Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]1[C:16](=[O:27])[C:17](=O)[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])C>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[C:16](=[O:27])[C:15](=[O:14])[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]#[N:11]
Reactant: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Reactant: N#Cc1ccc(CN)c(Cl)c1
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O)C(C)(C)C
Yield: 78.7 %

Procedure:
2-Chloro-4-cyano-benzylamine (0.30 g, 1.80 mmol, Example 2, Step 3) and (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (0.406 g, 1.80 mmol) were stirred in ethanol (10 mL) at 70° C. for 18 hours. The reaction was cooled and diluted with diethyl ether. Filtration afforded 0.49 g (79%) of (R)-3-chloro-4-{[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-methyl]-benzonitrile which was collected as a white solid: mp 237°-241° C.; [α]25D =+27.30° (10.99 mg/mL, DMSO); 1H NMR (DMSO-d6) δ8.10 (d, 1H), 7.89 (dd, 1H), 7.68 (m, 1H), 7.69 (d, 1H), 7.36 (br d, 1H), 4.87 (m, 2H), 3.90 (m, 1H), 1.12 (d, 3H), 0.86 (s, 9H) ppm. IR (KBr): 3100, 2950, 2250, 1800 cm-1. MS (m/z) 345/347 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[C:7]([F:17])[C:8]([F:16])=[C:9]([F:15])[CH:10]=2)[N:5]=1)[CH3:2].O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[C:11]2[C:6](=[C:7]([F:17])[C:8]([F:16])=[C:9]([F:15])[CH:10]=2)[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(O)c2cc(F)c(F)c(F)c2n1
Solvent: O
Product: CCOc1cc(Cl)c2cc(F)c(F)c(F)c2n1
Temperature: 0 °C

Procedure:
A suspension of 69.5 g of 2-ethoxy-6,7,8-trifluoro-4-hydroxyquinoline in 430 cm3 of phosphoryl chloride is heated, with stirring, at a temperature close to 100° C. for 30 minutes. The solution obtained is concentrated under reduced pressure (20 kPa) at about 60° C. until the volume is 100 cm3. The residue is taken up in 750 cm3 of ethyl acetate; the solution obtained is poured, with stirring, in the course of 10 minutes into a mixture of 400 cm3 of water and 200 g of ice and the mixture is stirred under these conditions for 30 minutes. After separating off the organic extract, the aqueous phase is extracted again with twice 250 cm3 of ethyl acetate. The combined organic extracts are washed with 3 times 250 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at about 40° C. The oily residue obtained is taken up in 370 cm3 of petroleum ether (40-60). After filtering through diatomaceous silica, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at about 30° C. 70.7 g of 4-chloro-2-ethoxy-6,7,8-trifluoroquinoline are obtained in the form of a beige solid melting at 45° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CCCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (172 mg, 0.492 mmol), 3-(methoxycarbonyl)phenylboric acid (177 mg, 0.984 mmol) and molecular sieves 4 Å (400 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (188 mg, 0.984 mmol) and triethylamine (0.344 mL, 2.46 mmol) were added and the mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was filtered through Celite, followed by addition of a saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=20:1->2:1) gave 88.2 mg (37%) of the desired compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([C:30]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)[CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 33.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-morpholin-4-ylmethyl-benzaldehyde (43.5 mg, 0.212 mmol) were reacted to produce 29 mg (34%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6) 13.09 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.47 (t, J=8 Hz, 1H), 7.39 (m, 1H), 7.17 (s, 1H), 6.91 (m, 1H), 6.41 (d, J=8 Hz, 1H), 6.34 (s, 1H), 3.88 (br s, 1H), 3.60 (br s, 4H), 3.54 (s, 2H), 2.88 (s, 1H), 2.77 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.40 (s, 4H), 2.24 (d, J=8 Hz, 1H), 1.43 (d, J=8 Hz, 1H). MS: 445 (M+H), HPLC: 1.54 min (G method).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH:18]([Mg]Br)=[CH2:19]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:18]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (326 mg) in THF (10 mL)-78° C. was added vinyl magnesium bromide (2.42 mL of 1.0 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 2 hr. The resulting mixture was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow gum. The yellow gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:17]I>CN(C=O)C>[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:17])[CH:8]=1
Reactant: CI
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)c2ccccc12
Reaction time: 1 h
Yield: 18.9 %

Procedure:
To a suspension of sodium hydride (104 mg, 7.61 mmol) in DMF (11 mL) was added a solution of 1H-indol-3-yl-acetic acid methyl ester (0.50 g, 2.6 mmol) in DMF (5.0 mL). The mixture was stirred for 1 h followed by addition of methyl iodide (1.1 g, 7.8 mmol). The reaction mixture was stirred for an additional 18 h, quenched, diluted with saturated ammonium chloride (200 mL), and then extracted with diethyl ether (3×100 mL). The combined organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexanes) giving 100 mg (19%) of (1-methyl-1H-indol-3-yl)-acetic acid methyl ester after purification. HPLC: Rt=8.91 (Method A). MS (ES+): mass calculated for C12H13NO2, 203.09; m/z found 204.09 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60 (d, J=7.9 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.13 (t, 7.4 Hz, 1H), 7.04 (s, 1H), 3.77 (s, 2H), 3.76 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:26][CH2:27]CBr)(=[O:25])[CH3:24]>>[CH3:27][O:26][C:23](=[O:25])[CH2:24][O:22][CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1
Reactant: CC(=O)OCCBr
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: COC(=O)COC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1

Procedure:
[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol prepared in Example 2 and bromoethyl acetate were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:14][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(C(F)(F)F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1cc(CBr)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 49.1 %

Procedure:
5-Methyl-2-(trifluoromethyl)benzonitrile (200 mg, 1.08 mmol) in 1,2-dichloroethane (3 mL) was stirred with N-bromosuccinimide (192 mg, 1.08 mmol) and azobisisobutyronitrile (36.1 mg, 0.22 mmol) at 80° C. for 2 hours. The reaction mixture allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane→ethyl acetate/hexane=1/3 (v/v)) to give the title compound as a colorless solid (140 mg, yield 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1.Br[C:14]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:17]3[C:16]=2[CH:15]=1>>[CH3:25][O:24][C:22]1[C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@@H:17]3[C:16]=2[CH:15]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:12])[CH:23]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Product: COc1ccc(-c2cc(OC)c3c(c2)[C@H]2CNC[C@H]2CN3)c(C)c1

Procedure:
Following the procedures described in Example 12, except that 4-methoxy-2-methylphenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 14. 1H NMR (CDCl3): δ 7.14 (d, 1H, J=8.1 Hz), 6.83-6.73 (m, 2H), 6.62 (s, 1H), 6.61 (s, 1H), 4.49 (broad s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78-3.70 (m, 1H), 3.62-3.05 (overlapping m, 6H), 2.83-2.75 (m, 1H), 2.28 (s, 3H). LRMS (ES)+: 325.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(OC(F)(F)F)ccc1C#N
Temperature: 85 °C
Yield: 90 %

Procedure:
2-Methyl-4-trifluoromethoxy-benzamide 14 (2.0 g, 9.1 mmol) was taken up in phosphorus oxychloride (15 mL) and heated to 85° C. for 2 hrs. The excess phosphorus oxychloride was removed under reduced pressure and the resulting residue partitioned between sat. aqueous sodium bicarbonate and ether. The organic layer was dried (sodium sulfate) and concentrated. The residue was passed through silica gel using 25% ether/hexanes to remove trace impurities and yielded a colorless solid (90%). 1H NMR (400 MHz,CDCl3) δ7.65 (d, J=8.4 Hz. 1 H, Ar), 7.17 (s, 1 H, Ar), 7.13 (d, J=8.4 Hz, 1 H, Ar), 2.6 (s, 3 H, CH3).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9]4=[C:10]([C:19](=[O:23])[NH:20][C:21](=[O:22])[N:8]4[C:7]=2[CH:6]=1)[CH:11]=[CH:12][CH:13]=3.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:20]1[C:19](=[O:23])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[S:15][C:16]4[CH:17]=[CH:18][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][C:7]=4[N:8]([C:9]=23)[C:21]1=[O:22])[CH3:27]
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cccc3c2n(c1=O)-c1cc(C(F)(F)F)ccc1S3
Reaction time: 1 h

Procedure:
57% Sodium hydride in mineral oil (4.2 g., 0.100 mol.) was added to a stirred solution of 28.0 g. (0.0834 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine -1,3(2H)-dione in 220 ml. of dry dimethylformamide. The mixture was stirred for 1 hour at 25°, then 16.8 g. (8.6 ml., 0.108 mol.) of ethyl iodide was added. The resulting greenish yellow, turbid mixture was stirred for 4.5 hours at 25°, then filtered to give a clear yellow solution. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with petroleum ether to remove the mineral oil. The crude solid product was precipitated from a methanol-water mixture to give the title compound, m.p. 150°-152° (ethanol).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[CH2:15][N:14]([C:17](=O)[CH2:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20]([NH:22][CH3:23])=O)[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]2[CH2:33][CH2:34][CH2:35][CH2:36][C:8]=12>CO>[NH2:6][C:7]1[C:16]2[CH2:15][N:14]([CH2:17][CH2:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:20][NH:22][CH3:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]2[CH2:33][CH2:34][CH2:35][CH2:36][C:8]=12
Reactant: CNC(=O)C(CC(=O)N1CCc2nc3c(c(N)c2C1)CCCC3)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: CNCC(CCN1CCc2nc3c(c(N)c2C1)CCCC3)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A tetrahydrofuran solution (1 ml) of (±)-10-amino-2-[3-(3,4-dichlorophenyl)-4-methylamino-1,4-dioxobutyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine (55 mg, 0.119 mmol) was added to a tetrahydrofuran solution (0.92N, 2.59 ml, 2.38 mmol) of a borane-tetrahydrofuran complex under cooling with ice water, and the solution was stirred for one hour and then refluxed under heating for 2 hours. The reaction solution was again cooled with ice water, then methanol (2 ml) was added thereto with case, and the solution was stirred for one hour. The reaction solution was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (1 ml), to which 4N hydrogen chloride/dioxane (2 ml) was added under cooling with ice water with care and the mixture was refluxed under heating for one hour. The reaction solution was concentrated and the residue was neutralized with a sodium hydroxide solution and extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, dichloromethane/methanol=40/1) to obtain the title compound (37.9 mg, 74%) as an colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11]([CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH3:16])[CH:12]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CCC1=O
Product: CC1CCN(C(=O)OC(C)(C)C)CCC1NCc1ccccc1

Procedure:
Racemic 4-benzylamino-5-methyl-azepane-1-carboxylic acid tert-butyl ester was prepared in the same manner from racemic 4-methyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16]P([O-])([O-])=O.[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N+:12]=2[O-:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)n1
Reactant: O=P([O-])([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=C(O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 60 °C
Yield: 68.2 %

Procedure:
A mixture of 6-phenylpicolinic acid (150 mg, 0.75 mmol), K2HPO4 (600 mg) m-CPBA (300 mg, max 70% from Aldrich) in dichloroethane (8.0 mL) was heated at 60° C. for 1.5 h. Additional m-CPBA (2×300 mg) was added and the mixture was heated at 60° C. for 40 min. The reaction mixture was purified by preparative HPLC to afford the desired product (110 mg, 68%) as a white solid. 1H NMR (DMF-d7) δ 8.57 (s, 1H), 8.43 (d, 1H, J=2.2 Hz), 8.10-7.88 (m, 5H), 7.59-7.57 (m, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O[C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:28]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 23 %

Procedure:
A solution of 4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.82 g, 5.2 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.0 g, 5.1 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.29 g, 5.1 mmol) and triphenylphosphine (1.34 g, 5.1 mmol) in toluene (5 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the object compound as an oily substance. 660 mg, (yield 23%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CS(O)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(#N)C>[Br:42][CH2:21][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(CBr)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a warm (90° C.) and stirred solution of ketone 57 (5 g, 0.016 mol) in a mixture of 4:1 toluene and acetonitrile (125 ml) was added methane sulfonic acid (2.64 ml, 0.041 mole) and stirred for 1 hour. The reaction mixture was cooled to 68° C., NBS (3.19 g, 0.018 mol) was added at once and stirred the contents at 65° C. for 4 hour followed by stirring at RT for 18 hour. The solid from the reaction mixture was collected by filtration and dissolved in dichloromethane (100 ml). dichloromethane layer was washed with 10% aq. sodium carbonate and subjected to usual workup and concentration to obtain alpha bromo-ketone 58 (3.0 g, 48%) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: O=C(O)c1[nH]cnc1Cl
Reactant: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 21.6 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile (0.068 g, 0.213 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.427 mmol) were combined in THF (6 mL) and treated with HATU (0.089 g, 0.235 mmol) at 25° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.0205 g, 0.046 mmol, 21.49% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br. s., 1H), 8.23 (br. s., 1H), 7.77 (s, 1H), 7.43-7.55 (m, 2H), 7.36 (t, J=7.71 Hz, 1H), 7.24 (br. s., 1H), 7.13 (br. s., 1H), 4.54 (d, J=4.99 Hz, 2H), 2.95 (spt, 1H), 1.18 (d, J=6.96 Hz, 6H). LC-MS (ES−) m/z 445.09, 447.18 [M−1]. LC-MS (ES+) m/z 447.08, 449.06 [M+H].
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:16]=O>O>[ClH:1].[ClH:1].[C:3]1([CH:9]2[CH2:10][NH:11][CH2:16][NH:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=O
Reactant: NCC(CN)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(C2CNCNC2)cc1
Reaction time: 8 h
Yield: 58 %

Procedure:
37.5 g (0.168 mol) of 2-phenylpropane-1,3-diamine dihydrochloride are dissolved in 100 ml of water, and 13.52 g (0.336 mol) of sodium hydroxide pellets are added. The mixture is cooled in a bath of water+ice and 17 ml of a 30% (w/v) aqueous solution of formaldehyde are added. The mixture is left overnight at room temperature (15°-20° C.) and extracted with 5×50 ml of CHCl3, and the chloroform phase is washed with 25 ml of water, dried over MgSO4 and filtered. The filtrate is evaporated to dryness, the evaporation residue is taken up with 500 ml of anhydrous C2H5OH and acidified with ethanol containing HCl, and the precipitate formed is collected by filtration, washed with a small quantity of anhydrous ethanol and dried in vacuo to give 24 g (yield: 58%) of CRL 41 365. M.p. (inst.)=192° C.