Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:39]=[CH:38][O:37][N:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccon1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(C2=NOC(COc3ccon3)C2)cc1
Reaction time: 18 h
Yield: 55.5 %

Procedure:
(5RS)-3-(4-Bromophenyl)-5-hydroxymethyl-4,5-dihydro-isoxazole (3.07 g, 12 mM), triphenylphosphine (3.78 g, 14.4 mM) and 3-hydroxyisoxazole (1.02 g, 12 mM) were dissolved in anhydrous tetrahydrofuran (50 ml), cooled to 0° with stirring under nitrogen, and treated with diisopropylazodicarboxylate (2.71 g, 13.4 mM). Stirring was continued for 18 hours, and the mixture evaporated to dryness. The residue was chromatographed on a 90 g Biotage silica column, eluting with 25% ethyl acetate in isohexane, appropriate fractions combined, and chromatographed again on a 40 g Biotage silica column, eluting with 5% methanol in dichloromethane. Appropriate fractions were combined to give the desired product (2.15 g). MS (ESP): 323 (MH+) for C13H11BrN2O3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:26]=[CH:25][C:16]2[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[S:19][C:15]=2[CH:14]=1.Br[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:28][CH2:29][CH:30]5[CH2:34][CH2:33][CH2:32][N:31]5[CH3:35])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[S:19][C:18]=1[CH3:20])=[O:22]
Reactant: CN1CCCC1CCBr
Reactant: CNC(=O)c1c(C)sc2cc(Oc3ccnc4ccc(O)cc34)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4ccc(OCCC5CCCN5C)cc34)ccc12

Procedure:
A solution of 25-F (70 mg, 0.19 mmol), 2-(2-bromoethyl)-1-methylpyrrolidine 25-B (110 mg crude and Cs2CO3 (94 mg, 1.5 mmol) in DMSO (2 ml) was heated to 120° C. for 2 hours. The title compound, N,2-dimethyl-6-({6-[2-(1-methylpyrrolidin-2-yl)ethoxy]quinolin-4-yl}oxy)-1-benzothiophene-3-carboxamide 25 (21 mg) was isolated by HPLC (Dionex System) using 20-60% CH3CN/H2O (0.1% AcOH) over 30 minutes.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.1 g) and triethylamine (0.026 mL) in dichloromethane (3 mL) was added methanesulfonyl chloride (0.013 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.11 g). This material was dissolved in a solution of acetonitrile (2 mL) and methanol (2 mL). To the solution were added 3-benzylaminopropionamide (46 mg) and sodium iodide (24 mg), and the mixture was stirred at 60° C. for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (78 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Mg]Br.FC1C=CC=CC=1CBr.[Mg].[CH3:21][CH:22]([CH3:30])[C:23](=[O:29])[C:24]([O:26]CC)=[O:25].[NH4+].[Cl-]>C(OCC)C>[CH:22]([C@@:23]([OH:29])([CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[C:24]([OH:26])=[O:25])([CH3:30])[CH3:21]
Reactant: Fc1ccccc1C[Mg]Br
Reactant: CCOC(=O)C(=O)C(C)C
Agent: Fc1ccccc1CBr
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)[C@@](O)(Cc1ccccc1F)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of (o-fluorobenzyl)magnesium bromide in diethyl ether (100 mL), prepared from the corresponding o-fluorobenzyl bromide (9.45 g, 50.0 mmol) and magnesium turnings (1.32 g, 55.0 mmol), was added to a solution of ethyl 3-methyl-2-oxobutanoate (7.2 g, 50 mmol) in diethyl ether (50 mL) cooled at −78° C. After 30 min at −78° C., the reaction mixture was warmed to 0° C. and poured into saturated aqueous NH4Cl. The organic layer was washed with brine, dried and concentrated. The residue was dissolved in methanol (200 mL) and kept with 2 N KOH (75 mL) for 2 hrs. at 50° C. The reaction mixture was diluted with water and washed with hexane. The aqueous layer was acidified with 2 N HCl, saturated with sodium chloride and extracted with ethyl acetate. Removal of solvents gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]2[OH:23])=[C:5]([NH:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[N:4]=1.[CH:36]([N:39]([CH:50]([CH3:52])[CH3:51])[CH2:40][CH2:41][NH:42][C:43](N1C=CN=C1)=[O:44])([CH3:38])[CH3:37]>>[CH:50]([N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41][NH:42][C:43]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]2[OH:23])=[C:5]([NH:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[N:4]=1)=[O:44])([CH3:52])[CH3:51]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(CNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared from (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 69) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) by similar procedure to that used in Example 3.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C(O)(=O)C>[Cl:1][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH3:9])[C:19]=1[CH3:20]
Reactant: Cc1cc2ccccc2cc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(Cl)c1C

Procedure:
N-Chlorosuccinimide (14 g) in glacial acetic acid (150 ml) was added to 2,3-dimethylnaphthalene (15.6 g) in refluxing glacial acetic acid (150 ml) over 30 min. The solution was evaporated to dryness and the residue was washed with ether (3 × 100 ml) and insoluble material discarded. The ether washings were evaporated and the residue recrystallised from ethanol to give 1-chloro-2,3-dimethylnaphthalene (1) m.p. 55°.
Reaction SMILES: [C:1]([O:4][C:5]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH:7]=[CH2:8])[CH3:6])(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].O.C(=O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:6])([CH2:9][CH2:10][CH:11]([Cl:15])[C:12]([CH3:14])=[CH2:13])[CH:7]=[CH2:8])(=[O:3])[CH3:2]
Reactant: [O-]Cl
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: O=C=O
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: C=CC(C)(CCC(Cl)C(=C)C)OC(C)=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 177.7 %

Procedure:
A stirred mixture of linalyl acetate (39 g, 0.2 mol), 65% calcium hypochlorite (22 g, 0.1 mol), water (70 mL) and dichloromethane (700 mL) was cooled to 10° C. and solid carbon dioxide was added until an exotherm was no longer observed upon addition. After stirring for an additional 1 h at 10° C., the organic layer was separated and washed successively with a solution containing 5% sodium bicarbonate and 1% sodium bisulfite (100 mL), and then with brine (100 mL). The organic layer was dried, the solvent evaporated, and the residue distilled to yield 41 g of 3-acetoxy-6-chloro-3,7-dimethyl-1,7-octadiene, bp 75°-80° C. (0.5 mm). IR (film) 1740, 1370, 1250, 920 cm-1. NMR (CDCl3) δ1.53 (3H, s), 1.8 (3H, bs), 1.8-2.4 (2H, m), 4.33 (1H, m), 4.84-5.33 (4H, complex) 6.0 (1H, dd).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:11]=1)([CH3:5])[CH3:4].BrCC(C1C=CC([C:28]#[N:29])=CC=1)=O.C1N=CN(C(N2C=NC=C2)=N)C=1>O1CCCC1>[NH:29]=[C:28]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[N:11]=2)[C:3]([CH3:5])([CH3:4])[CH2:2][O:1]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: N=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Yield: 19 %

Procedure:
A mixture of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.00 g, 7.31 mmol), prepared in the same manner as described in step 3 of Example 3, and replacing 3-(2-bromoacetyl)benzonitrile with 4-(2-bromoacetyl)benzonitrile, and C-(di-imidazol-1-yl)-methyleneamine (1.30 g, 8.07 mmol) in 35 mL of tetrahydrofuran was refluxed under nitrogen for three days. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of hexane in methylene chloride as the eluent gave the title compound (417.2 mg, 19%) as an off-white solid, mp 158-161° C.; MS (ES) m/z 299.0 [M+H]+. Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78. Found: C, 60.38; H, 4.82; N, 18.67.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:9][CH2:8]2)[N:15]=1)=[O:17])=[O:22]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NCC(O)CO
Product: O=C(NCC(O)CO)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 33 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-amino-propan-1,2-diol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (33%) as amorphous yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:4]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(methylsulfonyl)ethanamine (10.28 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9.2 mg, 0.017 mmol, 36.2% yield): LCMS=537.1 [M+H]+; 1H NMR (400 MHz, methanol-d4 and CDCl3) δ ppm 8.15 (2 H, d, J=8.28 Hz), 7.66 (4 H, t, J=7.78 Hz), 7.47-7.60 (3H, m), 5.13 (1 H, s), 3.73 (2 H, t, J=6.40 Hz), 3.23-3.31 (2 H, m), 2.94 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.4 min.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]([OH:30])[C:28]#[N:29])=[O:24])[C:12](=[O:38])[CH:11]1[CH:39]([CH3:41])[CH3:40])(=[O:9])[CH3:8].[C:42](OC(=O)C)(=[O:44])[CH3:43].CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OCC)(=O)C>[C:42]([O:30][CH:27]([C@@H:26]([NH:25][C:23]([CH2:22][N:13]1[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:10]([C:7](=[O:9])[CH3:8])[CH:11]([CH:39]([CH3:41])[CH3:40])[C:12]1=[O:38])=[O:24])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28]#[N:29])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C#N)C(=O)C1C(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C#N)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reaction time: 6 h

Procedure:
Pyridine (0.15 ml) is added to a solution of (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile (291 mg, Compound No. 8-1) in methylene chloride (3 ml). The mixture is cooled with ice, acetic anhydride (115 μl) and dimethylaminopyridine (catalytic amount) are added to the mixture, and the whole is stirred for six hours. Ethyl acetate is added to the reaction mixture and the whole is washed with 1 N hydrochloric acid and saturated brine successively. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (317 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Into the mixture solution of 2-bromo-5-iodopyridine (9.15 g, 32.2 mmol), tert-butyl piperazine-1-carboxylate (5 g, 27 mmol) in Toluene (90 mL) was added Tris(dibenzylideneacetone)dipalladium (0) (0.983 g, 1.1 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.17 g, 3.2 mmol) and NaOtBu (7.8 g, 80.5 mmol). Then the reaction mixture was flushed with Argon and stirred for 2 h. The reaction mixture was extracted with ethyl acetate and washed with brine. After drying with MgSO4, the organic solvent was removed under vaco., the residue was purified by crystallization from mixture of DCM and Hexane to get 8.4 g of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13. 1H NMR (400 MHz, CDCl3) ppm: δ 8.01 (d, J=3.2 H2, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.07 (d, d, J=3.2, 8.4 Hz, 1H), 3.59 (t, J=5.4 Hz, 4H), 3.237 (t, J=5.4 Hz, 4H), 1.478 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36](Cl)=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2([C:36](=[O:37])[CH2:35][C:30]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=3)[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc2c3c([nH]c2c1)CCNC3CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCCC2)NCCc2[nH]c3ccccc3c21

Procedure:
Prepared as Ex. No. 12, from 1.1 g (4.08 mmoles) of crude 1-(piperidin-1-yl)methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole, 1.12 g (8.10 mmoles) of anhydrous potassium carbonate and 1.1 g (4.92 mmoles) of 3,4-dichlorophenylacetylchloride in 40 ml of dry chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23]N1C(=O)CCC1=O>>[Cl:23][C:14]1[C:13]2[CH:12]3[N:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:9])=[O:10])[CH:19]([CH2:18][C:17]=2[NH:16][N:15]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Reactant: O=C1CCC(=O)N1Cl
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1c(Cl)n[nH]c1C2

Procedure:
Prepared by chlorination of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using N-chlorosuccinimide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:36][C:17]([F:16])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:29]=2)[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 62 from 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI): m/z 503 (M−1).
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(Cc3ccccc3)C2)C(=O)O1
Temperature: 80 °C
Yield: 13.2 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (530 mg, 1.67 mmol) in DMF (10 mL) was added benzyl bromide (573 mg, 3.35 mmol) and K2CO3 (924 mg, 6.7 mmol), and the mixture was heated to 80° C. for 5 hours. The reaction was quenched by H2O. The layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-benzylpiperidin-3-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (90 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:3]=1.[C:23]([OH:27])(=[O:26])[CH2:24][CH3:25]>C(O)(C)C>[CH3:13][CH2:12][O:11][C:9]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:3][C:2]=1[NH2:1])=[O:10].[C:23]([O-:27])(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)O
Agent: CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)nc1N
Solvent: CC(C)O
Product: CCC(=O)[O-]
Temperature: 60 °C

Procedure:
Under nitrogen atmosphere 30 g of 2-amino-3-carbethoxyamino-6-(4-fluoro-benzylamino)-pyridine and 7.5 g of propionic acid were added to 500 ml of isopropanol. The mixture was heated to 60° C. A transparent solution of flupirtine propionate was formed and was kept for 30 min at 50° C. The solution was filtered at 20° C. and crystallisation occurred while cooling the solution down to −5° C. for 12 h. The product was collected by filtration and dried at reduced pressure at room temperature for 12 h. As a result of drying 25 g white crystals of the product were obtained.
Reaction SMILES: [OH:1][B:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6]N1C=C(C)C(=O)NC1=O.[NH2:17][C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20]([Cl:27])[N:19]=1.BrCCCCB(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH2:6][CH2:5][CH2:4][CH2:3][B:2]([OH:16])[OH:1])=[C:20]([Cl:27])[N:19]=1
Reactant: Cc1cn(CCCCB(O)O)c(=O)[nH]c1=O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: OB(O)CCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(CCCCB(O)O)c2n1
Yield: 56 %

Procedure:
The title compound was synthesized in a similar manner as the compound of Example 1 with 2-amino-6-chloropurine (1.36 g, 8 mmol), 4-bromobutyl boronic acid (1.45 g, 8 mmol), and potassium carbonate (1.66 g, 12 mmol) in dimethylformamide (20 mL). Yield 56%; Wt. 1.2 g; mp 154°-156° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.20-1.32 (m, B CH2 CH2), 1.68-1.77 (m, B CH2 CH2 CH2), 4.00-4.08 (t, CH2 CH2 N), 6.85-6.92 (s, H2N C2 purine), 7.40-7.42 (s, (HO)2 B), 8.10-8.12 (s, H C8 purine). Electrospray Mass Spectrum (MH)+ (low resolution); Calcd. 270.09 (C9H13O2N5BCl); Found 270.10 (37 ppm).