Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]1[OH:33].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]5[OH:33])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCC[C@@H](O)[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Temperature: 120 °C
Yield: 30.5 %

Procedure:
To a suspension of 6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (350 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol), prepared as described in Gauthier Errasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous DMA (1.5 mL) was added DIEA (402 μL, 2.4 mmol). The mixture was heated in a sealed tube at 120° C. for 15 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (127 mg, 32%) as a yellow solid. LCMS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOCC>[Br:17][C:8]1[C:2]([F:1])=[CH:3][C:4]([NH2:5])=[CH:6][C:7]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Difluoroaniline (10.0 g, 77.5 mmol) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 mmol) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography (methylene chloride/hexanes) to give 4-bromo-3,5-difluoroaniline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([O-:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: O=C([O-])c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Reaction time: 0.5 h

Procedure:
To a 3 mL plastic tube fitted with a frit containing 50 mg of resin-bound 2-(3-indolyl)quinoline-4-carboxylate (0.035 mmol) was added I mL of a 50% mixture of TFA and DCM. The reaction mixture was agitated on an orbital shaker for 30 min. The mixture was filtered and the resin washed with DCM (3×3 mL). The organic solutions were combined and evaporated by a stream of nitrogen. The residual solid was lyophilized to give 2-(3-indolyl)quinoline-4-carboxylic acid or amide (80-100% yield).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:38]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:38]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 31.6 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin tert-butyl ester (4.0 g, 8.56 mmole), MeOH (24 ml) and NaOH (0.31 g) in water (2 ml). The mixture was heated to 35° C. and stirred for 4.5 h then water (10 ml) was added and the MeOH was evaporated. The volume of the water was completed to 8 vol. and the mixture was extracted with EtOAc (25 ml). The aqueous solution was evaporated to contain ca. 1 vol. water and ACN (60 ml) was added. The solution was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ACN and dried at 40° C. in a vacuum oven for 24 h to obtain 1.06 g (28.6%) of fluvastatin sodium crystal form XIV, having a peak at 12.4±0.2 degrees two-theta in the XRD pattern
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(-c2oncc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.07 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (3.50 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (3.00 g, yield 79%) of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid. melting point: 171–172° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][CH2:12]O)[N:7]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]=2[CH:26]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:12][CH2:11][CH:8]1[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6]2[CH:26]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9]1
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2cc(F)ccc2OCC1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2cc(F)ccc2OCC1CCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 11.27 g (0.031 mol) of (±)-6-fluoro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 140 ml of dichloromethane are added 9 ml (0.124 mol) of thionyl chloride and the mixture is stirred at room temperature for 5 h.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=1[CH3:29]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=3[CH3:29])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3sc(C#N)cc3C)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 182-184° C.; 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.83 (s, 1H), 7.57 (dd, J=4.88, 0.98 Hz, 1H), 7.46 (dd, J=8.3, 1.95 Hz, 1H), 7.33 (d, J=1.95 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.07 (dd, J=4.88, 3.42 Hz, 1H), 6.98 (dd, J=3.42, 0.98 Hz, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.98 (d, J=15.13 Hz, 1H), 2.47 (m, 1H), 2.35 (m, 1H), 2.21 (s, 3H), 0.77 (t, J=6.84 Hz, 3H); MS (ESI) m/z 395 ([M+H]+); MS (ESI) m/z 393 ([M−H]−); Anal. calcd for C21H18N2O2S2: C, 63.93; H, 4.60; N, 7.10. Found: C, 60.33; H, 4.13; N, 6.65.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].CC[O-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)N=C(N)C(Cc2ccccc2)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 17.1 g of benzyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-benzyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 208°C (29.4 g, 63% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=O)=[N:12]3)=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:23]
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Reactant: CN(C)CCN
Product: COc1nccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
4-Methoxypyrido [4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-methoxypyrido[4,3-α]phenazine-11-carboxylic acid (II.4) and N,N-dimethylethylenediamine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH2:23]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH2:23][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Cc1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2ccc(C)cc2O1
Yield: 47.3 %

Procedure:
To a solution of 2-amino-5-methylphenol (10 g, 81.3 mmol) in acetone (150 mL) was added K2CO3 (24.5 g, 243.9 mmol) and ethyl 2,3-dibromopropanoate (23.3 g, 89.4 mmol). The mixture was heated at reflux for 16 h. The filtrate was concentrated in vacuo to give an oil. Purification by silica gel chromatography (hexane/ethyl acetate gradient) provided ethyl 7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (8.5 g, 47.3% yield). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=0.8 Hz, 1H), 6.60 (dd, J=1.2, 8.0 Hz, 1H), 6.19 (d, J=8.0 Hz, 1H), 4.78 (t, J=3.6 Hz, 1H), 4.29-4.21 (m, 2H), 3.59-3.52 (m, 2H), 2.23 (s, 3H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23]CC#N)[CH2:18]1>>[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:18]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CCCC(O)C1
Product: O=c1[nH]c(CCN2CCCC(O)C2)cc2ccccc12
Yield: 19.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.2474 g) and 3-(3-hydroxypiperidin-1-yl)propionitrile (2.62 g), 3-[2-(3-hydroxypiperidin-1-yl)ethyl]-2H-isoquinolin-1-one (888.2 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[C:20]([F:27])[C:19]=1O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[C:20]([F:27])[C:19]=1[O:15][C:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([CH:5]2[CH2:6][CH2:7][C:2]([F:1])=[CH:3][CH2:4]2)[CH2:13][CH2:12]1)=[O:16]
Reactant: O=C(O)[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Reactant: CCCc1cc(F)c(O)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1cc(F)c(OC(=O)[C@H]2CC[C@H](C3CC=C(F)CC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude product from b), 0.79 g of 1-fluoro-4-(trans-4-carboxycyclohexyl)cyclohex-l-ene, was cooled to 0°C. under nitrogen together with 0.66 g of 2,6-difluoro-4-propylphenol and 60 mg of dimethylaminopyridine in 10 ml of methylene chloride and treated within 45 minutes with a solution of 1.0 g of dicyclohexyl-carbodiimide in 5 ml of methylene chloride. After stirring at room temperature for 30 minutes the white suspension was filtered over a Celite/silica gel pad. The filtrate was evaporated completely and gave 1.5 g of trans-4-(1-fluoro-cyclohex- 1 -en-4-yl)cyclohexanecarboxylic acid 2,6-difluoro-4-propylphenyl ester, which gave 0.62 g of white crystals by repeated recrystallization from hexane. M.p. (C/N) 58.40°C., c.l.p. (N/I) 96.1°C.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.C([BH3-])#N.[Na+]>>[CH:37]1([N:10]2[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9]2)[CH2:39][CH2:38]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCN(C4CC4)CC3)cc(C(F)(F)F)c2)cc1
Temperature: 90 °C

Procedure:
A microwave tube was charged with 3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (21.5 mg, 0.05 mmol), (1-ethoxycyclopropoxy)trimethylsilane (96.5 μL, 0.47 mmol), sodium cyanoborohydride (15 mg, 0.24 mmol). The tube was flushed with nitrogen and treated with methanol (2 mL) and acetic acid (3 drops). The tube was sealed and heated at 90° C. for 1 h via microwave. After cooling, the reaction was concentrated and purified by flash chromatography on silica gel (10% methanol/methylene chloride) to afford 13.5 mg (55%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.76 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.33-7.37 (m, 5H), 7.21-7.24 (m, 1H), 4.45 (s, 2H), 3.44 (s, 2H), 3.11-3.14 (m, 2H), 2.56-2.61 (m, 2H), 2.35-2.38 (m, 2H), 2.09-2.16 (m, 2H), 1.78-1.79 (m, 1H), 0.82 (m, 2H), 0.54-0.56 (m, 2H). Mass spec.: 491.44 (MH)+. Accurate mass spec.: m/z 491.2331 [MH]+, Δ=4.2 ppm.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][OH:27])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.N1C=CN=C1.[C:38]([Si:42](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:41])([CH3:40])[CH3:39]>O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][O:27][Si:42]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC(CCO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-hydroxyvalerate (401 g) and DMF (2000 mL) were mixed. To the mixture were added imidazole (160 g) and tert-butylchlorodiphenylsilane (287 mL) at ice temperature. The mixture was stirred at RT for 1 hr. After pouring water (1.2 L) into the reaction, the mixture was extracted with toluene (2.3 L). The organic layer was washed with aqueous 20 w/v % citric acid (1.6 L), water (2 L) and 10 w/v % brine (1.6 L), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (744.2 g) as a crude product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH2:12][C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1.[N:16]1[C:25]2[C:20](=[N:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:26][C:22]3[CH:23]=[CH:24][C:25]4[C:20](=[CH:19][CH:18]=[CH:17][N:16]=4)[N:21]=3)[C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: Cc1cnc(CNC2=NC(=O)CS2)cn1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1cnc(CNC2=NC(=O)C(=Cc3ccc4ncccc4n3)S2)cn1
Temperature: 130 °C
Yield: 18.3 %

Procedure:
To a suspension of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one (35.6 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-5-[1,5] naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (10.6 mg, 18.3%). HR-ES (+) m/e calcd. for C18H14N6OS: (M+H)+ 363.1023. Found: 363.1022.
Reaction SMILES: Br[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[Na].[O:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[NH:13]1.O>CN(C)C=O>[O:21]=[S:14]1(=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12](=[O:11])[N:13]1[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: CC1(Br)CCCNC1=O
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(N2C(=O)c3ccccc3S2(=O)=O)CCCNC1=O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
6.8 g of 3-bromo-3-methyl-2-piperidone and 8 g of the dried sodium salt of 2,3-dihydro-3-oxo-1,2-benzisothiazol-1,1-dioxide are heated while stirring to 110°-115° in 25 ml of distilled dimethyl formamide for a period of 75 minutes. After cooling 75 ml of water are added and the stirring is continued for further 30 minutes. The precipitate is filtered off, washed with water, dried in a vacuum at 80° C. and then recrystallized from n-butanol. 3-(2,3-Dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-3-methyl-2-oxo-piperidine melting at 211° to 215° C. is thus obtained in a yield of 24% of the theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:18]2[CH2:17][CH2:16][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:20][CH2:19]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(CCl)cc1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CCl)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[C:4]([CH3:18])=[N:3]1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[C:4]([CH3:18])=[N:3]1
Reactant: Cc1nn(C)c2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)c2c1CNCC2
Temperature: 23 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (all of the product from the previous reaction above) in DCM (2.0 mL) was treated with TFA (500 μL), then stirred for 3 h at 23° C. The reaction was then concentrated, giving the desired product in crude form. The material was immediately used in the next reaction. LCMS-ESI+: calc'd for C8H13N3: 152.1 (M+H+); Found: 152.0 (M+H+).
Reaction SMILES: [F: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.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=O.C[Si](C)(C)N[Si](C)(C)C.[Na]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
To a solution at 0° C. containing 5-fluorooxindole (0.30 g, 1.99 mmol) and phthalide (0.400 g, 2.98 mmol) in 5.0 mL DMF was added 4.2 mL of sodium hexamethyldisilazane (1.0 M in THF) over 5 min. The solution was stirred at room temperature for 3 h and then quenched into cold 1.0 M aqueous HCl solution to give a yellow solid. The solid was collected and then purified by chromatography (silica gel, hexanes/EtOAc, 4:1) to afford the title compound (32 mg, 6%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[CH2:11]([C:12]1[CH2:13][C:14](=[O:15])[N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:8]=1)[CH2:9][CH3:10]
Reactant: NNc1ccncc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccncc2)C(=O)C1

Procedure:
From the reaction of 4-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction wvith 2-ethylaniline yields 4-(2-ethyianilinomethylene)-2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazol-3-one, Mp 159.2° C.