Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCCCC1.S(=O)(=O)(O)O>O>[CH:13](=[C:11]([C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10])[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 40.0 g of 70% sorbitol, 29.4 g of benzaldehyde and 520 ml of cyclohexane under nitrogen gas was added 0.3 ml of 96% sulfuric acid dropwise with stirring, then the mixture was heated to allow to condense while eliminating the generated water by azeotropic distillation. After about 7 hours' continuation of the reaction, the reaction mixture was cooled to room temperature and then neutralized. The precipitate was settled and washed with water by decantation, then filtered and rinsed several times with hot water, further finally dried to obtain the reaction product as white powder.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)CC1(N)CCCCC1
Product: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1

Procedure:
2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide was prepared from 2-(1-Amino-cyclohexyl)-acetamide (2.0 g, 0.013 mol) (Suzuki, T.; Imanishi, N. Itahana, H.; Watauki, S.; Ohta, M.; Mase, T., Synthetic Communications, 1988, 28(4), 701-712) and 2,4,5-Trichloro-pyrimidine (1.5 mL, 0.013 mol) in an analogous manner to Example 1d. Product isolated as a white solid (2.28 g, 59%). MP: 124-128° C. 1HNMR (400 MHz, DMSO-d6, δ, ppm): 8.19 (s, 1H), 7.51 (br s, 1H), 7.34 (br s, 1H), 7.04 (br s, 1H), 2.62 (s, 2H), 2.58-2.52 (m, 2H), 1.55-1.30 (m, 8H). MS: 303.00 (MH)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@@:26]([OH:63])([CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:27]([N:29]1[C@H:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH2:40][C@H:32]2[O:31][C:30]1([CH3:42])[CH3:41])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([C@@:26]([OH:63])([CH2:43][CH2:44][OH:45])[C:27]([N:29]1[C@H:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH2:40][C@H:32]2[O:31][C:30]1([CH3:42])[CH3:41])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@](O)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@](O)(CCO)Cc1ccccc1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
TBAF (0.274 g, 1.05 mmol, 1M in THF) was added to a solution of (R)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-butan-1-one (46) (0.325 g, 0.52 mmol) in THF (20 mL) at room temperature and stirred for 3 h. The solvent was evaporated and the residue dissolved in dichloromethane and washed with water and brine, dried and evaporated. The product was purified by flash chromatography using petroleum ether:acetone (4:1) which gave 0.140 g of the title compound in 53% yield from two steps.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(CCCCNCCO)cc1
Reactant: CCCSCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CCO)CCCCc1ccc(C#N)cc1

Procedure:
5.0 g of 4-[4-[(2-hydroxyethyl)amino]butyl]benzonitrile and 4.9 g of 1-bromo-3-(propylthio)propane were dissolved in 50 ml of isopropanol. 6.3 g of potassium-carbonate was added and the mixture was refluxed over night and thereafter filtrated and evaporated. The oily residue was purified by column chromotography. Yield: 4.3 g of the title compound.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].I[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1>C(OCC)C>[S:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:3]#[C:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: C[Si](C)(C)C#Cc1cc2ccccc2s1
Reactant: Ic1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C(#Cc1cc2ccccc2s1)c1cccs1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The reaction mixture from Step A containing 2-trimethylsilylethynylbenzothiophene was stirred, and 4.96 grams (0.0157 mole) of tetrabutylammonium fluoride trihydrate and 10.1 grams (0.173 mole) of potassium fluoride were added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 4.5 hours. After this time 36.3 grams (0.173 mole) of 2-iodothiophene was added via syringe. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 60 hours. After this time the reaction mixture was dissolved in diethyl ether and a small amount of methylene chloride, and it was washed with two portions of an aqueous solution of 10% ammonium chloride, one portion of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with hexane and 20% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 35.1 grams of 2-(thien-2-ylethynyl)benzothiophene.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:3]1([N:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 70.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and benzanilide (118 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow solid (95 mg, 70%). mp 105-107° C. 1H NMR (DMSO) δ 7.24 (d, J=7.9 Hz, 1 H), 7.35-7.62 (m, 12 H), 7.84 (d, J=7.6 Hz, 1 H); 13C NMR δ 111.0, 118.1, 123.7, 124.1, 127.5, 127.9, 128.4, 129.2, 129.3, 130.0, 130.2, 135.5, 136.2, 139.3, 151.3. HRMS (FAB): cal. for C19H15N2 [M+H+]: 271.1235; found: 271.1230.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[I:1][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:10]([NH2:9])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: O=C1CCC(=O)N1I
Product: COC(=O)c1cc(I)c(OC)cc1N

Procedure:
Synthesized according to the method of reagent preparation 1 by N-iodosuccinimide iodination of methyl 2-amino-4-methoxybenzoate to give methyl 5-iodo-2-amino-4-methoxybenzoate then proceeding with step 1. 1H NMR (400 MHz, CDCl3): 8.97, (s, 1H), 8.75, 7.31 (s, 1H), 4.08 (s, 3H). GC-MS for C9H6ClIN2O: 319 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][C:64]=1[CH3:65]>ClCCl.CCOC(C)=O>[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH:67][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:62]=[CH:63][C:64]=1[CH3:65]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
6-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (2 g, 4.42 mmol) was partially dissolved in dichloromethane (100 mL), and HBTU (1.676 g, 4.42 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.884 g, 4.42 mmol), and TEA (1.232 mL, 8.84 mmol). The mixture was allowed to stir under argon over night at room temperature. The reaction was not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was added and the mixture was again stirred overnight. The reaction was still not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was again added and the mixture was stirred overnight. The reaction mixture was taken up in EtOAc (100 mL) and washed 3× with water (50 mL). Solid was recovered and washed with water and ethyl acetate. Drying the solid under vacuum gave N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1.97 g, 2.95 mmol, 66.7% yield). The ethyl acetate layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give another batch. This batch was taken up in methylene chloride and absorbed on Isolute® Sorbent (Biotage, Uppsala, Sweden; http://www.biotage.com/) and purified with a Combiflash on an 80 g silica column eluted with 0-10% DCM/MeOH. Product fractions were combined and evaporated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (704 mg, 0.987 mmol, 22.34% yield) as a white solid. LC-MS m/z 435 (M+H)+, 0.94 min (ret time).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:25])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].CI.[CH2:28](N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:25][CH3:28])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1nc(S)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)c1nc(SC)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 48.2 %

Procedure:
To a solution of 1-mercapto-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (0.2 g) in dichloromethane was added methyliodide (0.15 g) and triethylamine (0.1 g) with stirring. The mixture was refluxed on a steam bath for one hour, then cooled and washed with water. After drying, the organic phase was evaporated under water aspirator vacuum to give the product as a white solid (0.1 g, 49% yield). Recrystallized from acetonitrile, m.p. 202°-204° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][CH:3]([C:9]#[N:10])[CH2:2]2.P([S-])(OCC)(OCC)=[S:12]>Cl.C(OCC)(=O)C>[N:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][CH:3]([C:9](=[S:12])[NH2:10])[CH2:2]2
Reactant: N#CC1C[C@@H]2CCCN2C1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)C1C[C@@H]2CCCN2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 100 ml of 4N solution of hydrogen chloride in ethyl acetate, 5.10 g of a diastereomer mixture of (5S)-1-azabicyclo[3.3.0]octane-3-carbonitrile was dissolved. Then, 7 g of O,O-diethyl dithiophosphate was added, followed by stirring at room temperature for 16 hours. After the solvent was evaporated, the residue was washed with ethyl acetate, followed by drying under reduce pressure, whereby (5S)-1-azabicyclo[3.3.0]octane-3-carbothioamide was obtained. The resulting product was dissolved in 150 ml of isopropanol, 6.3 g of 2-bromo-1-indanone and 3.7 g of calcium carbonate were added, and the mixture was heated under reflux for 5 hours. After cooling, the insoluble matter was removed by filtration and the solvent was evaporated. To the resulting residue, ethyl acetate and 1N hydrochloric acid were added. The aqueous layer was separated, and neutralized with sodium bicarbonate, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was subjected to preparative medium-pressure column chromatography, whereby 0.32 g of a (3R,5S) form compound (Example 63A) and 0.18 g of a (3S,5S) form compound (Example 63B) of 3-(8H-indeno[1,2-d]thiazol-2-yl)-1-azabicyclo[3.3.0]octane was obtained from the fraction eluted with chloroform-methanol-aqueous ammonia (200:10:1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Product: O=S(=O)(NCc1ccccc1)c1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a tan solid. 1H NMR (DMSO) δ 1.27 (m, 2H), 1.86 (m, 2H), 2.75(m, 3H), 2.91(t, 2H, J=8.4 Hz), 3.82(m, 5H), 3.89(s, 2H), 4.89(m, 1H), 6.67 (d, J=6.6 Hz), 6.76(d, 2H, J=6.6 Hz), 7.02 (d, 2H, J=6.6 Hz), 7.26 (m, 5H), 7.57 (d, 2H, J=6.6 Hz), 7.78)bs, 1H), 8.87(bs, 1H); MS (ES) m/z: 512.1 (MH+); HRMS for C27H33N3O5S: 511.2215 (MH+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:27]CCl>FC(F)(F)C(O)=O>[Cl:27][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=[CH:8][CH:3]=1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(N2CCNCC2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of t-butyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (1.3 g, 4.39 mmol, 1.00 equiv) in dichloromethane (11 mL) and trifluoroacetic acid (6 mL) was placed in a 50-mL round bottom flask and stirred for 3 h at 20° C. in an oil bath. The solution was adjusted to a pH value of 7-8 with a saturated aqueous solution of sodium bicarbonate, and extracted with 6×15 mL of dichloromethane. The organic layers combined and dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under vacuum yielding 430 mg (50%) of 1-(3-chlorophenyl)piperazine as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
Piperidine (660 μl, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of 4-chloro-3-nitrotoluene (358 mg, 2.08 mmol, commercially available product). The resulting mixture was stirred at 100° C. for 17 hours. The mixture was cooled to room temperature, and then water was added thereto. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=50/1). Thus, 1-(4-methyl-2-nitrophenyl)piperidine (212 mg, 46.2%) was yielded as a colorless oily material. TLC Rf 0.54 (hexane/ethyl acetate=10/1).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O.C(Cl)Cl>CCOC(C)=O>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19]([I:28])=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3ncc(I)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2; 84.6 mg, 0.236 mmol) and 1-iodopyrrolidine-2,5-dione (79.7 mg, 0.354 mmol) were suspended in DCM (2.36 mL, 0.236 mmol) and stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with saturated sodium bicarbonate and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification of the resulting crude material by silica chromatography using 0-5% MeOH/EtOAc gradient afforded 3-cyclopropyl-3-(4-(3-iodo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (86.5 mg, 75.7% yield). MS (apci) m/z=485.2 (M+H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: BrCCCBr
Reactant: c1ccc2c(c1)NCCS2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCN1CCSc2ccccc21
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1.0 eq, 13.24 mmol), 1,3-dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrous Na2CO3 (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as yellow oil (2.13 g, 59% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:33])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[N:11]1([C:14](=[S:33])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OS(=O)(=O)c3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1ccc(COC(=S)N2CCNCC2)cc1)c1ccccc1
Reaction time: 18 h
Yield: 78 %

Procedure:
to a stirred solution of 4-benzenesulfonyloxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (44 mg) in ethyl acetate (2 mL) was added hydrogen chloride solution (4M, dioxane, 0.23 mL). The mixture was stirred for 18 h then concentrated under vacuum to give the product as a white crystalline solid (31 mg, 78%): HPLC (XTERRA, 50/80, 220 nm) 98.4% (2.54 min); NMR δH (400 MHz, DMSO-d6) 3.100(4H, bt), 3.672(4H, bt), 4.123(2H, s), 6.976(2H, d, J 8.5 Hz), 7.341(2H, d, J 9.0 Hz), 7.680(2H, t, J 8.0 Hz), 7.826(1H, t, J 7.5 Hz), 7.870(2H, d, J 7.0 Hz) and 9.258(2H, bs).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:15]([O:14][C:12]([CH2:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)COc1cc(O)cc(CO)c1
Product: CCOC(=O)CCCOc1cc(CO)cc(OCC(=O)OCC)c1

Procedure:
The subtitle compound was prepared from the product of step (i) (1.6 g) and ethyl 4-bromobutyrate (1.38 g) by the method of example 21 step (ii). Purified by chromatography eluting with 30% ethyl acetate in toluene. Yield 0.43 g.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@H:9]3[C@H:5]([CH2:6][C:7](=[O:16])[CH:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:2]1.C(Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:10][C@H:9]3[C@H:5]([CH2:6][C@@H:7]([OH:16])[C@@H:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:17]1
Reactant: CCOC(=O)C1C(=O)C[C@@H]2CC3(C[C@H]12)OCCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@H]2CC3(C[C@H]2C[C@H]1O)OCCO3
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of 2.09 g of (1S,5R)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one (I)' having [α]D21 +23.9° (c=2.55, CHCl3) in 21 ml of ethanol was added at -40° C. over 30 minutes 0.17 g of sodium borohydride. The mixture was stirred for 1 hour. After removal of ethanol in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting solution: 20-50% (v/v) diethyl ether/n-hexane) to obtain 1.60 g of the oily title compound.