2cc(CC(C)NCCOc3ccccc3OCC)cc(C(N)=O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccccc1OCCNC(C)Cc1cc2c(c(C(N)=O)c1)N(CCCC(=O)[O-])CC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 4-[5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]-7-carbamoylindolin-1-yl]butyrate (88 mg) in ethanol (1 ml) was added a 1N aqueous sodium hydroxide solution (180 μl), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was purified by medium pressure liquid column chromatography on ODS using a mixture of methanol and water (1/1) as eluent to give 51 mg of sodium 4-[5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]-7-carbamoylindolin-1-yl]butyrate as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>C(#N)C>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:8]([C:12]([NH:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:24]1
Reactant: N[C@H]1CCNC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CC#N
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43(a)) (500 mg) and (3S)-3-pyrrolidinamine (0.60 mL) in acetonitrile (3 mL) was heated at 100° C. in a microwave for 40 minutes after which it was cooled to room temperature and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 95:5:0.5 as eluant) and subsequent recrystallisation (acetonitrile) afforded the title compound as a solid (280 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[CH:15](N(C)C)[N:16]([CH3:18])[CH3:17])(C)(C)C>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccccc1C#N
Product: CN(C)C=Cc1ccccc1C#N

Procedure:
Reaction of 2-methylbenzonitrile with 1-(t-butoxy)-N,N,N′,N′-tetramethylmethanediamine to give 2-(2-dimethylaminovinyl)benzonitrile has been reported (Fisher, U. et al. Helvetica Chimica Acta, 1990, 73, 763).
Reaction SMILES: N1C2C(=CC=CC=2)C(C2[O:14]C(C)N(C(OC)=O)C=2)=C1.[C:20]([NH:23][CH:24]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])(=[O:22])[CH3:21].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1>[C:20]([NH:23][CH:24]([C:29]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:14])[C:25]([O:27][CH3:28])=[O:26])(=[O:22])[CH3:21]
Reactant: COC(=O)N1C=C(c2c[nH]c3ccccc23)OC1C
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(NC(C)=O)C(=O)c1c[nH]c2ccccc12
Yield: 84 %

Procedure:
Oikawa et al. (J. Org. Chem., vol. 42, pp. 1213-1216, 1977) describes preparation of methyl 5-(3-indolyl)-2-methyloxazole-3-carboxylate in 33% yield by oxidation of methyl 2-acetamido-3-(3-indolyl)propionate with DDQ in tetrahydrofuran. Use of aqueous tetrahydrofuran gave methyl 2-acetamido-3-(3-indolyl)-3-oxopropionate in 84% yield. Preparation of the corresponding thiazole or imidazole is not described.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[C:24]([CH3:36])([CH3:35])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CC#N.CCOC(C)=O>[CH3:35][C:24]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)([CH3:36])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)OCc1ccccc1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (554 mgs, 2.4 mmol) in CH3CN (5 mL) and K2CO3 (1.1 g, 8.0 mmol) was added benzyl 2-bromo-2-methylpropanoate (512 mgs, 2.0 mmol). The reaction mixture was heated to 80° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, stirred and filtered. The filtrate was then concentrated and purified by flash chromatography on silica gel with elution using 3% MeOH/CH2Cl2 to give Benzyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propanoate.
Reaction SMILES: [NH:1]([C:18]([O:20]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.[C:35]1([C:41]2[CH:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:44]=[C:43]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]C(O)=O)[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:35]1([C:41]2[CH:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:44]=[C:43]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:18]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]3[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)=[O:20])[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: *CC(*)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 18 h

Procedure:
To a teabag (5×5 cm polypropylene filters, 0.75 μm mesh) was added 0.30 g of Fmoc-Tyr(OtBu)-Wang Resin. The teabag was washed with the following (10 mL/bag): DMF 2×3 min, 20% piperidine in DMF 1×3 min, 20% piperidine in DMF 1×30 min, DCM 8×3 min, and DMF 3×3 min. About 2.5 equivalents of 6-[(4,6-Diphenyl-2-pyridinyl)oxy]-hexanoic acid, five equivalents of each of the following; HBTU, HOBT, diisopropylethylamine(DIEA) and DMF (10 mL/bag) were added. The bag was then shaken overnight for about 18 h. The bag was then washed with the following (10 mL/bag): DMF 3×3 min, DCM 8×3 min. The bag was dried under high vacuum. The contents of the bag was then placed in a small erlenmeyer flask. To the flask was added 10 mL of cleavage cocktail (95% trifluoroacetic acid, 2.5% triisopropylsilane, and 2.5% water). The resin was allowed to sit for 2 h while occasionally being swirled. After each swirl the sides of the flasks were rinsed with additional cocktail until the total volume of cocktail added was 15 mL. After 2 h, the resin was filtered and washed with TFA (2×4 mL). The filtrates were then concentrated to an oil under high vacuum. The oils were then purified by prep HPLC method 2 described above, to give 43.6 mg of N-[6-[(4,6-diphenyl-2-pyridinyl)oxy]-hexanoyl]tyrosine. ESMS: Calcd. For C32H32N2O5, 524.23; Found, 525.4 (M+H)+1
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:18]C(C)([O-])C.[K+].CI.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 94 %

Procedure:
A mixture of isomers of 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 5 Step 2, 12.7 g, 43.0 mmol) was dissolved in THF (210 mL) under N2 and cooled to 0° C. Potassium tert-butoxide (5.79 g, 51.6 mmol) was added portionwise and the mixture was stirred at 0° C. for 25 min. Methyl iodide (4.30 mL, 68.8 mmol) was added. The cooling bath was removed, and the mixture was stirred at r.t. Additional potassium tert-butoxide (0.483 g, 4.30 mmol) was added twice, after 2 h and 3 h respectively, and then the mixture was stirred for 2 h. Water (100 mL) was added and the resulting solution was partitioned between aq. NaCl solution (200 mL), and EtOAc (200 mL). The aq. phase was extracted with another portion of EtOAc (100 mL). The combined organic phases were dried (MgSO4) and evaporated to give 12.5 g (94% yield) of a mixture (approx. 80:20) of:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13]1>O>[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH2:13]1
Reactant: OCC1CCOC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OCC1CCOC1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
A mixture of phthalic anhydride (7.41 gm) and tetrahydro-3-furanmethanol were heated with stirring at 130° C. under nitrogen. After 1.5 h, the clear liquid was allowed to cool, treated with water and extracted with EtOAc (×3). The combined organics were dried by passing through a hydrophobic frit and evaporated to a clear oil which crystallised on trituration with light petrol. The solid was filtered, washed and dried, yield 11.93 gm.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:60][S:61][CH2:62][CH2:63][CH:64]([NH2:67])[CH2:65][NH2:66]>CN(C=O)C.C(#N)C.O>[NH2:67][CH:64]([CH2:63][CH2:62][S:61][CH3:60])[CH2:65][NH:66][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=12)=[O:16]
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CSCCC(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCC(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
A mixture of 70 mg of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (75% purity, 0.118 mmol) from Example 4A, 66 mg of HATU (0.174 mmol) and 0.083 ml (0.474 mmol) of N,N-diisopropylethylamine in 0.7 ml of DMF was stirred at RT for 10 min. This reaction mixture was added to a solution of 53 mg (0.236 mmol) of rac-4-(methylsulphanyl)butane-1,2-diamine dihydrochloride in 0.14 ml of DMF at 0° C. and the mixture was stirred for 60 min. The reaction mixture was admixed with water and acetonitrile and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 40 mg of the target compound were obtained (54% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][C@@H:13]([F:16])[C@H:12]1[C:11](=O)[N:10]([C@@H](C1C=CC=CC=1)C)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][C@@H:13]([F:16])[C@@H:12]1[CH2:11][N:10]([C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC[C@@H](F)[C@H]2C1=O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@]12CC[C@@H](F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reaction time: 5 h
Yield: 83.5 %

Procedure:
{(1S,5R,6R)-6-Fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octan-1-yl}carboxylic acid tert-butyl ester (420 mg, 1.21 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1 M borane-tetrahydrofuran complex (3.63 mL, 3.63 mmol) was added dropwise in a nitrogen atmosphere. After five hours, a 1 M borane-tetrahydrofuran complex (3.63 mL, 3.63 mmol) was added; after 15 hours, a 1 M borane-tetrahydrofuran complex (3.63 mL, 3.63 mmol) was further added. After stirring for three hours, ethanol (18 mL), water (2 mL), and triethylamine (2 mL) were added, and the mixture was stirred at 80° C. for two hours. The reaction solution was evaporated under reduced pressure, and a saturated ammonium chloride solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (3 mL). Benzyloxycarbonyl chloride (1.03 g, 6.04 mmol) was added, and the mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give 367 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][NH:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:17])[CH:5]=1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Temperature: 0 °C
Yield: 76 %

Procedure:
3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g, 0.03 mol), ethyl bromoacetate (5.39 g, 0.03 mol) and diisopropylethylamine (5.1 g, 0.03 mol) in 50 mL of DMF were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel, (hexane:ethyl acetate 90:10) to afford pure [3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](N)[CH:5]=[C:4]([Cl:12])[N:3]=1.[ClH:13].N([O-])=O.[Na+].[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Cl
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1c(Cl)cc(Cl)nc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
2,6-dichloro-3-nitropyridine-4-amine (2.27 g, 10.9 mmol) was added to 48 mL concentrated hydrochloric acid, and cooled to 0-5° C. To the solution was added sodium nitrite (2.26 g, 32.7 mmol) in batches. After the addition of sodium nitrite, the reaction solution was stirred for 1 h at 0-5° C., and then stirred for 2 h at 25° C., adjusted to pH=7 with 40% sodium hydroxide solution, and extracted with ethyl ether. After the organic phase was dried (Na2SO4) and concentrated, it was subjected to column chromatography eluted with petroleum ether to afford 2 g white solid with a yield of 80.7%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C#N)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 26449.5 %

Procedure:
To a solution of 6-chloronicotinonitrile (200 mg, 1.46 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-2-methylpropan-1-amine (290 mg, 1.75 mmol, 1.2 equiv) in isopropanol (3 mL) in a microwave vial equipped with a stir bar was added potassium carbonate (720 mg, 2.19 mmol, 1.5 equiv). The vial was fitted with a microwave vial cap and heated to 120° C. for 20 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After the residue was redissolved in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (1%-3% MeOH/DCM) provided the title compound as a beige solid (104 g, 27%), (m/z [M+H]=270.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=O)/C=C/N(C)C)cc1
Yield: 88 %

Procedure:
The title compound was prepared in 88% yield from 1-(4-methoxyphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.88-3.06 (6H, br s), 3.85 (3H, s), 5.71 (1H, d, J=12.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=12.0 Hz), 7.91 (2H, d, J=8.8 Hz).
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)/[C:6]([O:8]C)=[O:7].Cl[CH2:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[CH:27][CH:26]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:36][C:35]1[O:34][C:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:32][C:31]=1[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:3]/[N:4]=[C:5](\[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)/[C:6]([OH:8])=[O:7])=[CH:44][CH:43]=1
Reactant: COC(=O)/C(=N/O)c1cccc(Oc2ccccc2)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2cccc(Oc3ccccc3)c2)cc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Sodium hydride (60% in oil, 107 mg) was added under a nitrogen atmosphere to a solution of methyl E-2-hydroxyimino-2-(3-phenoxylphenyl)acetate (605 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at 40° C. for 2 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-phenoxyphenyl)acetic acid (745 mg, yield 62%) as a colorless amorphous material. m.p. 55-65° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:15])=[CH:7][CH:6]=1)#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2sccc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccsc1-c1ccc(CBr)cc1
Reaction time: 24 h
Yield: 40.9 %

Procedure:
24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide are added, as well as 0.1 g of benzoyl peroxide. The mixture is heated to reflux for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept in a freezer for 24 hours. The crystals formed are drained to give 14 g of 4-(3-cyano-2-thienyl)benzyl bromide in the form of crystals of melting point 80° C.