Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13]([CH3:15])=O)[N:9]=[C:8]([NH2:16])[N:7]=1.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([S:13][CH2:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: SCCc1ccccn1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 425 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@H:15]3[CH2:22][CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][C@@H:16]3[C:23]([OH:25])=O)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.F[P-](F)(F)(F)(F)F.[N:36]1([O:45][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:45][NH:36][C:23]([C@@H:16]1[C@@H:15]([C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:14])[CH2:22][CH2:21][C:18]2([CH2:19][CH2:20]2)[CH2:17]1)=[O:25]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NO)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
The product from step 9 (36 mg, 0.105 mmole), and hydroxylamine hydrochloride (22 mg, 0.315 mmole) were dissolved in DMF (0.70 ml). To the solution, BOP (49 mg, 0.11 mmole) was added with stirring at r.t. for 10 min. DIEA (61 mg, 0.47 mmole) was added. The mixture was stirred at r.t. for 2 hours. The product was purified with preparative HPLC providing 22 mg of (5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5) octane-5-carboxamide. Yield: 44%. MS: M/Z 358.2 (M+H)+; 380.2 (M+Na)+; 737.2 (2M+Na)+.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>CC(C)=O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: NC(=O)CCl
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred solution containing 5 g (0.022 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of acetone, 0.024 mole of chloroacetamide was added in one portion. The stirred reaction mixture was heated at 56°-60° C. for 22 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air dried at 25°-30° C. A product with a melting point of 139°-141° C. (determined after recrystallization from 6:1 mixture of heptane and isopropyl alcohol) was obtained with a 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21]O)[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:24]>C1C=CC=CC=1>[Br:24][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: COc1ccc(-n2nc(CBr)cc2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
To a solution of compound 3 (3.14 g, 10 mM) in benzene (100 ml) was added PBr3 (1.35 g, 5 mM) in benzene (10 ml) dropwise with stirring. The reaction mixture was refluxed 1 hr, cooled, poured into ice water (100 ml)and extracted with Et2O (2×100 ml). The combined organic layer was washed with 10% NaHCO3, dried (Na2SO4), filtered and concentrated to give a tan oilwhich crystallized on standing to afford compound 5, mp=88°-90° C., MS, (DCI) m/e 377 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:13])[C:8]([CH3:12])=[C:9]([OH:11])[N:10]=[C:5]2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>CN(C=O)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][O:11][C:9]3[N:10]=[C:5]4[S:4][CH:3]=[C:2]([CH3:1])[N:6]4[C:7](=[O:13])[C:8]=3[CH3:12])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1)([O-:22])=[O:21]
Reactant: Cc1c(O)nc2scc(C)n2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)nc2scc(C)n2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
To a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (537 mg) and potassium carbonate (618 mg) in DMF (10 ml) was added 4-(4-nitrobenzoyl)benzyl bromide (909 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (105 mg).
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=1>O1CCOCC1>[I:2][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: [I-]
Reactant: COc1cc(C)cc(Br)c1
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C)cc(I)c1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
Cu(I)I (0.05 g, 0.25 mmol) and NaI (1.49 g, 10 mmol) were added to an oven dried sealed tube and the tube sealed with a rubber septum and flushed with a stream of nitrogen for 15 min. Anhydrous dioxane (5 mL), N,N′-dimethyl ethylenediamine (0.055 mL, 0.50 mmol) and 1-bromo-3-methoxy-5-methylbenzene (1) (1.0 g, 5.0 mmol) were added via a syringe with vigorous stirring under a stream of nitrogen at room temperature. The rubber septum was replaced with the Teflon cap and the sealed tube was heated at 110° C. in an oil bath for 18 h. The reaction was allowed to cool to room temperature and then quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with CH2Cl2. The organic layer was washed with water, and then concentrated to dryness to give 1-iodo-3-methoxy-5-methylbenzene (2) (1.05 g, 87% yield) as a pale yellow oil.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].O1CCCC1.[C:15]([O-])(=[O:19])[CH:16]([CH3:18])[CH3:17].[Na+].Cl>O>[C:15]([NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)[O-]
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 35.2 g (0.20 mol of L-cysteine hydrochloride monohydrate in 100 ml of a mixture of 80% of tetrahydrofuran (THF) and 20% of water was stirred under nitrogen at room temperature and treated with 44.0 g (0.40 mol of sodium isobutyrate. The reaction mixture (white slurry) was cooled to 0°-5° C. and, under nitrogen, 35 ml (0.21 mol) of isobutyryl anhydride was added dropwise. The resulting mobile suspension was stirred for 6 h at room temperature, allowed to stand overnight, and finally heated under reflux for 4 h. The reaction mixture was cooled on an ice bath and 18 ml of concentrated hydrogen chloride was added. The organic phase was evaporated to give a colourless oil. The oil was washed with hexane and thereafter treated with ether to give 12.9 g of the title compound as a white solid, mp 103°-104° C. (recrystallized from butyl acetate), [α]D25 =+23.4° C. (c 5.0 , H2O, pH=7.0), 1H-NMR (CDCl3): δ1.2 (6H, d, CH3), 1.4 (1H, t, SH), 2.5 (1H, sept, CH), 3.1 (2H, m, CH2), 4.9 (1H, dt, NCH), 6.7 (1H, d, NH), 10.6 (1H, s, OH). 13C-NMR (CDCl3): δ19, 19.5; 26.5; 36; 54, 172, 178. ms: 335 (M+ +2TMS, after silylation).
Reaction SMILES: COC([C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:7][N:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=12)=O.[OH-].[Na+]>OS(O)(=O)=O.O>[Br:14][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([N:7]=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=2)[CH:13]=1
Reactant: COC(=O)c1c(C(C)(C)C)nn2cc(Br)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc2ccc(Br)cn2n1
Yield: 41.4 %

Procedure:
A solution of 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (example 41, step 2) (1.1 g, 3.53 mmol) in H2SO4 (5 ml) and H2O (5 ml) was heated at 80° C. for 36 hours. The reaction mixture was neutralized with 2N sodium hydroxide and extracted with ethyl acetate (4×60 ml). The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (heptane:EtOAc 95:5->90:10). The desired 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (370 mg, 38% yield) was obtained as a white solid, MS: m/e=254.2 (M+H+).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Reactant: CC(C)N
Solvent: CO
Product: COC(=O)CCC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 101.7 %

Procedure:
A stirred mixture of methyl 3-[2-(2,3-epoxypropoxy) benzoyl]-propionate (8.3g, 0.031 mole), methanol (85 ml), and isopropylamine (16.4 ml, 0.19 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave methyl 3-[2-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]propionate (10.2 g, 100%)as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:18](O)[C:19]#[CH:20]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:20][C:19]#[CH:18])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 13, 3.6 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate and 1 ml of propargyl alcohol were reacted and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with 0.1 N hydrochloric acid, with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in a 9-1 cyclohexane-ethyl acetate mixture and the mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate yielded 2.1 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-(propargyloxy-carbonyl)-ethenyl]-cyclopropane-carboxylate.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].I[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:15])[CH2:10]1)[CH3:22]
Reactant: CCOC(=O)CI
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidin-3-yl-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) and ethyl iodoacetate (0.99 g, 4.6 mmol) in acetonitrile (30 mL) is added K2CO3 (1.5 g, 10.5 mmol) and the mixture stirred overnight at room temperature. Volatiles are evaporated under reduced pressure and the residue taken up with water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The resulting material is purified via chromatography over silica gel eluting with a mixture of EtOAc/MeOH (95:5 v/v). Yield: 0.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O>C(#N)C>[C:13]([C:11]1[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([NH:1][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc2c1SCC2(C)C
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC2=NCCN2)cc2c1SCC2(C)C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a 0.33 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryonoff et al., (J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 155 mg (40%) of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncc(-c2cc(Cl)nc(Cl)n2)cn1
Solvent: CC#N
Product: Nc1ncc(-c2cc(N3CCOCC3)nc(Cl)n2)cn1

Procedure:
According to Method 6, the reaction of 2,6-dichloro-4,5′-bipyrimidin-2′-amine with morpholine in acetonitrile gave 2-chloro-6-morpholino-4,5′-bipyrimidin-2′-amine. LCMS (m/z): 293.0 (MH+); Rt 1.92 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:16]CC1>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(O)cn1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
At RT, 50 g (327 mmol) of 6-methoxypyridin-3-ylboronic acid were added to a solution of 46.0 g (392 mmol) of N-methylmorpholine N-oxide in 500 ml of dichloromethane, and the mixture was stirred at 50° C. for 14 h. Additional N-methylmorpholine N-oxide was added until the reaction had gone to completion. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 32.9 g (80% of theory)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:18]12[CH2:21][CH2:22][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:30]4[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][N:35]=4)=[CH:14][CH:13]=3)([CH2:20][CH2:19]1)[CH2:16][O:17]2
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)CO2
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Yield: 131 %

Procedure:
To a microwave vial containing methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (100 mg, 0.26 mmol), 6-bromopyridin-3-amine (49 mg, 0.28 mmol) and Pd2(PPh3)4 (60 mg, 0.05 mmol) was added 1,4-dioxane (1.3 ml) at room temperature. 2N sodium carbonate (0.39 ml, 0.78 mmol) was added and the mixture was subjected to microwave radiation at 120° C. for 50 minutes. The resulting mixture was concentrated to dryness and taken up in EtOAc, the slurry was dried over sodium sulfate and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography to afford the title compound (120 mg, 65% yield). LC/MS, ESI-MS(+): 353.4, RT: 1.12 (Condition E).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[O:15][CH2:16][CH2:17][O:18]C1CCCCO1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1>[CH:9]12[CH2:14][CH:12]([CH:11]([O:15][CH2:16][CH2:17][OH:18])[CH2:10]1)[CH2:13][NH:8]2
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2OCCOC1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCOC1CC2CC1CN2
Yield: 70.5 %

Procedure:
Tert-butyl-5-(2-tetrahydropyran-2-yloxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.08 g, 3.16 mmol) was stirred overnight in 5 M hydrochloric acid (30 mL, 990 mmol)/THF (30 mL). The reaction mixture was basified with NaOH and washed with DCM. The organic was dried over Na2SO4 and concentrated in vacuo to afford 2-(2-azabicyclo[2.2.1]heptan-5-yloxy)ethanol (350 mg). LCMS RT=0.57 min. M+1=158.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1)[CH3:14]
Reactant: CCI
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)n(C)n1
Yield: 93.7 %

Procedure:
Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), iodoethane (3.51 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL), and in the same manner as in Reference Example 57, the title compound (2.59 g, yield 94%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: COCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCc1ccc(C(F)(F)F)cc1N
Yield: 91.7 %

Procedure:
0.15 g (0.638 mmol) of 1-methoxymethyl-2-nitro-4-trifluoromethylbenzene is added, at a temperature in the region of 25° C., to a suspension of 0.02 g (0.188 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol. After hydrogenation for 3 hours in an autoclave under 1 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with 3 times 5 cm3 of methanol, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa), to give 0.12 g of 2-methoxymethyl-5-trifluoromethylphenylamine in the form of a yellow oil;
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:15][C:16](=[CH2:18])[CH3:17].[OH-].[Na+].[ClH:21]>CCOCC.O1CCOCC1>[ClH:21].[ClH:21].[C:16]([O:13][C:12]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:14])([CH3:18])([CH3:17])[CH3:15]
Reactant: O=C(O)N1CCNCC1
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml pyrex heavy-walled pressure bottle is charged with 50 ml of dioxane, 3 ml of concentrated sulfuric acid, 1.3 g (0.01 mole) of piperazic acid (II-A) and approximately 75 ml of isobutylene, liquified by passage into a large test-tube cooled in a dry ice-acetone bath. The bottle is closed with a rubber stopper, clamped securely in place, and is shaken mechanically at room temperature overnight. The bottle is chilled in an ice bath and opened. The contents are poured into a separatory funnel containing a cold mixture of 200 ml of ether and 125 ml of 1N sodium hydroxide. The aqueous layer is washed with ether. The combined ethereal solution is dried over sodium sulfate and evaporated under vacuum to afford an oil, which is dissolved in 25 ml of ether. Addition of dry hydrogen chloride gives 1.3 g of crystalline piperazic acid t-butyl ester dihydrochloride salt (II-B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:20])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of the 4′-chlorobiphenyl-4-sulfonic acid in 100 mL of thionyl chloride is heated at reflux for 6 h, and the resulting homogeneous solution is then cooled to RT. The mixture is concentrated under reduced pressure and the residue is triturated with diethyl ether and dried to afford 9.8 g (95%) of 4′-chlorobiphenyl-4-sulfonyl chloride as an off-white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[S:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: c1cscn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12l and thiazole
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1.[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C.CCCCCCC>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=C1N=C(NCCOCCO)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C1N=C(NCCOCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a suspension of 4-{[2-(2-hydroxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one (1.58 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.89 g) in 2-propanol (30 mL) was added piperidinium acetate (1.12 g). The reaction mixture was stirred at 80° C. for 8 hr and concentrated. Water and ethyl acetate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give an oil. The oil was diluted with ethyl acetate (9 mL) and heptane (45 mL). The mixture was gradually cooled from 50° C. to 0° C., and the mixture was stirred for 6 hr. The precipitate was collected by filtration, and the obtained solid was washed with a mixed solution of ethyl acetate and heptane to give a white solid. The obtained white solid was recrystallized from ethyl acetate/heptane to give the title compound (2.53 g).