Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[O:36])=[CH:33][CH:32]=1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (100 mg, 0.345 mmol) and triethyl amine (38 mg, 0.38 mmol) in tetrahydrofuran (THF) (2 ml) was added 4-fluorobenzoyl chloride (60 mg, 0.38 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white solid (90 mg, 63%). M.p. 145° C.; MS: m/e=412.3 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:29]([C:45]([NH:47][C@H:48]([C:50](O)=[O:51])[CH3:49])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:28]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[C@H:29]([C:45]([NH:47][C@H:48]([C:50]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:51])[CH3:49])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCNC(=O)OC(C)(C)C

Procedure:
compound SP305R. Same procedure as above with Trp-NH(CH2)4NHBoc (204.6 mg, 0.546 mmol), N-Boc-Tyr(Bn)-Ala-OH (242 mg, 0.546 mmol), EDC (116 mg, 0.61 mmol) and HOBt (82.2 mg, 0.61 mmol) in CH2Cl2/DMF (2.2 mL, 1/1). The crude tripeptide (282 mg) can be recrystallized from hot THF to give a white solid as an analytical sample (89.1 mg, 31.5%). 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.4 (m, 7H, 2 CH2 putrescine, CH3), 1.28 (s, 9H, (CH3)3), 1.37 (s, 9H, (CH3)3), 2.61 (m, 1H, CH2 Tyr or Trp), 2.85-3.1 (m, 7H, CH2 Tyr, CH2 Trp, 2 CH2 putrescine), 4.08 (m, 1H, CHα), 4.29 (m, 1H, CHα), 4.45 (m, 1H, CHα), 5.03 (s, 2H, CH2 (Bn)), 6.73 (m, 1H), 6.87-7.43 (m, 14 aromatic H), 7.56 (d, J=7.7 Hz, 1H), 7.83 (m, 1H), 7.99 (m, 2H), 10.8 (s, 1NH). 13C NMR (75 MHz, DMSO-d6) δ 18.2 (CH3), 26.2, 26.8 (2 CH2 putrescine), 28.1 (CH2 Trp), 28.2 ((CH3)3), 36.3 (CH2 Tyr), 38.2, 39.2 (2 CH2 putrescine), 48.2, 53.4, 55.8 (CHα Ala, Tyr, Trp), 69 (CH2 (Bn)), 77.3, 78 (2 C(CH3)3), 109.8, 111.1, 114.2, 118.1, 118.4, 120.7, 123.4, 127.3, 127.5, 127.7, 128.3, 130.1, 130.3, 136, 137.2 (19 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 170.7, 171.4, 171.8 (3 CO amide). Anal. Calcd. for C44H58N6O8: C, 66.14; H, 7.32; N, 10.52. Found: C, 65.89; H, 7.34; N, 10.77.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2CN(C)[CH2:11][N:10](C)[C:9]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1.C([O-])(O)=O.[Na+].CO.O>C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([NH:10][CH3:11])=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1
Reactant: CN1CN(C)C(=N[N+](=O)[O-])N(Cc2cnc(Cl)s2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g of 1-(2-chlorothiazol-5-ylmethyl)-2-nitroimino-3,5-dimethyl-1,3,5-triaza-cyclohexane, 0.3 g of NaHCO3, 20 ml of methanol and 20 ml of water is stirred for 16 hours at 50° C. The reaction mixture is poured onto 100 ml of ethyl acetate and the aqueous phase separated. The organic phase is concentrated by evaporation and the residue purified on silica gel with dichloromethane/methanol 95:5 as the eluant. This yields the title compound with a melting point of 167-169° C. (compound 2.45).
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Reactant: COC(=O)C(C=O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cncnc4)c[nH]3)cc2)cc1Cl
Yield: 6.8 %

Procedure:
Prepared in a manner similar to that described for E149 using 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-(5-pyrimidinyl)propanoate (84 mg, 0.431 mmol) and K2CO3 (198 mg, 1.436 mmol) in NMP (2 ml), to afford the title compound (11 mg, 6.83% yield). LCMS: rt=3.33 min, [M+H+]=449
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:17][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(O)COc1ccccc1
Temperature: 60 °C
Yield: 85 %

Procedure:
In a two neck flask equipped with a condenser under nitrogen atmosphere were placed 15.017 g (0.1 mol) of 1,2-epoxy-3-phenoxypropane, 9.039 g (0.105 mol) of methacrylic acid, 1.35 g (0.013 mol) of triethylamine and 30 mg of BHT. The reaction mixture was stirred at 60° C. 1H NMR showed reaction completion at 24 hours. Reaction mixtures was dissolved in methylene chloride and extracted with saturated solution of sodium hydroxide (NaOH) 3×25 ml, diluted solution of acid chloride (HCl) 2×25 ml, 2×25 ml of saturated solution of sodium bicarbonate (NaHCO3) and finally with brine 1×25 ml. Organic layer was dried over sodium sulfate (Na2SO4), filtered and vacuum dried. 20.14 grams (yield: 85%) of low viscosity (η=0.0891 Pa*s) amber material was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:31]3[CH2:32][CH2:33][CH:28]([N:27]([CH3:34])[CH3:26])[CH2:29][CH2:30]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Reactant: CN(C)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCC(N(C)C)CC3)ccc2S(C)(=O)=O)c1OC
Yield: 19.4 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (100.0 mg, 0.26 mmol), N,N-dimethylpiperidin-4-amine (66.0 mg, 0.51 mmol), N,N-diisopropylethylamine (133.0 mg, 1.03 mmol) were stirred at 100° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (25.0 mg, 19.6% yield). 1H NMR (400 MHz, CDCl3): δ 7.53 (d, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 6.50 (d, 1H), 6.21 (d, 1H), 5.90 (d, 1H), 4.85 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.74 (m, 2H), 3.24 (m, 1H), 3.05 (s, 3H), 2.76 (q, 2H), 2.26 (s, 6H), 1.78 (t, 2H), 1.55 (d, 3H), 1.45 (m, 2H); MS (ESI) m/z: 496.1 (M+).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: OCC1CCC2CCCCN2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[CH:31]=[C:30]1[CH:38]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:38]([C:30]2[N:29]([CH3:28])[CH:33]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: CCC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Product: CCC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 1-methyl-4-propionyl-1H-pyrrole-2-carbaldehyde. 521 (M+H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)O>ClCCl>[Cl:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH:36]1[CH2:38][CH2:37]1)[C:22]1[C:21]2[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=2)[NH:24][CH:23]=1
Reactant: Cc1ccc(C(O)C2CC2)c(Cl)c1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cccc23)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
135 mg (0.61 mmol) of indium(III) chloride and 0.07 ml (0.92 mmol) of trifluoroacetic acid were added to 132 mg (0.61 mmol) of the compound from Example 86A and 100 mg (0.51 mmol) of the compound from Example 152A in 5 ml of dichloromethane, and the mixture was stirred at RT overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29.0 mg (15% of theory) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.C([O-])(O)=O.[Na+].C(O)(C)C.C(Cl)Cl>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:13]1[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3ccccc3n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(C3CNC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(quinolin-2-yl)azetidine-1-carboxylate (2.8 g, 9.8 mmol, as prepared above) in DCM (10 mL), TFA (10 mL) was added. The resulting mixture was stirred at rt for 2 h and concentrated to obtain a viscous oil which was dried under reduced pressure. The residue obtained was dissolved in DCM (50 mL) and stirred with saturated NaHCO3 (50 mL). The DCM layer was separated and the aqueous layer was concentrated. To the residue obtained, 20% iso-PrOH/DCM (50 mL) was added and stirred for 10 min and filtered. This procedure was repeated three times. The combined filtrates were dried over Na2SO4, filtered, and concentrated to obtain compound 24d as a gummy solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.34 (d, J=8.6 Hz, 1H), 7.94-8.01 (m, 2H), 7.76 (s, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 3.89-4.30 (m, 4H), 3.72-3.82 (m, 1H).
Reaction SMILES: Cl.[N:2]1([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][N:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=[C:27]([NH2:29])C=1.N1(CCOC2N=CC(CN[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[CH2:77][CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[C:73]([O:78][CH3:79])[CH:74]=4)[CH2:69]3)=CC=2)CCCCCC1>>[N:2]1([CH2:9][CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([CH2:16][NH:29][CH2:27][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[CH2:69][CH2:70][C:71]4[C:76](=[CH:75][CH:74]=[C:73]([O:78][CH3:79])[CH:72]=4)[CH2:77]3)=[CH:19][CH:20]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)nc1)C2
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCc1ccc(OCCN3CCCCCC3)nc1)C2

Procedure:
Synthesized from 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine according to an analogous synthetic method to Example 337 described below, [6-(2-azepan-1-ylethoxy)pyridin-3-ylmethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (274 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide [6-(2-azepan-1-ylethoxy)pyridin-3-ylmethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (264 mg). This compound (262 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (122 mg).
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30]COC)=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[OH:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:34][CH2:35][CH3:36])[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])=[CH:21][C:20]=1[O:19][CH3:18]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
25.43 g (0.64 mol) of a 60% strength by weight sodium hydride dispersion in mineral oil are added in portions at room temperature to 100 g (0.58 mol) of commercially available 3-bromophenol in 600 ml of dimethylformamide, the mixture is stirred for a further half an hour, and 66.5 ml (0.58 mol) of commercially available benzyl chloride are added dropwise. The mixture is stirred at room temperature for 1 hour, 11 of water is added, and the solid which precipitates is filtered off, washed with water and recrystallized from 600 ml of isopropanol, giving 108 g of 3-benzyloxybromobenzene. ##STR12##
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]=1[CH:6]=O.Cl.[NH2:18]O.Cl>C(O)C.O>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]=1[CH:6]=[N:18][OH:1]
Reactant: CC(C)COc1cccc(F)c1C=O
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)COc1cccc(F)c1C=NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
50% aq. Sodium hydroxide (1.2 mL, 15.0 mmol) was added to a mixture of 2-fluoro-6-isobutoxybenzaldehyde (1.2 g, 6.1 mmol, EXAMPLE 16, Step 2) and hydroxylamine hydrochloride (0.47 g, 6.7 mmol) in ethanol (24 mL) and water (48 mL) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was neutrized with 2N hydrochloric acid and extracted with dichloromethane (100 mL×2). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a solid. The residual solid was purified by silica gel column chromatography (hexane/ethyl acetate 9:1 to 6:1) to give 0.99 g (77%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](#[N:24])[CH:22]=[CH2:23]>CN(C)C=O>[C:21]([CH2:22][CH2:23][C:9]1[N:8]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[O:11][C:10]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[N:24]
Reactant: O=C(NCC(=O)c1cccs1)c1ccc(F)cc1
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(4-fluorobenzoylamino)acetyl]thiophene (527 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (88 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred under argon atmosphere at room temperature for one hour. After ice-cooling, acrylonitrile (127 ml) was added to the mixture and the mixture was stirred at room temperature for 3 hours. After addition of ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 ml), and phosphoryl chloride (240 μl) was added to the solution under ice-cooling. The mixture was stirred under argon atmosphere at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=9:1→7:1), and triturated with hexane and ethyl acetate to obtain 4-(2-cyanoethyl)-2-(4-fluorophenyl)-5-(2-thienyl)oxazole (132 mg) as colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:30](OCC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].[OH2:35].[NH2:36][NH2:37]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:36][NH:37][C:30](=[O:35])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: O
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CC)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: CO
Product: CCc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (290 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) was stirred at 30° C. for overnight. Methanol was removed under reduced pressure. The crude product was purified by chromatography (silica gel, Petroleum ether/ethyl acetate=1:1) to give the title compound (112 mg, yield 42%). LC-MS (ESI) m/z: 425 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.12 (t, 3H), 2.10 (s, 6H), 2.52 (q, 2H), 3.34 (s, 2H), 4.31 (d, J=8.0 Hz, 1H), 4.76 (d, J=8.0 Hz, 1H), 7.04 (m, 4H), 7.15-7.20 (m, 3H), 7.25-7.27 (m, 2H), 7.38-7.41 (m, 3H), 7.59-7.61 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1.[CH2:45]([N:52]1[CH2:57][CH2:56][N:55](C(OCC)=O)[CH:54]([C:63]([F:66])([F:65])[F:64])[CH2:53]1)C1C=CC=CC=1.CSC.CS(O)(=O)=O>C(Cl)Cl>[F:25][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:45]([N:52]4[CH2:57][CH2:56][NH:55][CH:54]([C:63]([F:66])([F:65])[F:64])[CH2:53]4)=[O:28])[CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)N1CCN(Cc2ccccc2)CC1C(F)(F)F
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1N
Agent: CS(=O)(=O)O
Solvent: CSC
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC(C(F)(F)F)C1
Reaction time: 2 h

Procedure:
N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine 29a (0.4 mmol), 4-nitrophenyl chloroformate (0.48 mmol) and pyridine (0.8 mmol) in dry DCM (2 mL) are stirred at rt for 10 min. Then ethyl 2-(trifluoromethyl)piperazine-1-carboxylate 34b (0.48 mmol) is added and the reaction mixture is stirred for 2 h. After the reaction is complete, the mixture is diluted with 20 mL of DCM and washed with water. The organic layer is separated, dried over Na2SO4, filtered and concentrated under vacuum to afford a residue D11a. To this residue is added dimethylsulfide (1.2 mmol) and methanesulfonic acid (1.0 mL) and the resulting mixture is stirred at rt for 12 h. HPLC purification (ACN gradient 10-70%) affords D11 as a TFA salt. 1H NMR (400 MHz, d6-DMSO) δ 9.73 (s, 1H), 8.80 (s, 2H), 8.43 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.27 (m, 1H), 4.02 (m, 1H), 3.17 (m, 1H), 3.0 (s, 1H), 2.51 (m, 4H), 2.11 (s, 3H). MS (m/z) (M+1)+: 523.2.