Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(3-fluoro-4-methoxyphenyl)-N-phenylpyrimidin-2-amine (Step 2, 0.066 g, 0.22 mmol), thiophenol (0.20 g, 1.0 mmol), and K2CO3 (0.15 g, 1.1 mmol) in NMP (2 mL) was heated at 120° C. for 20 h. The mixture was cooled to RT and diluted with H2O (4 mL). After stirring for 10 min, the resulting suspension was filtered, and the solid was further washed with H2O. The solid was washed with hexanes to provide the title compound as a brown solid. MS (ESI pos. ion) m/z: 282. Calc'd for C16H12FN3O: 281.10.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH2:15][CH2:16][CH:9]1[C:10](=O)[N:11]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2CCC1CN(C)C2)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCC(C(=O)N2Cc2ccccc2)N1Cc1ccccc1
Agent: CN1CC2CCC(C1)N2Cc1ccccc1
Product: c1ccc(CN2CC3CCC2CN3Cc2ccccc2)cc1
Yield: 88.2 %

Procedure:
Reduction of 6.1 g (0.019 mole) of 2.5-dibenzyl-2,5-diazabicyclo[2.2.2]octane-3,6-dione by the procedure employed to prepare 8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane as related under Example 5 gave 4.9 g (88%) of 2,5-dibenzyl-2,5-diazabicyclo[2.2.2]octane as a colorless oil.
Reaction SMILES: C(N1CC2(CCN(C3C=CC(O)=CC=3)CC2)OCC1=O)C.Br.[Br:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][C@H:29](C)[CH2:28]1>>[BrH:23].[Br:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C[C@H]1CCCN(CCCBr)C1
Agent: Br
Agent: CCN1CC2(CCN(c3ccc(O)cc3)CC2)OCC1=O
Product: BrCCCN1CCCCC1

Procedure:
The entitled compound was obtained as a pale yellow solid, according to the same method as in Example 5-(c) or according to a method similar to it but using 4-ethyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecan-3-one obtained in Example 5-3-(b), and (3S)-1-(3-bromopropyl)-3-methylpiperidine hydrobromide obtained in Reference Example 4 in place of 1-(3-bromopropyl)piperidine hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:14]=[CH:13][CH:12]=1.[Cl:23][S:24](O)(=[O:26])=[O:25]>>[Cl:23][S:24]([C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2ccnn2-c2ccccc2Cl)c(OC)c1
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1ccnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.1 18.0 g of 5-(2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole are added at −5° to 30 ml of chlorosulfonic acid, and the mixture is stirred at room temperature for a further 3 hours. The mixture is poured onto ice, and the deposited crystals are separated off and washed with water, giving 23.6 g of 5-(5-chlorosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“2a”).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (4.03 g, 21.1 mmol), 1-bromotetradecane (6.41 g, 23.1 mmol), potassium carbonate (5.59 g, 40.5 mmol) and butanone (115 ml).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCN=C=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Product: CCCCNC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
A solution of 1.0 g of n-butyl isocyanate in 5 ml of tetrahydrofuran was added to a solution of 1.76 g of 1-benzylpiperazine in 20 ml of tetrahydrofuran with ice cooling. The mixture was stirred at room temperature for 2 hours and, then, concentrated under reduced pressure to give 2.8 g of crude 1-benzyl-4-butylaminocarbonylpiperazine. The intermediate was submitted to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH2:15][OH:16])[N:3]=1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([CH2:15][OH:16])[CH:5]=[C:6]2[CH:9]=[C:10]([Si:11]([CH3:12])([CH3:14])[CH3:13])[O:8][C:7]=12
Reactant: C[Si](C)(C)C#Cc1cc(CO)nc(Cl)c1O
Solvent: CCO
Product: C[Si](C)(C)c1cc2cc(CO)nc(Cl)c2o1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
C3 (7.9 g, 31.2 mmol) and cuprous iodide (297 mg, 1.6 mmol) in 60 mL EtOH/60 mL TEA are added to a flask. The reaction is placed in an oil bath at 70° C. for 3.5 h, is cooled to room temperature, and concentrated in vacuo. The residue is partitioned between 100 mL 5% HCl and CH2Cl2 (4×50 mL). The combined organic layer is dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 6.5 g of a crude amber solid. The crude material is chromatographed over 300 g silica gel (230–400 mesh) eluting with 30–40% EtOAc/hexane. Two sets of fractions with two different desired compounds are identified by TLC/UV. The two compounds eluted separately. The early-eluting pool of fractions is combined and concentrated to afford [7-chloro-2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methanol (C5 as a white solid (46% yield). The later-eluting pool of fractions is combined and concentrated to provide (7-chlorofuro[2,3-c]pyridin-5-yl)methanol (C4) as a white solid (27% yield). MS (EI) for C8H6ClNO2, m/z: 183 (M)+ for C4. HRMS (FAB) calculated for C11H14ClNO2Si m/z: 255.0482, found 255.0481 for C5.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(Cl)c(Cl)c2)c2cc(-c3ccccc3)ccc21
Yield: 30 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3,4-dichlorophenyl boronic acid. The title compound (46 mg) was obtained as a beige solid, (yield=30%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]([NH:15][C@@H:16]([C:18]([NH:20][C@H:21]2[CH2:25][C:24](=[O:26])[O:23][C@@H:22]2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[CH3:17])=[O:14])[NH:11][CH:12]=1)C1C=CC=CC=1.[K+].[Br-]>>[C:29]1([CH2:28][CH2:1][C:8]2[N:9]=[C:10]([C:13]([NH:15][C@@H:16]([C:18]([NH:20][C@H:21]3[CH2:25][C:24](=[O:26])[O:23][C@@H:22]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH3:17])=[O:14])[NH:11][CH:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@H](NC(=O)c1nc(Cc2ccccc2)c[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C[C@@H](NC(=O)c1nc(CCc2ccccc2)c[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1

Procedure:
(2R,S,3S) N2-(4-Benzylimidazole-2-carbonyl)-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-alaninamide (17b), was isolated (75%) as a pale yellow glass: IR (KBr) 3294, 3031, 2937, 1792, 1650, 1530, 1453, 1444, 1119; 1H NMR(CDCl3) δ 7.99 (brm), 7.75 (brd), 7.36-7.11 (10H, m), 6.81 (1H, s), 5.51, 5.45 (d, s, J=5.3), 4.85-4.47 (4H, m), 3.95 (2H, s), 3.04-2.72 (1H, m), 2.48-2.35 (1H, m), 1.44 (d, J=6.9), 1.43 (d, J=7.1). (2R,S,3S) N2-[4-(2-Phenylethyl)imidazole-2-carbonyl]-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-alaninamide (17c), was isolated (79%) as a pale yellow glass: IR (KBr) 3292, 3029, 2936, 1793, 1650, 1530, 1453, 1444, 1119; 1H NMR(CDCl3) δ 8.06 (brm), 7.70 (brs), 7.39-7.15 (10H, m), 6.82 (s), 6.81 (s), 5.53 (d, J=5.2), 5.48 (s), 4.87-4.53 (4H, m), 2.95 (4H, m), 3.11-2.37 (2H, m), 1.48 (d, J=5.6), 1.45 (d, J=6.7). (2R,S,3S) 1-[4-(2-Phenylethyl)imidazole-2-carbonyl]-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-prolinamide (18c), was isolated (79%) as a pale yellow glass: IR (CH2Cl2) 3422, 2959, 1795, 1685, 1611, 1497, 1116;
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[N:14]([N:18]=[C:19]([NH2:21])[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Br[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]3[N:14]([N:18]=[C:19]([NH:21][C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(CS(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.165 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (51.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.009 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44-8.40 (m, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.60-7.54 (m, 3H), 7.51-7.46 (m, 2H), 7.00-6.93 (m, 3H), 6.70 (s, 1H), 4.32 (s, 2H), 3.21-3.14 (m, 4H), 2.83 (s, 3H), 2.66-2.56 (m, 4H), 2.37 (s, 3H). MS=477 (MH)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[CH3:21][N:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[CH:37]=[CH:38][N:39]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:24]=2[C:23]1=[O:48]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:26]2[C:25]3[CH:37]=[CH:38][N:39]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:24]=3[C:23](=[O:48])[N:22]([CH3:21])[CH:27]=2)=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccn(COCC[Si](C)(C)C)c2c1=O
Reactant: Nc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Product: Cn1cc(-c2ccc(N)c([N+](=O)[O-])c2Oc2ccc(F)cc2F)c2ccn(COCC[Si](C)(C)C)c2c1=O

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-(2,4-difluorophenoxy)-2-nitroaniline and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C26H29F2N4O5Si (M+H)+: m/z=543.2. found: 543.2.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:9](=[O:11])[C@@H:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:28][CH2:29]2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (0.556 g, 2.62 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.378 g, 1.31 mmol) in dry DMF (7 mL) was treated with Triton® B (2.40 mL, 5.28 mmol, 40 weight percent solution in methanol), a clear solution was obtained. The resulting reaction solution was cooled to 0° C. in an ice-water bath. To this solution was added solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.993 g, 2.62 mmol). After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution. White solid which forms was removed by filtration. The two layers of the filtrate were separated; the organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (30% EtOAc in hexanes) affording 0.48 g (76%) of the pure titled compound as a white foam: mp 45-54° C. APCI-MS m/z 484.4 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:10]1[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([OH:29])(=[O:28])[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21]>C(OC)(C)(C)C>[C:19]([OH:29])(=[O:28])[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21].[CH3:1][C@H:2]([N:9]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCCN1[C@@H](C)c1ccccc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1CCCCN1[C@@H](C)c1ccccc1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
Methyl N-[(S)-α-methylbenzyl]-(RS)-pipecolate (157 mg) was dissolved in methyl tert-butyl ether (2 ml) at room temperature. To this solution was added a mixture of L-(+)-mandelic acid (86 mg) and methyl tert-butyl ether (2 ml) at room temperature and stirred. The resulting solution was allowed to stand at −20° C. for one day to form a crystal. The crystals were separated by filtration and dried to yield an L-(+)-mandelic acid salt of methyl N-[(S)-α-methylbenzyl]-(S)-pipecolate (79.9 mg) in an optical purity of 73% de and a yield of 23%.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)nc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 195 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.307 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 6′-(cyclohexyloxy)-5-fluoro-3,3′-bipyridin-2-amine (280 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (81.1 mg) as colorless crystals.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH:32]4[CH2:34][CH2:33]4)[N:26]=[C:25]3[CH2:35][CH3:36])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45]>C1COCC1>[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([NH2:3])=[O:31])=[C:27]([CH:32]4[CH2:33][CH2:34]4)[N:26]=[C:25]3[CH2:35][CH3:36])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][S:44]([C:47]([F:49])([F:48])[F:50])(=[O:45])=[O:46]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Solvent: C1CCOC1
Product: CCc1nc(C2CC2)c(C(N)=O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1,1'-Carbonyldiimidazole (14.3 g) was added in one portion to a solution of the product of Example 5 (18 g) in dry THF (600 ml) at room temperature under nitrogen. The mixture was stirred for 16 h, then ammonia was bubbled through the solution for 30 mins, and the mixture then stirred for 5 h. Ammonia was again bubbled through the reaction mixture for 30 mins, and the solution stirred for a further 16 h. The reaction mixture was diluted with ethyl acetate (1 liter) and cooled in an ice-bath. Cold dilute hydrochloric acid (0.25M ca. 1 liter) was added dropwise to the vigorously stirred reaction mixture until pH6 was achieved. The aqueous phase was separated and extracted further with ethyl acetate (3×500 ml). The combined organic extracts were washed with brine (2×800 ml) and dried. The solvent was evaporated to give a colourless foam (18 g) which was triturated under ether (250 ml) and filtered to give a colourless amorphous solid (13.8 g), m.p. 155.6°-159.2°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, light brown solid, m.p. 121° C. and MS: m/e=324.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].O.[OH-].[Li+].Cl>C(O)C>[CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N(CC)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(c1cc(S(C)(=O)=O)ccc1C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate (11.4 g) and lithium hydroxide monohydrate (1.37 g) in aqueous ethanol (50%) was stirred at room temperature for 19 hours. The mixture was then acidified with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoic acid as a brown solid (9.48 g), NMR (acetone-d6); 1.15(t,3H), 2.98(s,3H), 3.22(s.3H), 3.85(q,2H), 8.0-8.25(m,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:15])[CH2:27]1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Clc1ccccc1CC1CCNC1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (6.5 mg). Calcd for C21H18C12 N2O2: 400.0745, found 400.0746.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH2:12][NH2:13]>C(O)C>[CH2:6]([C:5]1[NH:13][N:12]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)[CH3:7]
Reactant: CCC(=O)CC(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Product: CCc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1,1,1-Trifluoro-hexane-2,4-dione (1 g, 5.95 mmol) in absolute ethanol (10 mL) was added NH2NH2.xH2O drop-wise at 0° C. The reaction mixture warmed to the room temperature during 1 hour and refluxed overnight. Ethanol was then evaporated, residue dissolved in ethyl acetate (20 mL), washed consecutively with saturated brine solution and water, dried with Na2SO4 and concentrated to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O>O1CCCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)o1
Yield: 15.1 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (600 mg, 2.72 mmol)[prepared in Example 116] and N-bromosuccinimide (485 mg, 2.72 mmol) in tetrahydrofuran (13 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (5-15% EtOAc in hexanes yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (130 mg, 0.41 mmol, 15% yield) as an orange oil: LCMS (ES) m/e 299, 301 (M, M+2)+.