Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:24][O:25][CH2:26][CH2:27][OH:28].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:4]([C:5]([NH:24][O:25][CH2:26][CH2:27][OH:28])=[O:7])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:14]=1[F:23]
Reactant: NOCCO
Reactant: COC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
3,4-difluoro-2-[2-fluoro-4-(methoxycarbonyl)anilino]benzoic acid (320 mg, 0.99 mmol) was dissolved in MeOH (50 mL) to which was added 2-(aminooxy)ethanol followed by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methymorpholinium chloride [DMT-MM, prepared according to the procedure of Kunishima et al [Tetrahedron, 55, 13159-13170 (1999)]] (326 mg, 1.18 mmol), This mixture was stirred 15 h. at room temperature. The MeOH was removed under reduced pressure and the resulting oil dissolved in EtOAc (100 mL), which was washed with water (2×100 mL), brine (100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford a crude yellow oil which was purified by filtration through a plug of silica gel (100% EtOAc as eluant) to give methyl 4-(2,3-difluoro-6-{[(2-hydroxyethoxy)amino]carbonyl} anilino)-3-fluorobenzoate as a cream solid (79%); m.p. (EtOAc/hexane) 162-165° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.82 (v br s, 1 H), 9.08 (v br s, 1 H), 7.70-7.62 (m, 2 H), 7.49-7.43 (m, 1 H), 7.38-7.29 (m, 1 H), 6.81 (ddd, J=8.6, 8.6, 4.7 Hz, 1 H), 4.76 (v br s, 1 H), 3.83-3.78 (m, 5 H), 3.53 (t, J=4.8 Hz, 2 H). Anal. calcd. for C17H15F3N2O5: C, 53.1; H, 3.9; N, 7.3. Found C, 53.3; H, 4.2; N, 7.3.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[C:23]([CH2:28][NH:29][C:30]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])=[O:31])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[CH3:41])=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][CH2:67][C:68]1[C:73]([CH2:74][CH3:75])=[N:72][C:71]2[N:76]([CH2:79][CH3:80])[N:77]=[CH:78][C:70]=2[C:69]=1[NH:81][CH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:79]([N:76]1[C:71]2=[N:72][C:73]([CH2:74][CH3:75])=[C:68]([CH2:67][NH:66][C:35]([C:34]3[CH:33]=[C:32]([C:30]([NH:29][CH2:28][C:23]4[CH:24]=[CH:25][C:26]([F:27])=[C:21]([C:17]5[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]6[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[C@@H:9]([CH3:41])[CH2:10]6)[CH:16]=5)[CH:22]=4)=[O:31])[CH:40]=[CH:39][CH:38]=3)=[O:36])[C:69]([NH:81][CH:82]3[CH2:83][CH2:84][O:85][CH2:86][CH2:87]3)=[C:70]2[CH:78]=[N:77]1)[CH3:80]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
205(a) 3-{[({3′-[((3S)-4-{[(1,1-Dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)amino]carbonyl}benzoic acid (1150 mg, 2.0 mmol) was dissolved in dichloromethane (DCM) (100 mL), and then HBTU (830 mg, 2.2 mmol), 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (620 mg, 2.0 mmol), and DIPEA (1.4 mL, 8.0 mmol) were added. The mixture was allowed to stir under argon at room temperature overnight. Solvents were concentrated and then purified on a 40 g Redi-Sep cartridge and eluting with 0.5% MeOH in DCM. Collected clean fractions were combined solvent concentrated to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (1.15 g, 66.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].CS(C)=O.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][N:12]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CCCl
Reactant: Fc1ccc(-c2c[nH]cn2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCn1cnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 45 °C
Yield: 43.3 %

Procedure:
Charge a round bottom flask with 4-(3-chloro-4-fluoro-phenyl)-1H-imidazole (1.85 g; 1.00 equiv; 9.41 mmol), KOH (3.00 equiv; 28.23 mmol; 1.58 g, crushed to a fine powder), in DMSO (281.56 mmol; 20.00 mL). Add 2-dimethylaminoethyl chloride hydrochloride (1.20 equiv; 11.29 mmol; 1.63 g) in one portion and the solution becomes yellow. Heat at 45° C. for 2 days. Dilute the reaction with EA and wash with water, brine and dry the organics over MgSO4; filter, and concentrate to an orange oil. Purify the crude with ISCO chromatography over a Biotage 40M column eluting with a gradient of 5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min to give the title compound (1.09 g; 4.07 mmol; 43.27%) as a light orange oil. MS(ES): (m/z)=268.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13]>CC(O)=O>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[NH:1][C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:10][C:3]=2[CH:4]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)c(F)cc1N
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)c(F)cc2[nH]1
Temperature: 75 °C
Reaction time: 0.83 h
Yield: 76.8 %

Procedure:
A mixture of (S)-tert-butyl 1-(2-amino-4,5-difluorophenylamino)-1-oxopropan-2-ylcarbamate (3.454 g, 10.96 mmol) in AcOH (21.91 mL) was heated at 75° C. After 50 min, the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with satd. sodium bicarbonate solution (50 mL×2), water (100 mL×1), and brine (100 mL×1). The product was precipitated from DCM. In order to dissolve the precipitate, EtOAc (100 mL) was added. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-tert-butyl 1-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate (2.5025 g, 8.42 mmol, 77% yield) as orange solid. The orange solid was suspended in DCM-hexane (1:1) and filtered to give (S)-tert-butyl 1-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate (2.0003 g, 6.73 mmol, 61.4% yield) as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1H, br. s.), 7.47-7.57 (2H, m), 7.38 (1H, d, J=7.2 Hz), 4.83 (1H, quin, J=6.6 Hz), 1.45 (3H, d, J=7.0 Hz), 1.40 (9H, s); LC-MS (ESI) m/z 298.1 [M+H]+.
Reaction SMILES: NC1C(OC)=CC2CCN(CC(NC)=O)CCC=2C=1.ClC1N=C(N[C@@H]2CCCC[C@H]2NS(C)(=O)=O)C(Cl)=CN=1.[Cl:40][C:41]1[C:42]([NH:67][C@@H:68]2[CH2:73][CH2:72][CH2:71][CH2:70][C@H:69]2[NH:74][S:75]([CH3:78])(=[O:77])=[O:76])=[N:43][C:44]([NH:47][C:48]2[C:64]([O:65][CH3:66])=[CH:63][C:51]3[CH2:52][CH2:53][N:54]([CH2:57][C:58]([N:60](C)[CH3:61])=[O:59])[CH2:55][CH2:56][C:50]=3[CH:49]=2)=[N:45][CH:46]=1>>[Cl:40][C:41]1[C:42]([NH:67][C@@H:68]2[CH2:73][CH2:72][CH2:71][CH2:70][C@H:69]2[NH:74][S:75]([CH3:78])(=[O:77])=[O:76])=[N:43][C:44]([NH:47][C:48]2[C:64]([O:65][CH3:66])=[CH:63][C:51]3[CH2:52][CH2:53][N:54]([CH2:57][C:58]([NH:60][CH3:61])=[O:59])[CH2:55][CH2:56][C:50]=3[CH:49]=2)=[N:45][CH:46]=1
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(=O)N(C)C)CC2
Agent: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Agent: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)CN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1

Procedure:
Following a procedure similar to Example 258c, 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide, prepared in analogous manner to Example 258a-b, and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were converted to 2-{7-[5-chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide (42 mg, 40%) as a white solid. MP: 92-104° C.; 1H-NMR (CDCl3) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.33 (br s, 1H), 7.32 (s, 1H), 6.65 (s, 1H), 5.36 (d, J=8.0 Hz, 1H), 5.27 (d, J=6.8 Hz, 1H), 3.95 (m, 1H), 3.87 (s, 3H), 3.22 (m, 1H), 3.13 (s, 2H), 2.89 (m, 4H), 2.88 (s, 3H), 2.79 (s, 3H), 2.72 (m, 4H), 2.23 (m, 2H), 1.83 (m, 2H), 1.37 (m, 2H), 0.86 (m, 2H); LC/MS (ESI+): 565.99 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:38]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[C:38]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:11](=[O:13])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:51][CH2:52]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: O=C(O)/C=C/c1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (E)-3-(3,5-dichlorophenyl)acrylic acid (step 2) (1.365 g, 6.29 mmol) in NMP (12 ml) was added HATU (2.87 g, 7.55 mmol) and the mixture was stirred for 5 minutes at RT. tert-Butyl(2-(piperidin-4-yl)ethyl)carbamate (1.436 g, 6.29 mmol) was added followed by DIPEA (3.30 ml, 18.87 mmol) and stirring continued at RT overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic portion was washed with water, saturated sodium bicarbonate solution, water, brine and dried using a phase separating column and the solvent removed under reduced pressure. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:31])=[C:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:9]([O:16][CH:17]([F:19])[F:18])=[N:10]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([O:16][CH:17]([F:19])[F:18])[C:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)=[C:7]2[CH3:31]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(OC(F)F)nc2c(Cl)ccc(CC(=O)O)c12
Reaction time: 2 h

Procedure:
A solution of [8-chloro-2-difluoromethoxy-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yl]acetic acid methyl ester (0.030 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.20 mL) and water (0.40 mL) was stirred at room temperature for 2.5 hours and then at 40° C. for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and methanol and then dried to afford title compound as a white solid, 0.016 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([O:13]CC)=O)=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[NH3:16]>>[NH2:1][C:2]1[C:3]([C:11]([NH2:16])=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: N
Reactant: CCCc1ccnc(C(=O)OCC)c1N
Product: CCCc1ccnc(C(N)=O)c1N
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of ethyl 3-amino-4-n-propylpyridine-2-carboxylate (Preparation 5; 7.4 g, 0.035 mol) and liquid ammonia (60 ml) was heated in an autoclave at 100° C. for 18 hours. The mixture was allowed to cool and the ammonia to evaporate, then the residue was crystallized from methanol to give the title compound as a colourless solid (4.84 g, 76%), m.p. 139-141° C.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:17][C:18]1[S:19][C:20]([CH3:23])=[N:21][N:22]=1.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:17][C:18]1[S:19][C:20]([CH2:23][S:8][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:21][N:22]=1
Reactant: Cc1nnc(CCl)s1
Reactant: OC(=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(CSC(=O)c2ccccc2)s1
Reaction time: 0.17 h

Procedure:
Under nitrogen atomosphere, thiobenzoic acid (2.52 ml) was added dropwise to a solution of potassium tert-butoxide (2.30 g) in DMF (15 ml) under ice cooling. After stirring for 10 minutes, 2-chloromethyl-5-methyl-1,3,4-thiadiazole in DMF (15 ml) was added to the mixture. The whole mixture was and stirred for 45 minutes. The mixture was poured into a mixture of water and ethyl acetate, and the pH was adjusted to 8.5 with 30% aqueous sodium hydroxide. Organic layer was separated, was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on silica gel (eluent: n-hexane-ethyllactate) to afford 2-methyl-5-benzoylthiomethyl-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:12]2[O:6][C@@H:3]([CH2:4][OH:5])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8]2)=[CH:14][CH:15]=1
Reactant: CC(C)(CO)[C@@H](O)CO
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2OCC(C)(C)[C@H](CO)O2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of compound obtained in Step A (5.6 g, 41.76 mmol) in dry CH2Cl2 (115 mL) was added p-methoxybenzaldehyde dimethyl acetal (11.42 g, 62.64 mmol) and pyridinium p-toluenesulfonate (2.1 g, 8.35 mmol). The mixture was heated at reflux for 18 h, then was cooled to room temperature and the reaction was quenched with saturated aqueous NaHCO3 solution (50 mL). The separated aqueous layer was extracted with Et2O (3×75 mL) and the combined extracts were washed with saturated aqueous NaCl solution (100 mL) and dried (MgSO4). Filtration and concentration of the filtrate in vacuo left a residue which was purified by flash chromatography (silica gel, gradient elution from 20% Et2O in hexanes to 40% Et2O in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:15]>C1COCC1>[Cl:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][CH2:4][NH:2][CH3:1]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methylamine in THF (2 M, 200 mL) was added 2-(2-bromoethyl)-1-chloro-3-nitro-benzene (14.0 g, 0.053 mole) in a pressure bottle, the reaction mixture was stirred at 60° C. overnight and the solvent was removed. The solid residue was treated with sodium hydroxide (1 N, 100 mL) and the aqueous extracted with methylene chloride (2×100 mL). The combined organic layers were washed with water (100 mL), saturated sodium chloride (100 mL), dried (sodium sulfate) and concentrated to provide 11.0 g of the title compound as a light brown oil. 1H NMR (DMSO-d6): 7.70 δ (d, 1H); 7.60 δ (d, 1H); 7.35 δ (t, 1H); 3.15 δ (t, 2H); 2.90 δ (t, 2H); 2.60 δ (s, 3H); 1.60 δ (broad, 1H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][C:11](OCC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>ClCCl>[C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC/C=C\c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=CCC/C=C\c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(Z)-Ethyl 5-phenylpent-4-enoate (1.600 g, 7.833 mmol) was taken up in dichloromethane (100 mL) under N2 and chilled to −78° C. DIBAL (1M in hexanes, 9 mL, 9.0 mmol) was added and the reaction mixture was stirred at −78° C. for 3 hours. The excess DIBAL was quenched with the slow addition of methanol (25 mL). The resulting solution was poured into a saturated solution of sodium/potassium tartarate (400 mL). Further hexane (150 mL) was added and the mixture was stirred at room temperature over night. The organic phase was collected and solvent removed under reduced pressure. The resulting oil was purified by column chromatography (0–20% EtOAc/n-hexane, silica) to give (Z)-5-phenylpent-4-enal as a pale yellow oil. 1H NMR (CDCl3): δ 9.77 (s, 1H), 7.36–7.29 (m, 2H), 7.25–7.21 (m, 3H), 6.49 (d, 1H, J=11.5), 5.62 (dt, 1H, J1=11.6, J2=7.2, Ph-CHCH), 2.70–2.62 (m, 2H), 2.60–2.55 (m, 2H). Contains ca. 16% (E)-5-phenylpent-4-enal.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[O:36][C:10]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH2:11][CH2:12][CH:13]([N+:25]([O-])=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:9][CH2:8]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:8]1[O:9][C:10]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([CH2:11][CH2:12][CH:13]([NH2:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:36][CH2:7]1
Reactant: COc1ccc(CC(CCC2(CCc3ccccc3)OCCO2)[N+](=O)[O-])cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CC(N)CCC2(CCc3ccccc3)OCCO2)cc1OC

Procedure:
To a suspension of 12.4 g (0.33 mole) of LiAlH4 in 500 mL of dry tetrahydrofuran was added dropwise a solution of 45.3 g (0.11 mole) of 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone ethylene ketal in a minimum amount of dry tetrahydrofuran. After the addition, the reaction mixture was refluxed gently for 2 hours. The excess LiAlH4 was decomposed with saturated Na2SO4 solution. The inorganic salts were filtered off and washed with ether. The organic layer was extracted twice with water, dried over anh. MgSO4, filtered, and concentrated under reduced pressure to 250 mL. This was used in the next step.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[CH3:31])/[S:3]1.[C:35]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[C:14]([CH3:31])=[C:13]([O:12][C:11]3[CH:32]=[CH:33][CH:34]=[C:9](/[CH:8]=[C:4]4/[C:5](=[O:7])[N:6]([CH3:35])[C:2](=[O:1])[S:3]/4)[CH:10]=3)[N:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)N(C)C4=O)c3)c2C)CC1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution (Z)-ethyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (300 mg, 0.0006198 mole) in dimethyl acetamide (10 ml), K2CO3 (171 mg, 0.001239 mole) was added followed by addition of methyl iodide (0.060 ml, 0.0009297 mole) at 0° C. and reaction mixture was stirred at 27° C. for 30 minutes. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. Organic layer was washed with water and brine, dried over sodium sulfate and evaporated on a rotavpour to yield the product as yellow solid (300 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: O=C1Cc2cc(-c3ccco3)ccc2N1

Procedure:
The title compound was prepared as described for Example 37 using 5-bromooxindole and tri-n-butyl(2-furyl)tin: MS (ES) m/z 200 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28]N1C(=O)CCC1.C[Mg+].[Br-].CCOCC>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[F:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([CH3:28])[CH:7]=3)[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Intermediate D4 (1.1 g, 2.80 mmol) was dissolved in THF (15 ml) and iron(III) acetylacetonate (0.099 g, 0.28 mmol) and NMP (1 ml) were added. The reaction mixture was then cooled to 0° C. Under N2 (gas) protection, CH3MgBr 3M in Et2O (4 ml, 12 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for one hour until the reaction was finished. The reaction mixture was then quenched with saturated NH4Cl solution and then extracted by CH2Cl2 (3×30 ml). The combined organic phase was washed by brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 or 3 mobile phases was applied (phase A: a 0.25% NH4HCO3 solution in water; phase B: CH3OH (optional); phase C: CH3CN).