Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[CH:52])=[CH:47][CH:46]=1>C(N(CC)CC)C.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[C:52][C:2]2[CH:3]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[N:5]=[C:6]([CH2:8][N:9]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH:7]=2)=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(I)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(C#Cc2ccc(N)cc2)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Reaction time: 1.5 h

Procedure:
A mixture of compound 1 (1.08 g, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.03 mmol), copper(I) iodide (11 mg, 0.06 mmol) and p-aminophenylacetylene (176 mg, 1.5 mmol) in 10 mL of triethylamine was deaerated with nitrogen and kept at 40° C. for 1.5 h. The mixture was diluted with 40 mL of chloroform, washed with water and dried with sodium sulfate. The solution was evaporated in vacuo and the product was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(N)c2cn[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(Cl)(Cl)Cl)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methyl-1H-indazol-4-amine (J. Chem. Soc. 1955, 2412; 550 mg, 3.74 mmol) and triethylamine (1.6 mL, 11.5 mmol) were combined in CH2Cl2 (22 mL) and treated with trichloroacetyl chloride (0.54 mL, 4.84 mmol) dropwise at 0° C. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was concentrated and the residue was purified by flash chromatography (98:2, CH2C12:CH3OH), to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]2[C:8]([N:9]=[C:18]3[C:17](=[C:15]2[OH:14])[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc2nc3c(c(O)c2c1)CCCC3
Temperature: 25 °C

Procedure:
A solution prepared from 25.0 g of 4-t-butylaniline-29.0 g of 2-ethoxycarbonylcyclohexanone, 100 ml of benzene and 0.20 g of p-toluenesulfonic acid was refluxed for 6 hours. At the end of this time no more water was collected from the reaction (Dean-Stark trap), so the benzene was evaporated and the residue was dissolved in 80 ml of diphenyl ether. This mixture was refluxed for 1 hour and then allowed to cool to room temperature overnight. The product which had precipitated from this solution was filtered off and washed well with diethyl ether to give 11.52 g of analytically pure product, m.p. 320°-322°.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][P:9]2(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][P:9]2(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CP2(=O)CCCCC2)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
A mixture of 1-(4-nitrobenzyl)phosphorinane-1-oxide (2.25 g) and 10% Pd—C (0.2 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 24 hours. The catalyst was filtered off, and the filtrate was concentrated recrystallized from ethanol-diethylether to give 1-(4-aminobenzyl)-phosphorinane-1-oxide (1.5 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=5)=[N:23][N:24]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(=O)=O.CC(C)=O>ClCCl>[CH:10]1[C:11]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:23][N:24]=4)=[CH:16][CH:15]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(4-carbazol-9-ylphenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (1.0 g, 2.40 mmol) in dichloromethane (10.0 ml) was dropwise added BBr3 (10.0 ml, 1M in dichloromethane) at −78° C. (dry-ice/acetone) under nitrogen. After addition of BBr3 solution, the reaction was taken to room temperature and kept at room temperature for 5 h. The reaction mixture was poured into ice-water (50.0 ml). Dichloromethane was evaporated under reduced pressure. The white solid was collected by filtration. After drying under vacuum, product as white solid was obtained in 0.97 g (100%) yield. 1H NMR (400 MHz, acetone-d6, δ): 8.91 (s, 1H, OH), 8.48 (m, 2H), 8.24 (dt, J1=8.0 Hz, J2=1.2 Hz, 2H), 7.91 (m, 2H), 7.71 (t, J=1.2 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H), 7.56 (d, J=0.8 Hz, 1H), 7.54 (t, J=0.8 Hz, 1H), 7.46 (m, 3H), 7.32 (m, 2H), 7.12 (m, 111), 3.93 (s, 3H, OCH3). 13C NMR (100 MHz, acetone-d6, δ): 165.43, 164.72, 158.87, 141.48, 141.12, 131.44, 129.41, 128.23, 127.17, 126.04, 124.56, 123.65, 121.43, 121.26, 119.88, 118.89, 114.18, 110.62. MS-EI (m/z): [M]+ calcd for C26H17N3O2, 403.1. found 403.1.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][C:6]=2[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:23]>O1CCOCC1>[ClH:23].[CH:13]([NH:12][C:8]1[N:9]=[CH:10][C:11]2[CH:2]([OH:1])[CH2:3][NH:4][CH2:5][C:6]=2[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)OC(C)(C)C)CC2O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Nc1ncc2c(n1)CNCC2O

Procedure:
A solution of 128 (400 mg, 1.30 mmol) and 4 N HCl in dioxane (4 mL) was stirred for 1 h. The reaction was concentrated to afford crude 2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-5-ol hydrochloride (130) which was used without additional purification.
Reaction SMILES: O[CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=[S:13])[S:12][C:4]=2[C:3]1=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>C(Cl)Cl>[OH:7][C:6]([C:5]1[S:10][C:11](=[S:13])[S:12][C:4]=1[C:3]1[CH:2]=[N:22][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:21]=1)([CH3:9])[CH3:8]
Reactant: CC1(C)OC(O)C(=O)c2sc(=S)sc21
Reactant: Nc1ccccc1N
Solvent: ClCCl
Product: CC(C)(O)c1sc(=S)sc1-c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 6-hydroxy-4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-7(6H)-one 6 (101.0 mg, 0.41 mmol) in CH2Cl2 (15 mL), 136.6 mg (1.26 mmol) of o-phenylenediamine was added, the resulting solution was refluxed for 1 hour. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by radial chromatography using CH2Cl2 as a mobile phase that yielded 4-(2-hydroxypropan-2-yl)-5-(quinoxalin-2-yl)-1,3-dithiole-2-thione 9 as a yellow-orange solid (119.6 mg, 0.37 mmol, 92.0%). 1H NMR in CDCl3 (δ, ppm): 9.01 (1H, s), 8.18 (1H, m, ArH), 8.07 (1H, m, ArH), 7.89 (2H, m, ArH), 1.59 (6H, s, CH3); 13C NMR in CDCl3 (δ, ppm): 207.8, 158.0, 145.1, 144.3, 141.9, 140.0, 133.81, 132.3, 131.9, 129.8, 128.7, 72.3, 31.0; IR (neat, cm−1): 3199, 3007, 2962, 2917, 1531, 1045, 759, 571, 457; HR APCIMS+ (m/z): 321.0179 (M+, C14H12N2OS3, 321.0185).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([CH2:26][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)c1
Yield: 28 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 3-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 28% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[N:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=2)=[CH:9][CH:8]=1>C1COCC1>[N:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[CH2:29][NH2:30])=[N:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[CH:17]=2)=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(C#N)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CN)c2)n1
Yield: 57.2 %

Procedure:
Lithium aluminium hydride (1 M in THF, 68.2 mmol, 10 eq) was added to a solution of 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzonitrile (2.57 g, 6.82 mmol) in dry THF (45.0 mL) under nitrogen and the reaction mixture was stirred at reflux for 3 hours. The reaction was cooled down in an ice bath and distilled water was added dropwise followed by a 1M NaOH solution (7.5 ml). The organic layer was removed under vacuum and DCM was added (30 ml) to the water phase. The dichloromethane layer was washed with brine and dried over Na2SO4. The filtrate was evaporated to dryness to give an oil, which was purified over silica gel, using DCM/MeOH/NH4OH (9.8:0.2:0.05) as eluent, to afford 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine (1.48 g, 3.90 mmol, 56%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([S:24][CH3:25])[C:3]=1[C:4]#[N:5].CCO.CCN(C(C)C)C(C)C.[NH2:38][NH2:39]>O>[CH3:23][NH:22][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:38][NH:39]3)=[C:6]([S:24][CH3:25])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCC[C@H]2C)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Into a sealable tube, 2-fluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (86 mg, 0.241 mmol), EtOH (5 mL), Hunig's base (0.042 mL, 1.44 mmol), and hydrazine anhydrous (0.045 mL, 0.241 mmol) were added, and the yellow suspension mixture was heated overnight at 100° C. in an oil bath. After overnight, there was yellow solution as well as a little amount of white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was further purified by flash column chromatography. The fractions containing product were combined, and the solvent was removed under reduced pressure to afford the title compound (20.5 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.1 Hz, 3H), 1.67 (m, 1H), 1.84-2.10 (m, 3H), 2.61 (s, 3H), 2.79-2.91 (m, 3H), 3.41-3.66 (m, 2H), 4.27 (m, 1H), 5.09 (s, 2H), 6.23 (s, 1H), 6.44 (s, 1H), 7.34-7.46 (m, 1H), 7.72 (s, 1H), 11.75 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[C@@H:11]([OH:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:21])[C:12]([CH3:22])([CH3:23])[C@@H:11]([OH:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(CC(=O)O)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate from Step C (64 mg, 187 mmol) in THF (1 mL) and H2O (0.5 mL) was added LiOH monohydrate (14 mg, 334 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1 N HCl (0.40 mL, 400 mmol), concentrated in vacuo and dried to afford the title compound. MS: m/z=314 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([N-]C(C)C)(C)C.[Li+].[CH3:18][N:19]([CH3:33])[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25](F)[CH:24]=1)(=[O:22])=[O:21]>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:25]1[CH:24]=[C:23]([S:20](=[O:22])(=[O:21])[N:19]([CH3:18])[CH3:33])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: Nc1ccc(I)cc1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(Nc2ccc(I)cc2Cl)c1
Reaction time: 0.08 h

Procedure:
To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (1 molar equivalent) in anhydrous tetrahydrofuran under a nitrogen atmosphere is added a commercially available lithium diisopropylamide solution (Aldrich, 2.0 M in tetrahydrofuran/heptane/ethylbenzene, 1 molar equivalent). After stirring for 5 minutes, a solution comprised of 4-dimethylsulfamoyl-2-fluoro-benzoic acid (1 molar equivalent) in tetrahydrofuran is added. The cold bath is removed and the reaction mixture is stirred for 2 hours. The reaction mixture is then partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford a product which may be purified by chromatography of recrystallization from an appropriate solvent like chloroform or heptane-ethanol.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][CH:12]([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][CH:12]([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(C)(N)C(=O)O
Reactant: CC(Br)C(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -12 °C

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (52.08 g, 0.51 mol), sodium hydroxide (20.20 g, 0.51 mol), 200 mL water, and 50 mL chloroform cooled to −12° C., was added a solution of 2-bromopropionyl bromide (100 g, 0.46 mol) in 150 mL chloroform over 15 minutes. The temperature was maintained between −15 and −12° C. during the addition. The reaction mixture was then allowed to warm to room temperature and the precipitated solid was filtered. The solid was mixed with 700 mL hot toluene, and then cooled. The white solid was then filtered and dried under vacuum. A yield of 77.60 g (70%) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:25]2[CH:26]=[C:27]3[N:34]([CH3:35])[CH2:33][CH2:32][N:28]3[C:29](=[O:31])[N:30]=2)=[CH:10][C:9]=1[C:16]([F:17])([F:18])[F:19]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C(F)(F)F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (15.78 mg, 0.394 mmol), (4-(3,4-difluorophenoxy)-3-(trifluoromethyl)phenyl)methanol (80 mg, 0.263 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (48.8 mg, 0.263 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[N:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClN1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:28]([OH:33])[CH2:29][CH2:30][CH:31]=[CH2:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:32][CH:31]([CH2:30][CH2:29][CH2:28][OH:33])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CCCCO
Reactant: COc1ccc(C=NO)cc1OC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C2=NOC(CCCO)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
(3,4-dimethoxyphenyl)(hydroxyimino)methane (1.05 g, 5.801 mmol) was dissolved in 30 mL of tetrahydrofuran under N2. After adding N-chlorosuccinimide (0.93 g, 6.96 mmol) and pyridine (46.9 L, 0.580 mmol) at room temperature, the reaction was continued for 30 min at 60. After cooling to room temperature, 4-pentene-1-ol (0.90 mL, 8.701 mmol) dissolved in 2 mL of tetrahydrofuran was added. Then, after adding triethylamine (0.97 mL, 6.961 mmol) dissolved in 2 mL of tetrahydrofuran, the reaction was continued for 1 hr at 50. When the reaction was completed, saturated NaHCO3 solution was added, and then the same was extracted with ethyl acetate. After drying over anhydrous MgSO4, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=1/2, v/v) to obtain 1.38 g (90.6%) of the target compound.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH2:23](O)C>[Pd]>[O:1]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH3:23])=[CH:21][CH:22]=1)[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: COC(=O)C=Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Product: COC(=O)C(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.53 g) in ethanol (25 ml) was added a 10% palladium on activated carbon (0.15 g), and the mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (35 ml) was added lithium bis(trimethylsilyl)amide (1.0 mol/l solution in tetrahydrofuran, 3.9 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.533 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.724 g) as a colorless oily liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1([C:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[S:45][N:44]=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>[I-].[K+].CN(C=O)C>[S:45]1[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:43]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[N:44]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (1.36 g) and DMF (40 ml) was added anhydrous potassium carbonate (0.3 g), diisopropylethyl amine (0.8 ml), 3-piperazinyl-1,2-benzisothiazol (1.26 g) and potassium iodide (27 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 12 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 20% triethylamine/ether) afforded 1.0 g of 5-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one as a foam. The product was flushed through alumina with dichloromethane. The hydrochloride was prepared by dissolving the free amine with menthanol and adding ethereal HCl. The salt was filtered and washed with pentane, m.p. 215° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:25])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:25])[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Process A: (3S,4R)-1-Benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine (2.70 g) was dissolved in dichloromethane (60 mL). While the solution was chilled in an ice water bath, diethylaminosulfur trifluoride (2.30 mL) was added dropwise and the mixture was stirred at room temperature for 20 hours. Following addition of a saturated aqueous solution of sodium bicarbonate (30 mL) in an ice water bath, the dichloromethane layer was separated. The dichloromethane layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine as a yellow-brown tar (2.20 g).