Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18].[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:17]=[CH2:18])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cccc2cccc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cccc2cccc(C(=O)OCC)c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A stream of argon was passed through a solution of 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.44 g) in toluene (15 ml) for 15 min. Then tetrakis(triphenylphosphine)palladium (179 mg) and vinyltributylstannane (1.65 ml) were added. The reaction mixture was heated under an Argon atmosphere to 100° C. overnight, then cooled to r.t. and treated with 4M potassium fluoride solution. The suspension was stirred for 10 min and then filtered. The solids were washed with toluene. The filtrate was washed with 4M KF solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 3:2) to give 8-vinyl-naphthalene-1-carboxylic acid ethyl ester (1.11 g) as light yellow liquid. MS (ISP): 227.1 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:13][CH3:14])=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ccnc(Cl)c2cc1F
Yield: 55 %

Procedure:
A solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (3.1 g, 16.05 mmol) in POCl3 (25 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (1.9 g, 55%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.22-8.20 (d, J=8 Hz, 1H), 7.97-7.94 (m, 1H), 7.49-7.48 (m, 1H), 7.18-7.16 (d, J=8 Hz, 1H), 4.04 (s, 3H); MS: MS m/z 211.7 (M++1).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[N:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:18]=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NCCCCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1)C=NCCCCCCN=CC=Cc1ccccc1
Yield: 97 %

Procedure:
Cinnamaldehyde (198.2 g, 1.5 mole) is carefully added to a solution of 1,6-hexanediamine (87.2 g, 0.75 mole) in toluene (400 ml). Slight exotherm to 60° C. is observed. The resulting solution is heated at reflux until water (27 ml, 1.5 mole) is evolved. Evaporation of the solution gives 250.7 g of a brown viscous oil. 1H NMR: δ 1.0-2.85 (broad bands 8H); δ 3.6 (triplet 4 H); δ 6.82-8.22 (broad multiplete 16 H). Elemental analysis: Theory for C24H28N2 : C,83.72; H,8.14; N,8.14%. Found: C,83.61; H,8.35; N,8.05%.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:18]([CH2:21][N+]1C=CC=CC=1)(=[O:20])[NH2:19].[OH-].[Na+]>CO.O>[C:11]1([C:9]2[CH:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:19][C:18](=[O:20])[CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NC(=O)C[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzylideneacetophenone (41.6 g) and N-carbamoylmethylpyridinium chloride (34.4 g) (prepared according to the method of O. ALBRECHT et al., Helv. Chim. Acta 24, 241E (1941)) in methanol (600 cc), is added, at room temperature, a 1N aqueous solution of sodium hydroxide (200 cc). The initially yellow solution takes on an orange colour and a yellow solid precipitates. The mixture is stirred at room temperature for 15 minutes and acetic acid (400 cc) Is then added. The green solution obtained is stirred for 1 hour at room temperature. The solvent Is then distilled in 4 hours under atmospheric pressure. The solid residue obtained is taken up in distilled water (500 cc). After stirring for 1 hour at room temperature, the solid is separated by filtration, washed with distilled water (3×100 cc) and dried under reduced pressure at 60° C. (whitish solid; m.p.=209°-212° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][C@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@H:12]([CH3:53])[C@@H:11]([OH:54])[C@@:10]1([OH:56])[CH3:55]>>[CH3:53][CH2:12][C@@H:11]([OH:54])[C@@:10]([OH:56])([C@@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@@H:8]1[CH3:7])[CH3:55]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC[C@@H](O)[C@@](C)(O)[C@@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C

Procedure:
Glacial acetic acid solution of erythromycin (12.4 g) was stirred at room temperature for 2 hours, added slowly aqueous sodium hydrogen carbonate and neutralized. The reaction mixture was extracted with chloroform, dehydrated the organic layer with mirabilite, filtered off the mirabilite and removed the solvent by distillation to obtain crude substance. The crude substance was purified with silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM201 (7.7 g). Subsequently, potassium carbonate (1.4 g) was added to the methanol solution of EM201 (7.6 g) and refluxed for 2 hours. After distilled off the solvent, the residue was dissolved in aqueous sodium hydrogen carbonate and extracted with chloroform. The mixture was dehydrated with mirabilite, filtered and removed the mirabilite, then the obtained crude substance was purified by silicagel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM701 (5.9 g, white powder).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:4]([OH:6])=[O:5].[H][H]>O.[Pd]>[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:4]([OH:6])=[O:5]
Reactant: NC(CCc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1ccccc1CCC(N)C(=O)O

Procedure:
Alternatively, a solution of 2-amino-4-(2-nitrophenyl)butyric acid hydrochloride (2.5 g) in water (200 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% Pd-C (0.5 g) as catalyst. After uptake of hydrogen ceased, the catalyst was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in water (50 ml) and the pH adjusted to 7 by the addition of 10% sodium hydroxide. The solid was filtered off, washed with water, and dried to give 2-amino-4-(2-aminophenyl)butyric acid. A solution of the 2-amino-4-(2-aminophenyl)butyric acid (1.0 g), hexamethyldisilazane (5.4 g), and chlorotrimethylsilane (0.1 g) in xylene (125 ml) was refluxed for 65 hours. The reaction mixture was cooled, poured into ethanol (200 ml) and evaporated under reduced pressure. Water (100 ml) was added, and the solution extracted with dichloromethane (2×125 ml). The combined dichloromethane solutions were washed with water (50 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as above.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22](=[O:25])[CH2:23][O:16][C:13]1[CH:14]=[N:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1ccc(-c2ccccc2F)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 63.4 mg (1.45 mmol) of sodium hydride (55% in mineral oil) were added to 250 mg (1.32 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ol in 10 ml of DMF. The mixture was stirred at room temperature for 60 min. Then 283.5 mg (1.45 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined extracts were dried and concentrated. Yield: 311 mg.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13](Br)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([Si:29]([CH3:55])([CH3:54])[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[N:35]=[C:34]2[Sn](CCCC)(CCCC)CCCC)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([O:30][Si:29]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:54])[CH3:55])[CH:32]=4)[N:36]([CH3:40])[N:35]=3)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(O[Si](C)(C)C(C)(C)C)cc34)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (100 mg, 0.24 mmol) and 5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-3-tributylstannanyl-1H-indazole (crude from Step 4) were dissolved in DMF (2 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 80° C. for 2 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 104 mg (72%) of 2-[5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1.[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]4[N:23]([CH2:28][CH3:29])[C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:16]3)[CH:9]=2)[N:3]=1
Reactant: Cc1nc(N2CC(c3nc4ccccc4[nH]3)C2)cc(-n2nc(C)nc2C)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(C2CN(c3cc(-n4nc(C)nc4C)nc(C)n3)C2)nc2ccccc21
Temperature: 60 °C

Procedure:
Example 107 (13 mg, 0.036 mmol), ethyl iodide (5.6 mg, 0.036 mmol), and cesium carbonate (58 mg, 0.18 mmol) were combined in degassed DMF (1 mL) and heated at 60° C. for 30 min. The mixture was cooled to room temperature, filtered and purified by reverse phase HPLC, providing Example 114 as a solid. 1H NMR: (400 MHz, d6-DMSO) δ 7.71-7.67 (m, 2H), 7.37-7.30 (m, 2H) 6.56 (s, 1H), 4.62-4.58 (m, 3H), 4.47-4.44 (m, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.77 (s, 3H), 2.45 (s, 3H), 2.29 (s, 3H), 1.34 (t, J=7.1 Hz, 3H) ppm; MS: m/z=389.4 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was stirred for 3 hours. To the mixture was added TMSC1 (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: ClC[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]4[O:22][CH2:21][CH2:20][O:19]4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:23])[N:8]2[CH2:7][C:6]1[CH:24]=[CH:25][C:3]([S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:5]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(CCl)cc1
Solvent: C1CCOC1
Product: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
1-(4-Chloromethylbenzyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.79 mmol), thiophenol (0.37 ml, 3.63 mmol) and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) (0.84 ml, 5.59 mmol) were added to THF (30 ml), followed by heating under reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.13 g (yield: 94%) of 5-(1,3-dioxolan-2-yl)-1-(4-phenylsulfanylbenzyl)-3,4-dihydro-1H-quinolin-2-one as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (See Example 54A) (1.5 g) and NaOH (3N, 30 ml) in ethanol (30 ml) was stirred at 50° C. for 3 h after which it was cooled to room temperature and neutralized with concentrated HCl. The solvent was removed under reduced pressure to obtain crude 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:26])[N:14](CCC3C=CC=CN=3)[C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(OC(=O)[NH:33][CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(C)(C)C>>[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:7]2[N:6]=[CH:5][N:10]=[C:9](/[CH:11]=[C:12]3/[C:13](=[O:26])[NH:14][C:15](=[O:17])[S:16]/3)[CH:8]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)N(CCc3ccccn3)C2=O)n1
Product: NCC1CCN(c2cc(/C=C3\SC(=O)NC3=O)ncn2)CC1

Procedure:
(Z)-5-((6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure, (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)-3-(2-(pyridin-2-yl)ethyl)thiazolidine-2,4-dione, and tert-butyl(piperidin-4-ylmethyl)carbamate followed by the general de-protection procedure (16 mg, 30.6 mg theoretical, 52.3%). LC-MS m/z 425.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.082 g (0.22 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.059 g (0.29 mmol) of benzyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 237A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.056 g (0.29 mmol) of EDC and 0.009 g (0.067 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: Br[CH:2]([C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:20][C:21]([NH2:23])=[S:22].C(O)C>O>[NH2:23][C:21]1[S:22][C:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:20]=1
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCc1sc(N)nc1-c1ccc(Cl)cc1
Yield: 89.8 %

Procedure:
A mixture of ethyl 5-bromo-5-(4-chlorobenzoyl)valerate (17.4 g), thiourea (4.57 g) and ethanol (50 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give ethyl 2-amino-4-(4-chlorophenyl)-5-thiazolebutanoate (14.6 g, 85%) as pale yellow prisms. Melting point 114-115° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25](O)=[O:26])[CH2:9]2)=[O:7])[CH2:3]1.O[N:29]=[C:30]([NH2:35])[CH2:31][CH2:32][O:33][CH3:34]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25]3[O:26][N:35]=[C:30]([CH2:31][CH2:32][O:33][CH3:34])[N:29]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
150 mg (0.324 mmol) of the compound from Example 110A and 77 mg (0.649 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 23 mg (15% of theory).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH2:19][CH2:18]1.B.[Na].O>CO>[ClH:29].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH2:21][CH2:22]1
Reactant: Cc1c(C(=O)CCN2CCN(c3ccccc3Cl)CC2)cnn1-c1ncccn1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1c(/C=C/CN2CCN(c3ccccc3Cl)CC2)cnn1-c1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
3.7 g of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl)-1-piperazinyl]-1-propanone hydrochloride was dissolved in 300 ml of methanol. After adding 1.25 g of sodium boron hydride, the obtained mixture was stirred at room temperature for 2 hours. To the reaction mixture was further added 0.6 g of sodium boron hydride followed by stirring for 2 hours. Under ice cooling, water was added to the reaction mixture and the methanol was removed by evaporation. The residue was extracted with chloroform and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography and developed with a solvent mixture (chloroform/methanol, 30:1) to thereby give 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl-)1-piperazinyl]-1-propanol. Next, 16 ml of a 1N hydrochloric acid/ethanol solution was added to the product. After dissolving by heating, ether was further added thereto. The crystals thus precipitated were collected by filtration to thereby give 1.26 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[CH:11]([CH3:13])[CH3:12]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)C=O
Solvent: ClCCl
Product: CC(C)/C=N/CC(=O)OC(C)(C)C
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isobutyraldehyde (Aldrich) (0.4 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 97%).