Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[I-].[K+]>CC(=O)CC>[N:27]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:20]=[CH:19][C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1O2
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Reaction time: 48 h

Procedure:
A mixture of 19.6 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)-xanthene, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide and 200 ml. of butanone was refluxed with stirring for 21/2 days. The reaction mixture was poured into 1000 ml. of water, and the solid which precipitated was filtered and recrystallized from methylene chloride-acetone then from acetone to give the desired product. M.P. 115°-117°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.CC(C)=O.[I-:15].[Na+].CCCCCC>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][I:15]
Reactant: COc1ccccc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1CI
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g of 2-methoxybenzyl chloride in 22 ml of abs. acetone are treated with 9.3 g of sodium iodide and the reaction mixture is stirred at RT overnight. It is then diluted with 250 ml of ether and the whole is washed with 10% sodium thiosulfate solution and saline. After drying over sodium sulfate, and removing the solvent, the title compound, which is subjected, without purification, to further processing, is obtained. TLC Rf (hexane:ethyl acetate=4:1)=0.46. 1H-NMR (200 MHz, CDCl3): 7.36-7.2 (m, 2H); 6.92-6.8 (m, 2H); 4.48 (s, 2H); 3.91 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1.[CH2:55]([N:62]=[C:63]=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([NH:62][C:63]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C=NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(COC(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(m), reaction of tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate with benzyl isocyanate gave tert-butyl (3RS,4RS,5SR)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which by cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86(u) there was obtained tert-butyl (3SR,4RS,5RS)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate. Subsequent alkylation with methyl iodide analogously to Example 1(g) yielded tert-butyl (3SR,4RS,5RS)-4-[4-[(benzyl-methyl-carbamoyloxy)-methyl]-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 656 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1([CH3:39])[OH:38].CCN(C(C)C)C(C)C.[Na+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]4([CH3:39])[OH:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(O)CCCCC1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCC4(C)O)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.97 g, 2.09 mmol) and 2-amino-1-methylcyclohexanol, 30b, (0.40 g, 3.13 mmol) in DMF (10 mL) was added iPr2NEt (0.73 mL, 4.17 mmol). The reaction mixture was heated at 90 C for 17 hours. The reaction mixture was cooled to room temperature and diluted into aqueous saturated NaCl solution. The aqueous phase was extracted twice with EtOAc. The organic phases were washed with twice with aqueous saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/hexanes-loaded with CH2Cl2) to afford the desired product, 30c, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[CH:24]([F:36])[O:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:16]1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:47])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[CH:24]([F:36])[O:25][C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 77.9 %

Procedure:
0.15 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 73 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.12 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methylamino-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [N:1]([CH:4]([CH3:8])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3].[CH3:9][CH2:10][CH2:11][N:12]([C@@H:20]1[CH2:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]=2[CH2:22][CH2:21]1)[CH2:13][CH2:14][C:15]1[S:19][CH:18]=[CH:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:9][CH2:10][CH2:11][N:12]([C@@H:20]1[CH2:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]=2[CH2:22][CH2:21]1)[CH2:13][CH2:14][C:15]1[S:19][CH:18]=[CH:17][CH:16]=1.[N:1]([CH:4]([CH3:8])[C:5]([O-:7])=[O:6])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])C(=O)[O-]
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask was placed 2-azidopropionic acid (251 mg, 2.02 mmol, 1.3 equiv.—in 3 mL of DCM), rotigotine (500 mg, 1.55 mmol, 1 equiv.), and 4-DMAP (249 mg, 2.02 mmol, 1.3 equiv.—in 6 mL of DCM) and the mixture was allowed to stir under argon. The solution was cooled by placing the flask in an ice-water bath for 5 min. To the solution, DCC was added (421 mg, 2.02 mmol, 1.3 equiv.). The progress of the reaction was followed by reversed phase HPLC. Following overnight stirring at room temperature, additional 2-azidopropionic acid (126 mg, 0.65 equiv.) in 2 mL of DCM and 4-DMAP (124 mg, 0.65 equiv.) were added to the reaction mixture, followed by DCC (211 mg, 0.65 equiv.). The solution was allowed to stir at room temperature for another 3.5 hours. HPLC result shows 94% of conversion to ester. The reaction mixture was filtered, and the filtrate was concentrated to dryness on a rotary-evaporator. The crude product was then purified by silica gel chromatography. The crude product was dissolved in hexane-ethyl acetate (6 mL, 4:1 v/v), and then loaded on to a 300 mL Silica Gel Column (30 mm id). The column was eluted with a hexane-ethyl acetate (4:1 v/v). The fractions (10 mL each) were analyzed by TLC and reversed phase HPLC. The product fractions were pooled, evaporated by rotary-evaporation, and then dried in vacuum overnight. Yield: 307 mg.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[C:30]([C:33]([C:35]3[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=3)=O)[CH:31]=[CH:32][C:23]1=2>C1COCC1>[O:22]1[CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[C:30]([C:33]([C:35]3[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=3)=[CH:9][C:10]#[N:11])[CH:31]=[CH:32][C:23]1=2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCCO3)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.3 mL, 8.3 mmol) in THF (10 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.2 mL, 8.2 mmol) dropwise. The mixture was stirred at room temperature for 40 min. A solution of (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-(3,5-dimethoxy-phenyl)-methanone (1.3 g, 4.1 mmol) in anhydrous THF (10 mL) was added to the mixture. The mixture was refluxed overnight. The solution was poured into ice water (20 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an oil (1.23 g, 89% yield): 1H NMR (DMSO-d6) δ 2.09-2.16 (m, 4H, 2CH2), 3.73 (s, 6H, 2CH3), 4.12-4.25 (m, 8H, 4CH2), 6.24 (s, 1H, CH), 6.30 (s, 1H, CH), 6.44-6.45 (m, 4H, Ar), 6.62-6.65 (m, 2H, Ar), 6.93-7.09 (m, 6H, Ar); 13C NMR (DMSO-d6) δ 30.97, 31.13, 55.40, 70.37, 70.52, 95.05, 95.87, 100.90, 101.82, 106.72, 107.06, 118.06, 118.12, 121.09, 121.61, 121.64, 122.39, 123.41, 124.47, 131.71, 132.26, 138.98, 140.12, 150.42, 150.55, 152.09, 152.89, 160.31, 160.39, 160.43.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[F:23])#[N:13].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[C:15]([F:23])[CH:16]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1F
Temperature: 65 °C
Yield: 64.6 %

Procedure:
A mixture of 4-bromo-2-nitroaniline (5.02 g, 23.1 mmol), 4-cyano-3-fluorophenylboronic acid (3.62 g, 21.9 mmol), and sodium carbonate (6.1 g, 58 mmol) in water (10 mL) and tetrahydrofuran (35 mL) was sparged with nitrogen for 10 minutes. To this was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.42 g, 0.51 mmol). The reaction mixture was heated at 65° C. for 6 hours. The mixture was allowed to cool, concentrated in vacuo, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (3.64 g, 65%) as a yellow solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1)=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)NCCSc1ccc2nccn2n1
Agent: Cl
Product: NCCSc1ccc2nccn2n1
Reaction time: 0.33 h

Procedure:
To 100 ml of 3N-hydrochloric acid is added 5.89 g of 6-(2-tert-butoxycarbonylaminoethylthio)imidazo[1,2-b]pyridazine and the mixture is refluxed with stirring for 20 minutes. The solvent is distilled off under reduced pressure and the residue is diluted with 50 ml of toluene and concentrated again under reduced pressure. To the residue is added ether and the resulting powers are collected by filtration and washed with ether, ethanol and ether in the order mentioned to give 5.26 g of 6-(2-aminoethylthio)imidazo[ 1,2-b]pyridazine dihydrochloride as colorless powders.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@@H:4]1[NH2:5].C(N([CH2:19][CH3:20])CC)C>CN(C=O)C>[C:3]([NH:5][C@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])(=[O:2])[CH2:4][CH2:6][C:19]#[CH:20]
Reactant: CCN(CC)CC
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CN(C)C=O
Product: C#CCCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of D-mannosamine hydrochloride (863 mg, 4.0 mmol), N-succinimidyl 4-pentynoate 9 (781 mg, 4.0 mmol), triethylamine (1.67 ml, 12.0 mmol) in DMF (31 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (CHCl3/MeOH 8:1) to give N-4-Pentynoylmannosamine, 10 (898 mg, 87%); 1H-NMR (500 MHz, D2O) 2.37 (t, 2.63H, J=2.5 Hz), 2.48-2.63 (m, 10.5H), 3.38-3.42 (m, 1H), 3.52 (t, 1H, J=10 Hz), 3.63 (t, 1.63H, J=10 Hz), 3.69-3.91 (m, 7.89H), 4.05 (dd, 1.63H, J=4.5 and 10 Hz), 4.35 (dd, 1.63H, J=1.5 and 4.5 Hz), 4.47 (dd, 1H, J=1.5 and 4.5 Hz), 5.03 (d, 1H, J=1.5 Hz), 5.13 (d, 1.63H, J=1.5 Hz); 13C-NMR (125 MHz, D2O)□ 14.78, 14.91, 34.62, 34.79, 53.67, 54.50, 60.91, 60.93, 67.01, 67.28, 69.25, 70.56, 70.71, 72.47, 72.50, 76.80, 84.04, 84.45, 93.36, 93.67, 175.68, 176.41; ESI-TOF-HRMS m/e calculated for (M+H)+ C11H17NO6260.1129; found 260.1120.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.C1(C2NN=C(NC3C=CN=C([C:33]4[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=4)N=3)C=2)CC1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([C:33]2[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Product: NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1

Procedure:
Using 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine as starting material, following same procedure as described in Compound 50, the HCl salt of 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 42) was prepared (92.7 mg, 33.4%). LC-MS (m/z)=397.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.78-0.79 (m, 2H), 1.00-1.02 (m, 2H), 1.97-1.99 (m, 1H), 6.42 (s, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.78 (d, J=3.6 Hz, 1H), 7.84 (s, 2H), 8.50 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].Br[C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][C:38]=1[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.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>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][C:38]=2[CH3:46])=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: Cc1nc2ccccn2c1Br
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#C[Si](C(C)C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-bromo-2-methylimidazo[1,2-a]pyridine (842 mg, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 2 h at 60° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 0.6 g (34%). HPLC-MS: M+H=590; tR=2.05 min (*Method—3).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.CN(C)C=O>[O:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)[C:29]([C:21]2[N:20]=[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]3[CH:22]=2)=[O:30])[CH2:10][CH2:11]1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Reactant: O=C(O)c1cn2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cn2ccccc2n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Yield: 77.6 %

Procedure:
N-[3-(Trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (242 mg), imidazo[1,2-a]pyridine-2-carboxylic acid (194 mg), EDC.HCl (199 mg), HOBt (138 mg), dimethylformamide (5 mL) and triethylamine (0.33 mL) was stirred overnight at room temperature. The solvents were distilled off under reduced pressure and following extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and, thereafter, the solvents were concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (286 mg).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][S:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:16]>>[Cl:12][CH2:13][CH2:14][S:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:6])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CS(=O)CCCl
Product: COC(=O)CS(=O)(=O)CCCl

Procedure:
The title compound was prepared from 3-chloroperoxybenzoic acid and the title compound of Example 11 according to the procedure of Example 11 and identified by its NMR and IR spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: C1CCNCC1
Product: COc1cccc2cc(C(=O)N3CCCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-Methoxybenzofuran-2-carboxylic acid, and piperidine to give 2-piperidinocarbonyl-7-methoxybenzofuran (Compound 319a). Successively, it was formylated to give 2-piperidinocarbonyl-4-formyl-7-methoxybenzofuran (Compound 319b), then compound 319b was reacted with methylamine hydrochloride to give compound 319 as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].BrBr.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(OCC)C.CCOC(C)=O>[CH3:16][C:15]1[S:17][C:7]2[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]=2[N:18]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(N)=S
Agent: BrBr
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1CCCc2sc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (15 g, 88 mmol) in anhydrous diethyl ether (40 mL) cooled at 0° C. was added bromine (4.5 mL, 88 mmol) dropwise over 15 mins. After complete addition mixture allowed to warm to room temp over 90 min. Mixture diluted with EtOAc (100 mL) and washed with sat. NaHCO3, sat. NaCl, dried over MgSO4, filtered and evaporated. Residue taken up in ethanol (100 mL) and thioacetamide (6.6 g, 88 mmol) added. Mixture stirred at room temp for 1 h then at reflux overnight. Mixture evaporated and residue partitioned between sat. NaHCO3 and DCM. Organic layer dried over MgSO4, filtered and evaporated. Residue purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (500 mL), gradient 0 to 25% EtOAc in Hexanes (1200 mL) then 25% EtOAc in Hexanes (1200 mL) to give the title compound (6.14 g, 31%) as a pale orange oil. 1HNMR (500 MHz, CDCl3) δ: 4.22 (q, J=7.1, 2H), 3.84 (t, J=5.5, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.65 (s, 3H), 2.18 (m, 1H), 2.11-1.95 (m, 2H), 1.85 (m, 1H), 1.29 (t, J=7.1, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:19])[C@H:17]2[C@@H:13]1[CH2:14][O:15][C:16]2=[O:18].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:19])[C@H:17]2[C@@H:13]1[CH2:14][O:15][C@@H:16]2[OH:18]
Reactant: CC1(C)[C@@H]2C(=O)OC[C@@H]21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2[C@@H](O)OC[C@@H]21
Temperature: -65 °C
Reaction time: 0.27 h
Yield: 93 %

Procedure:
404 ml of a toluene solution of 1.2 moles of diisobutyl aluminum hydride were slowly added at -70° C. to a solution of 60 g of the product of Step A in 720 ml of toluene and the mixture was stirred at -65° C. for 16 minutes and slowly poured into an aqueous solution of sodium potassium tartrate. The mixture was stirred and allowed to stand and the decanted aqueous phase was extracted with ether. The combined organic phases were evaporated to dryness and the residue was taken up in methylene chloride. The solution was evaporated to dryness under reduced pressure to obtain 56.7 g of (1R,2S,5S) 6,6-dimethyl-3-oxa-bicyclo (3,1,0) hexane-2-ol with a boiling point of ≃50° C. at 0.5 mm Hg and a specific rotation of [α]D20 =+66.5° (c=1% in ethanol).