Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:17]1([CH2:16][NH:23][CH2:2][C:3]([NH:5][C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[NH:8][N:7]=2)=[O:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CNCc1ccccc1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.67 cm3 of benzylamine. The reaction medium is refluxed for 1 hour and the precipitate formed is filtered off, washed with 5 cm3 of acetonitrile and 5 cm3 of methylene chloride, then purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (97/2.5/0.25 by volume). The fractions containing the expected product are combined and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 305 mg of 2-[(phenylmethyl)amino]-N-(6-chloro-1H-indazol-3-yl)acetamide in the form of a white powder melting at 156° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]O)[CH3:2].[Br:10]P(Br)Br>ClCCl>[Br:10][CH2:8][C:7]1[S:6][CH:5]=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ncsc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1ncsc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-ethyl-1,3-thiazol-5-yl)methanol (1.0 g, 7.0 mmol) in anhydrous dichloromethane (50 mL) was added tribromophosphane (725 μL, 7.6 mmol). The mixture was stirred at room temperature for 2 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-4-ethyl-1,3-thiazole. The crude product was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C@@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@H:10]3[O:20][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[C:13]2[O:12][C@@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@@H:10]([OH:20])[C@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Reactant: COC(OC)[C@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H]2O[C@@H]21
Product: COC(OC)[C@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 14.8 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (751 mg, 2.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, 2.67 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (200 mg, yield: 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:26][NH2:27]>C(O)C>[CH3:26][NH:27][C:20]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:21]
Reactant: CN
Reactant: Cc1ccc(-n2nc(C(=O)Cl)cc2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of 1-(4-methylphenyl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid chloride in ml of CH2Cl2 is added dropwise to 100 ml of a 33% solution of methylamine in ethanol. After stirring for hours at room temperature, the mixture is concentrated under vacuum, the residue is taken up with a mixture of 5% Na2CO3 +AcOEt, the organic phase is decanted, washed with a saturated solution of NaCl and dried over MgSO4 and the solvents are evaporated off. The residue is taken up in isopropyl ether and the crystals obtained are filtered off and dried under vacuum to give 0.44 g of the expected amide.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1.[CH3:22][CH:23]([CH3:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:22][CH:23]([CH3:29])[CH2:24][S:25]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)CC(C)C)CC2
Reaction time: 0.17 h
Yield: 93 %

Procedure:
Triethylamine (750 μl, 5.15 mmol, 3 eq) was added at 0° C. to a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (1.72 mmol, 1 eq) in dichloromethane (10 ml), and stirring was carried out for 10 min. A solution of 2-methylpropane-1-sulfonyl chloride (404 mg, 2.58 mmol, 1.5 eq), dissolved in dichloromethane (5 ml), was added dropwise, and stirring was carried out for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 30% ethyl acetate in hexane). The desired product was obtained in the form of a white solid. Yield: 93% (500 mg, 1.6 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][C@@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)=[O:8].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][C@@H:12]([OH:13])[CH2:16][OH:15])=[O:8]
Reactant: CC1(C)OC[C@@H](CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NOC[C@@H](O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A 3L single necked round bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g, 122 mmol) in tetrahydrofuran (1.5 L). Aqueous 1N hydrochloric acid (500 mL) solution was added and the reaction mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was concentrated and extracted with ethyl acetate (3×800 mL). The organic extracts were washed with saturated aqueous sodium bicarbonate (500 ml) and brine (500 ml), and dried (MgSO4). The crude pale yellow solid was recrystallized from ethyl acetate/hexane and dried at 70° C. in vacuum oven to afford 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,3-dihydroxy-propoxy)-3,4-difluoro-benzamide (35 g, 54%) as pale yellow crystals: m.p. 153-154° C.; [α]=+3.36° (c=1.04, methanol); 1H NMR (d6-DMSO) δ 12.02 (s, 1H), 8.85 (s, 1H), 7.74 (s, 1H), 7.64 (d, 1H), 7.45 (d, 1H), 6.66 (t, 1H), 4.82 (s, 1H), 4.58 (s, 1H), 3.88 (m, 2H), 3.74 (m, 3H); 19F NMR (d6-DMSO) δ −133.21 (s, 1F), −137.18 (s, 1F); MS (m/z): 534 (68), 532 (100), 483 (28), 481 (41), 440 (51). Anal.calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.36; H, 2.46/2.38; N, 5.25/5.30; F, 7.13/7.15; Cl, 13.30/13.76; I, 23.80/23.83.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:19]1[CH2:23][CH2:24][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])([C:11]#[N:12])[CH2:21][CH2:20]1)=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.28 g, 45 mmol) was suspended in DMF (20 mL) and cooled in an ice bath under a nitrogen atmosphere. (2-Chloro-phenyl)-acetonitrile (1.77 g, 11.7 mmol) in DMF (5 mL) was added slowly, and the mixture stirred for 2 hours. Bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol) in DMF (5 mL) was then added and the mixture heated to 75° C. for 6 hours. The solvent was removed by evaporation under vacuum and the residue dissolved in ethyl acetate (50 mL), washed with water, then brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by silica chromatography eluting with a mixture of ethyl acetate and hexane. The fractions containing the desired products were combined and the solvent removed by evaporation to give the title compound as an orange gum (1.1 g). LCMS m/z 321.0 [M+H]+. R.T.=4.76 min (Analytical Method 4).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:32]1[CH2:31][CH2:30][N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[CH2:34][CH2:33]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCN(c2ccccc2Cl)CC1
Yield: 81.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.091 g, 0.243 mmol) obtained in Example 22, step 3 and 1-(2-chlorophenyl)piperazine (0.057 g, 0.239 mmol), the title compound (0.102 g, 69%) was obtained.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.ClCCl.[Si:13]([O:30][CH2:31][C:32]1[N:33]=[C:34]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[N:35]([CH2:40][C:41]#[C:42][CH3:43])[C:36]=1[C:37](=[S:39])[NH2:38])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[Si:13]([O:30][CH2:31][C:32]1[N:33]=[C:34]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[N:35]([CH2:40][C:41]#[C:42][CH3:43])[C:36]=1[C:37]([S:39][CH3:6])=[NH:38])([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(N)=S
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(=N)SC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
1.23 g of trimethyloxonium tetrafluoroborate was added to a 100 ml dichloromethane solution of 4.351 g of t-butyl 4-[4-(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate was added to the solution, and the organic layer was washed successively with 100 ml of a saturated sodium bicarbonate solution and 100 ml a saturated ammonium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 4.439 g of the title compound.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[C:34]([F:37])([F:36])[F:35])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:39]=1)=O)C>>[CH2:1]([NH:6][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[C:34]([F:35])([F:37])[F:36])[CH2:22][CH2:21]3)=[N:16][N:15]2[CH:39]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Product: CCCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 39 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-pentylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 39% yield. 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 7.76-7.66 (m, 2H), 7.33 (s, 1H), 7.27-7.18 (m, 1H), 7.09-7.03 (m, 1H), 6.89 (d, J=9.9 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.8 (m, 1H), 3.69-3.54 (m, 2H), 3.15-3.37 (m, 4H), 3.65-3.29 (m, 2H), 1.67-1.55 (m, 2H), 1.42-1.27 (m, 4H), 0.88 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.6, 162.3, 154.8, 138.3, 136.9, 135.6, 129.7, 129.6, 129.57, 129.5, 126.3, 125.1, 125.4, 122.9, 121.4, 118.3, 116.8, 116.5, 114.9, 114.6, 111.9, 46.2, 45.6, 41.2, 39.2, 29.4, 29.1, 22.4, 14.0. MS (ES+) m/z 507 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])([CH3:37])[CH3:36])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (2.02 g, 6.21 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.05 g, 12.42 mmol) and ethyl-2-bromoisobutyrate (3.64 mL, 24.83 mmol). The mixture was heated to 60° C. under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 1.36 g (50%) of the desired 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([OH:27])([CH3:26])([CH3:25])[CH3:24]>>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH2:24][C:23]([OH:27])([CH3:26])[CH3:25])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 40 °C

Procedure:
A solution of 20.4 g (0.30 mol) of 50% aqueous hydrogen peroxide mixed with 25 mL of tert-butyl alcohol is added over three hours to a mixture of 27.6 g (0.10 mol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 7.13 g (0.036 mol) of ferrous choride tetrahydrate and 115 mL of tert-butyl alcohol at 40° C. The reaction temperature is maintained at 40° C. for twenty hours after the peroxide addition is complete. The crude reaction mixture is purified by flash chromatography on silica gel to afford 16.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:35][CH2:36]3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(F)cc2)CC=CCN1OCc1ccccc1
Solvent: CS(C)=O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(N3CCC(c4ccccc4)CC3)cc2)CC=CCN1OCc1ccccc1
Temperature: 70 °C
Yield: 61 %

Procedure:
To a solution of 100 mg of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-fluoro-benzenesulfonamide from Step A in 2 mL of methylsulfoxide was added 100 mg of 4-phenyl piperidine. The solution was heated to 70° C. for 5 days. The reaction was cooled, and the mixture extracted with ethyl acetate. The organic layers were washed twice with NaCl(aq.) solution, followed by drying over Na2SO4(s). Filtration, solvent removal, was followed by dilution with ethyl ether. Filtration of the resulting solids, washing with ethyl ether and methanol, and drying gave 83 mg of an off-white solid. MS: 1063 (2M+H), 532 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>O>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Brc1nccs1
Solvent: O
Product: c1csc(N2CCNCC2)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To piperazine (48 g) dissolved by heating at 110° C. was added dropwise 2-bromothiazole (5 ml) over 20 min. The mixture was stirred at 150° C. for 1 hr, poured into water (150 ml) and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (9.5 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[C:14]2[N:15]([C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:32]=2)[CH:16]=[CH:17][C:18]=1[C:19]([O:22][Si](CC)(CC)CC)([CH3:21])[CH3:20]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[F:12][C:13]1[C:14]2[N:15]([C:30]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=3)=[CH:31][N:32]=2)[CH:16]=[CH:17][C:18]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(F)c(C(C)(C)O[Si](CC)(CC)CC)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2c1F
Reaction time: 3 h

Procedure:
2-Trifluoromethyl-4-chloropyrimidine (100 mg, 0.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) were combined with a THF solution of 8-fluoro-3-(tri-n-butylstannyl)-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (circa 0.2 M; 3 ml, circa 0.6 mmol) and heated to reflux, with stirring, for 3 h. After cooling, the solution was concentrated onto silica and purified by column chromatography (silica; 50% EtOAc/isohexane), then the silyl protection removed by treatment with an ethanolic solution of 37% hydrochloric acid (5 drops in 2 ml of ethanol), affording the title compound as a white amorphous solid: δH (360 MHz, CDCl3) 1.77 (6H, s), 7.48 (1H, m), 7.78 (1H, d, J 5.6), 8.42 (1H, s), 9.42 (1H, m), 9.71 (1H, d, J 7.6); m/z (ES+) 341 (100%, [MH]+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12].Cl>>[ClH:5].[CH2:1]([N:19]1[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[C@H:17]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18]1)[CH:2]=[CH2:3]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC[C@@H]1CN1CCCC1
Reactant: C=CCBr
Agent: Cl
Product: C=CCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@H](CN2CCCC2)C1
Yield: 81 %

Procedure:
The compound was prepared by coupling of allyl bromide with 1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine in 81% yield; mp: (HCl salt) 157-160° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-2.0 (6 H, m), 2.3-3.0 (6 H, m), 3.1-3.8 (4 H, m), 4.3-4.8 (1 H, m), 4.9-5.1 (2 H, m), 5.7-5.9 (1 H, m), 7.0-7.3 (3 H, m); MS (FAB) 396 (M+H)+ ; Anal. Calcd for C20H27Cl2N3O.2HCl: C, 51.19; H, 6.23; N, 8.95. Found: C, 50.89; H, 6.42; N, 8.65.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].N([O-])=O.[Na+].[CH:14]([CH:16]=[CH2:17])=[O:15]>Cl.O.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH2:17][CH2:16][CH:14]=[O:15])[CH:7]=1
Reactant: C=CC=O
Reactant: Cc1ccc(Cl)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a suspension of 2-amino-4-chlorotoluene (1.41 g, 10 mmol) in 24% aq. HCl (5 mL) Was added dropwise NaNO2 (710 mg, 1.03 mmol) in H2O (3 mL) over 30 min at 0° C. The resulting solution was added dropwise to a solution of acrolein (1 mL, 15 mmol) in a mixture of DMF (15 mL) and 20% aq. TiCl3 (20 mL, 26 mmol). After the addition was completed, the mixture was stirred for 30 min at room temperature and extracted with diethyl ether. The extracts was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/AcOEt to give 1.11 g of the title compound (60%): 1H NMR (CDCl3) δ9.83 (s, 1H), 7.06~7.12 (m, 3H), 2.90 (t, 2H, J=7.2 Hz), 2.74 (t, 2H, J=7.2 Hz), 2.27 (s, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>>[OH:4][CH2:3][CH2:2][S:1][C:10]1[C:5](=[O:12])[CH:6]=[C:7]([S:1][CH2:2][CH2:3][OH:4])[C:8](=[O:11])[CH:9]=1
Reactant: OCCS
Reactant: O=C1C=CC(=O)C=C1
Product: O=C1C=C(SCCO)C(=O)C=C1SCCO
Reaction time: 0.5 h

Procedure:
2-Mercaptoethanol (3.5 ml, 0.05 mole) is added in a single amount to an ethanolic solution of p-benzoquinone (10.81 g, 0.1 mole) and the mixture is allowed to stand, with stirring, for 1/2 hour. Further 2-mercaptoethanol (1.75 ml, 0.025 mole) is added and the mixture is allowed to stand, with stirring, for 2 hours. The mixture is filtered and the precipitate is washed with absolute ethanol. Dark red crystals of the expected derivative are obtained: