Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[OH:22][C:23]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:24]=1[CH:25]=[O:26]>C1COCC1.O>[OH:26][CH:25]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1)[C:24]1[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:23]=1[OH:22]
Reactant: Cc1cc(C)c(C=O)c(O)c1
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C)c(C(O)c2ccc(C(C)C)cc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 1-bromo-4-isopropylbenzene (3.32 g, 16.7 mmol) in THF (30 mL) was added dropwise n-butyllithium (a 1.59 M hexane solution, 9.2 mL, 14.7 mmol) under argon atmosphere at −78° C. The reaction solution was stirred for 30 minutes, a solution of 2-hydroxy-4,6-dimethylbenzaldehyde obtained in Reference Example 146 (1.0 g, 6.7 mmol) in THF (10 mL) was added dropwise thereto at −78° C., and the mixture then was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1.64 g (yield 91%) of the title compound. Melting point: 103-104° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Yield: 100.8 %

Procedure:
A solution of 3-bromophenol (400 g, 2.31 mol), tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole (346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred overnight at room temperature. The reaction solution was poured into 2000 mL of water and the layers were separated. The organic layer was washed with 1N aqueous sodium hydroxide solution (3×1500 mL) and water (2×1500 mL) before passing through a pad of silica gel (400 g, silica 60, 230-400 mesh). The silica gel was washed with dichloromethane (2×500 mL), the filtrates were combined and the solvent removed under reduced pressure to give 669 g (98.4%) of 3-bromophenoxy-tert-butyldimethylsilane as a clear pale yellow liquid. 1H NMR (CDCl3, 300 MHz): δ7.1 (m, 2H); 7.0 (br s, 1H); 6.75 (m,1H); 1.0 (s, 9H); 0.2 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.C([O:27][C:28](=[O:44])[CH2:29][CH:30]([NH:42][CH3:43])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)C.[OH-].[Na+].Cl>COC(C)(C)C.CO>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:42]([CH:30]([CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:29][C:28]([OH:44])=[O:27])[CH3:43])=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(Cc1ccc2ccccc2c1)NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1ccc2ccccc2c1
Reaction time: 12 h

Procedure:
25.3 g (91.4 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride followed by 13.3 ml (95.6 mmol) of triethylamine are added dropwise over a period of 5 minutes to a solution of 22.5 g (83.1 mmol) of 3-methylamino-4-(2-naphthyl)-butanoic acid ethyl ester in 500 ml of tert-butyl methyl ether. After 12 hours at room temperature, 16.6 g (415 mmol) of sodium hydroxide dissolved in 150 ml of methanol are added over a period of 10 minutes and the mixture is stirred for 5 hours. Then, at 0° C., 275 ml of 2N hydrochloric acid are added and the mixture is washed with 300 ml of ethyl acetate. After concentration in a rotary evaporator, the title compound crystallises out from tert-butyl methyl ether/hexane in the form of white needles. M.p.: 128-130° C.; IR: 3400-2500 (b), 1710, 1635 cm1 ; 1H-NMR, 200 MHz, CDCl3, delta, (ppm): 7.9-6.93 (m, 10H), 5.01, 4.30 (2m, rotamer, 1H), 3.9-2.6 (m, 4H), 3.18, 2.68 (2s, rotamer, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:46]1[C:42]2[CH:41]=[C:40]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:48]=[CH:47][C:43]=2[N:44]=[CH:45]1
Reactant: CC1(C)OB(c2ccc3ncsc3c2)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ncsc2c1
Yield: 39.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and intermediate 19 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.098 g; 0.5 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.041 g (39%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([OH:14])=[O:13].C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:33][C:34]([CH3:36])=[CH2:35])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:35][C:34](=[O:33])[CH3:36])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: C=C(C)OC(C)=O
Reactant: Cc1c(C(=O)O)oc2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc2oc(C(=O)O)c(C)c2c1

Procedure:
A solution of methyl 5-bromobenzofuran-2-carboxylic acid (2.4 g, 9.3 mmol), tributyltin methoxide (4.0 mL, 14 mmol), isopropenyl acetate (1.4 mL, 14 mmol), palladium (II) acetate (0.1 g, 0.5 mmol) and tri-o-tolylphosphine (0.3 g, 1mmol) in toluene (6 mL) were heated at 95° C. for 2 hours. The reaction solution was concentrated in vacuo and subjected to flash chromatography on silica gel (25% ethyl acetate:hexanes) to afford the title compound as a colorless solid, (1.8 g; m.p. 77-79° C., Analytical Calculated for C13H12O4 :C, 67.25; H, 5.21. Found: C, 67.12; H, 4.95).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CCN(CC)CC.CCOC(C)=O>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(S(=O)(=O)c3ccc(C)cc3)C2)c(Cl)c1
Yield: 71.7 %

Procedure:
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (560 mg), p-toluenesulfonyl chloride (318 mg) and Et3N (0.7 ml) in DMF (15 ml) was stirred at ambient temperature for 10 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was crystallized from AcOEt-n-hexane to give ethyl (2E)-3-[5-chloro-6-({(3R)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylate (490 mg).
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)([OH:5])(=[O:4])=[O:3].[N-:13]=[N+:14]=[N-:15].[Na+].O>CC(C)=O>[S:2]([CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)([OH:5])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCS(=O)(=O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(O)CCn1nnnc1S

Procedure:
A mixture of 21.5 g. (0.087 mol.) of methyl 2-sulfoethyldithiocarbamate potassium salt (0.5 hydrate) and 7.16 g. (0.11 mol.) of sodium azide in 200 ml. of water was refluxed for two hours. The solution was cooled to 25° and extracted with ethyl acetate. The aqueous phase was treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. The oil was dissolved in acetone, the solution was filtered and the filtrate was evaporated to dryness to give 1-(2-sulfoethyl)-tetrazole-5-thiol. The thiol was dissolved in isopropanol, cyclohexylamine was added until pH 8-9 and acetonitrile was added to give 1-(2-sulfoethyl)tetrazole-5-thiol as the di-cyclohexylamine salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[CH3:20])=[CH:7]2.[OH-].[NH4+:33]>C1COCC1>[NH2:33][C:24]1[N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=1
Reactant: C[C@H](Nc1nc(Cl)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(N)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 75 (450 mg, 0.99 mmol) was dissolved in THF (45 mL), treated with concentrated ammonium hydroxide solution (9 mL), and stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo and the residue suspended in water (50 mL) and brine (20 mL), and extracted with DCM (3×35 mL). The combined organic layers were washed with brine (15 mL each), dried over Na2SO4, and concentrated to afford (S)-3-(1-(2-amino-5-nitropyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 76, 430 mg (0.99 mmol, quant.). ESI-MS m/z: 437.16 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:42]([CH:38]4[CH2:39][CH2:40][CH2:41][O:37]4)=[O:43])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: O=C(O)C1CCCO1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)C1CCCO1)CC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol), 2-tetrahydrofuroic acid (10.1 μL, 0.105 mmol), HATU (40.0 mg, 0.105 mmol) in DMA (0.75 mL) was added DIPEA (0.037 mL, 0.211 mmol) at 23° C. The mixture was stirred at 60° C. for 30 min, cooled to 23° C., filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (20.8 mg, 48.1%) as a hygroscopic, yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.3 Hz, 6H), 1.78-1.94 (m, 4H), 1.97-2.13 (m, 4H), 2.63 (t, J=5.7 Hz, 0.9H), 2.71-2.77 (m, 1.1H), 2.85-2.95 (m, 2H), 3.24-3.33 (m, 2H), 3.69-3.85 (m, 4H), 4.11 (dt, J=12.9, 6.4 Hz, 1H), 4.38-4.57 (m, 3H), 4.75 (ddd, J=14.0, 7.8, 5.7 Hz, 1H), 5.81 (br s, 1H), 6.99-7.05 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 502.5.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[O:30])[CH3:29])[CH2:17][CH2:16]1.[OH-].[K+].[ClH:33]>CCO.O>[ClH:33].[ClH:33].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[O:30])/[CH:29]=[CH:1]/[C:3]2[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=2)[CH2:17][CH2:16]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1ccccc1CN1CCN(C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formylcinnamic acid (189 mg, 1.077 mmol), 1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 11, 250 mg, 1.077 mmol) and 1.7 M KOH (1.26 ml) in EtOH (5 ml) and H2O (5 ml) was stirred at room temperature overnight and then acidified with 10% HCl. The resulting precipitate was filtered to give 350 mg of (E)-3-(4-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid bis-hydrochloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([C:10]3[N:14]=[CH:13][S:12][CH:11]=3)[NH:7][C:5]=2[CH:6]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23].[K+].[Br-]>C(Cl)(Cl)Cl>[Cl:26][CH2:25][O:24][C:22]([N:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=[C:8]1[C:10]1[N:14]=[CH:13][S:12][CH:11]=1)=[O:23]
Reactant: O=C(Cl)OCCl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCCl)n1c(-c2cscn2)nc2ccccc21

Procedure:
To a suspension of 15.0 g of thiabendazole in 300 ml of chloroform, 6 g of pyridine was added and the suspension cooled in an ice bath. Chloromethyl chloroformate (10.6 g) was added to the reaction mixture dropwise during 10 minutes with stirring. A clear solution was formed which was kept stirred at room temperature for 16 hours. After washing the chloroform solution with water, it was dried over Na2SO4 and evaporated to a light yellow solid weighing 20.4 g. It was crystallized from EtOAc-CHCl3. Obtained in two crops were 15.07 g of compound, m.p. 143°-144° NMR (CDCl3) δ5.9 (2H, s, OCH2Cl), 7.2-8.2 (5H, m, aromatic), 8.93 (1H, d, J=3 Hz, aromatic). IR (KBr) ν3095, 1780, 1460, 1374, 1340, 1194, 1140, 1078 cm-1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.CO.C1COCC1.CO.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([N+:50]([O-])=O)[NH:48][CH:49]=2)[CH2:40][CH2:39]1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([NH:50][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])[NH:48][CH:49]=2)[CH2:40][CH2:39]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN4CCN(C)CC4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0 [M+H]+; tR=3.07 min (System 1); TLC: Rf=0.23 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([C:8]([OH:18])([C:14]([NH:16][NH2:17])=O)[C:9]([O:11][CH2:12]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:24]#[N:25].C([O-])([O-])=O.[K+].[K+].[Si](C=[N+]=[N-])(C)(C)C>C(O)CCC.C(OCC)(=O)C.O.CO>[CH3:30][O:29][C:27]1[CH:26]=[C:23]([C:24]2[NH:25][C:14]([C:8]([OH:18])([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([O:11][CH3:12])=[O:10])=[N:16][N:17]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:28]=1
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)NN
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: COC(=O)C(O)(Cc1ccccc1)c1nnc(-c2cc(OC)cc(OC)c2)[nH]1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To the mixture of ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (40 mg), 3,5-dimethoxybenzonitrile (55 mg) and K2CO3 (44 mg) in 2 mL of n-butanol was heated at 160° C. for 1.5 h. The mixture was then diluted with ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then acidified until pH=1. The mixture was then extracted with 30% isopropanol in chloroform. The organic layer was dried with magnesium sulfate and concentrated to give the crude acid, which was then dissolved in methanol. To the resulting solution was added TMSCHN2 (0.3 mL, 2 M in Et2O) at rt. After 30 min, the mixture was concentrated and purified by Gilson RP-HPLC (30-100% ACN/water/0.05% TFA) to give methyl 2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])=[O:9])=[C:4]([N+:27]([O-:29])=[O:28])[CH:3]=1.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([CH3:38])[CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:13]=[CH:12][C:11]=3[CH3:26])=[O:9])=[C:4]([N+:27]([O-:29])=[O:28])[CH:3]=2)=[C:33]([CH3:38])[CH:32]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1ccc(COc2ccc(C)c(C(=O)c3ccc(Br)cc3[N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4C)cc3[N+](=O)[O-])c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Compound 504 (0.6 g, 1.35 mmol) was dissolved in 1,4-dioxan (15 mL). 4-Fluoro-2-methylaniline (0.22 mL, 2.0 mmol), Cs2CO3 (0.61 g, 1.88 mmol), BINAP (0.06 g, 0.1 mmol) and Pd2(dba)3 (0.031 g, 0.03 mmol) were added and the reaction mixture was stirred under an argon atmosphere at 100° C. for 18 h. H2O was added and the water phase was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 0:100→30:70. This afforded the title compound. 1H NMR (CDCl3) δ 7.32 (d, 1H), 7.30-7.14 (m, 4H), 7.11 (d, 1H), 7.06-6.91 (m, 3H), 6.88 (m, 2H), 6.84-6.77 (m, 2H), 5.87 (bs, 1H), 4.88 (s, 2H), 3.80 (s, 3H), 2.49 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>CS(C)=O>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)C(=O)COc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours, 2-chloro-N,N-dimethyl acetamide (0.3 ml, 2.4 mmol) was added and the reaction mixture was heated to 120° C. for 6 hours. The reaction was allowed to cool, the crude mixture was applied to a SCX cartridge ion exchange (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo to afford the title compound (E68). MS (ES+) m/e 303 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[C:28]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:28]1([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: O=CC1=CCCCCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4=CCCCCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclononene-1-carbaldehyde (0.085 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(cyclononen-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 59) (0.08 g) as colorless prisms.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[N:6]=1
Reactant: O=C(O)c1csc(S)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc(S)n1

Procedure:
To 2-mercaptothiazole-4-carboxylic acid (Ex. 19b, 4.2 g) in 50 mL ethyl alcohol was added 2 mL conc. H2SO4. The mixture was heated to reflux for 8 h and cooled. The solvent was removed under reduced pressure and the residue was poured onto 50 mL ice water. The solid was collected, washed with water and dried under vacuum. The crude product was recrystallized from 8 mL ethyl alcohol to afford ethyl 2-mercaptothiazole-4-carboxylate (2.3 g) as a yellow solid.