Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)#[N:21]>N1C=CC=CC=1>[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][S:34]([C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(NS(=O)(=O)c2ccc(-c3ccc(C#N)cc3)cc2)n1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of dichloromethane (3 mL) was added 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (0.15 g, 0.63 mmol), 4′-cyanobiphenyl4-sulfonyl chloride (0.18 g, 0.63 mmol) and pyridine (1.0 mL). The mixture was stirred for 3 hours then was washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and combined fractions were concentrated to afford the above-titled intermediate as a white solid (0.21 g, 76%). HPLC: Rt4.236 min. (81% area). 1H NMR (400 MHz, CDCl3), δ: 7.89 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.52-7.49 (m, 4H), 7.43 (t, J=7.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.59 (d, J=7.3Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 4.55 (s, 2H), 0.82 (s, 9H), 0.05 (s, 6H); LRMS (ESI): m/z: 480.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18][CH2:19]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (0.47 mL, 5 mmol) in THF (20 mL) was cooled to −60° C. and treated dropwise with nBuLi (1.6M in hexanes, 5.2 ml, 5.2 mmol). The reaction mixture was stirred for 30 minutes at −60° C. and then benzyl 4-oxo-1-piperidine carboxylate 1.14 g, 4.9 mmol) in THF (10 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at −60° C. for 15 minutes and then quenched with saturated NH4Cl. The cooling bath was removed and reaction mixture was allowed to warm to room temperature. The mixture was were extracted with CH2Cl2 and the organics were dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography using hexane:ethyl acetate (1:1) to provide the title compound, 400 mg (27%). 1H NMR (d6-DMSO, 300 MHz) δ 1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1H), 7.25 (m, 2H), 7.35 (m, 5H), 7.68 (m, 1H), 7.79 (m, 1H), 8.5 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Li:10]CCCC>C1COCC1>[CH3:1][Si:2]([N-:3][Si:4]([CH3:7])([CH3:6])[CH3:5])([CH3:9])[CH3:8].[Li+:10]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]
Temperature: -5 °C
Reaction time: 0.21 h

Procedure:
A solution of lithium bistrimethylsilylamide was prepared as follows. To hexamethyldisilazane (4.04 Kg, 5.28 L, 25 mol) was added anhydrous THF (4 L). The solution was cooled to -5° C. and n-BuLi (2.4M in hexanes, 9.7 L) was added over a period of 1.5 hr, while maintaining the reaction temperature between -5° and 0° C. The mixture was then aged for 10-15 min, allowed to rise to room temperature and stored under N2 overnight.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[F:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13].C(Br)C=C.[OH-].[Na+]>C1COCC1.C(OCC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:3][CH:2]=[CH2:1])[C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1cc(F)c(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (7.89 mL; 2.66 M solution in hexane) was added to a solution of 3,4,5-trifluorophenylacetic acid (2 g) in THF (50 mL) at −78° C. The reaction solution was stirred at −78° C. for 20 minutes. Then, the reaction solution was heated to 0° C. and further stirred for 30 minutes. Allyl bromide (0.999 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for three hours. A 1 N sodium hydroxide solution and diethyl ether were added to the reaction solution, and the aqueous layer was separated. 5 N hydrochloric acid and ethyl acetate were added to the resulting aqueous layer, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.45 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.C[O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23]1)=O>C(OCC)C.C(O)(=O)C>[O:19]=[C:20]([CH:22]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCC1CCC(C(=O)OC)C1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCC1CCC(C(=O)CP(=O)(OC)OC)C1

Procedure:
17 ml. of a 2 M solution of n-butyllithium in diethyl ether were added dropwise with stirring, under an atmosphere of nitrogen, to a solution of 4.2 g. of dimethyl methylphosphonate in 40 ml. of dry tetrahydrofuran at -50° to -60° C. After stirring for 10 minutes, 2.9 g. of 1-methoxycarbonyl-3-propylcyclopentane in 10 ml. of dry tetrahydrofuran were added dropwise at -78° C. and the reaction mixture was stirred for 4 hours at -78° C. and further stirred overnight at 0° C. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give 3.1 g. of the title compound having the following physical characteristics:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:20][CH2:21][C@@H:22]1[C@@H:27]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH:25]=[CH:24][CH2:23]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CCCCCC>[C:30]([O:29][CH2:28][C@@H:27]1[C@@H:22]([CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:23][CH:24]2[CH:25]([O:9]2)[CH2:26]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OC[C@H]1CC=CC[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
m-Chloroperbenzoic acid (777 mg, 4.5 mmoles) was added to a solution of (4S,5S)-4,5-bis(benzoyloxymethyl)-1-cyclohexene (1.05 g, 3.0 mmoles) in methylene chloride (6 ml) under cooling with ice. After stirring the mixture at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogen sulfite was added to the reaction mixture and the excessive peracid was decomposed, after which a saturated aqueous solution of sodium hydrogen carbonate was added and the whole mixture was subjected to extraction with ethyl ether. The ether extract solution was washed with water and then with saturated aqueous solution of sodium hydrogen carbonate, and dried on anhydrous sodium sulfate. After distilling off the solvent therefrom under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3, v/v) to obtain (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo[4.1.0]heptane (1.025 g, Yield 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:3]=1.[Br:18]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[N:3]=1
Reactant: Cc1ccnc(-c2ccccc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1-c1nccc(CBr)n1
Temperature: 25 °C

Procedure:
247 mg (1.04 mmol) of the compound from Example 67A together with 185 mg (1.04 mmol) of N-bromosuccinimide and 17 mg (0.10 mmol) of 2,2′-azobis-2-methylpropanenitrile in 3 ml of carbon tetrachloride were heated under reflux for 18 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was briefly dried under high vacuum and reacted further without further purification. This gave 303 mg of product which contained the target compound in a purity of 20% (corresponds to 20% of theory). The main component of the crude product was unreacted starting material (Example 67A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)C(C#N)[CH2:6][CH2:5]2.[CH3:14][C:15]([OH:17])=[O:16]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:14]([C:15]([OH:17])=[O:16])[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: N#CC1CCc2cc(Cl)cc(Cl)c21
Agent: Cl
Product: O=C(O)C1CCc2cc(Cl)cc(Cl)c21
Temperature: 100 °C

Procedure:
A suspension of 5,7-dichloro-2,3-dihydro-1H-indene-1-carbonitrile (0.77 mmol) in 2 mL 25% HCl solution and 2 mL AcOH was heated to 100° C. for 5 h. At RT, the reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired compound as brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CO[C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13]N=1.[C:20]([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:16]1[CH:11]=[CH:20][CH:13]=[C:14]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ncc(B(O)O)cn1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C
Yield: 51 %

Procedure:
6-Chloropyrimidin-4-amine (0.35 g, 2.70 mmol), 2-methoxypyrimidin-5-ylboronic acid (0.520 g, 3.38 mmol), Na2CO3 (0.859 g, 8.11 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.038 g, 0.054 mmol) were suspended in a mixture of DME/EtOH/water. (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (0-5% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.28 g, 1.378 mmol, 51% yield) as an off-white solid. LCMS R.T.=0.53; [M+H]+=204.11.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:11][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=2[CH3:23])(=[O:20])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)C1(N)CCCC1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(NS(=O)(=O)c2cccc(Cl)c2C)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
methyl-1-aminocyclopentanecarboxylate hydrochloride (300 mg, 1.67 mmol) was dissolved in CH2Cl2 (7 ml), added with 3-chloro-2-methylbenzene-1-sulfonyl chloride (413 mg, 1.83 mmol) and triethylamine (0.9 ml, 6.68 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(3-chloro-2-methylphenylsulfonamido)cyclopentanecarboxylate (554 mg, 1.67 mmol, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][C:37]1([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][C:37]2([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC1(O)CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC2(O)CCCCC2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-sulfonyl chloride, and 1-(aminomethyl)cyclohexanol, the title compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(C(C)C)CC)(C)C.ClC1N=C(NC2C=CC=CC=2C(NC)=O)C(C(F)(F)F)=CN=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC=CC=2C(NC)=O)N=1.[NH2:77][C:78]1[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:90])([O:87][CH2:88][CH3:89])[O:84][CH2:85][CH3:86])=[CH:80][CH:79]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][NH:18][C:16]([C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=1[NH:13][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:77][C:78]2[CH:79]=[CH:80][C:81]([CH2:82][P:83](=[O:90])([O:84][CH2:85][CH3:86])[O:87][CH2:88][CH3:89])=[CH:91][CH:92]=2)[N:7]=1)=[O:17]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Agent: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Agent: CNC(=O)c1ccccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1)OCC

Procedure:
Reaction of 2,4-dichloro-5-(trifluoromethyl)pyrimidine XL with commercially available 2-amino-N-methyl-benzamide and diisopropylethylamine at room temperature overnight affords a mixture of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide and 2-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzamide (XLIIIa/XLIII b). Trituration of the mixture with methylene chloride affords a pure sample of the desired 4-substitiuted product XLIIIa. Concentration of the mother liquors and purification of the residue by chromatography over silica gel using 5% EtOAc in methylene chloride as eluent isolating the less polar material affords further pure 4-substituted isomer plus a mixture of isomers which may be subjected to further chromatography if desired. Reaction of pure 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide XLIIIa with anilines such as diethyl (4-aminobenzyl)phosphonate in the presence of TFA and TFE under microwave irradiation yields the desired products (e.g. diethyl (4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, Ex. 20)
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17]C(CO)=[CH:15][CH:14]=2)=[N:3]1.S(Cl)(Cl)=O.[C:26](=O)([O-])O.[Na+].[CH2:31]([Cl:33])Cl>>[CH3:21][C:2]1([CH3:1])[CH2:6][O:5][C:4]([C:7]2[C:12]([CH3:26])=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:31]([Cl:33])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: ClCCl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1cccc(-c2ccc(Cl)cc2)c1C1=NC(C)(C)CO1
Reaction time: 1 h

Procedure:
1.0 g (3.55 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in methylene chloride (15 ml). Under cooling with ice, 0.51 g (4.29 mmol) of thionyl chloride was dropwise added thereto, followed by stirring for one hour. The reaction liquid was poured into an aqueous solution of sodium hydrogencarbonate, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 1.05 g of the title compound was obtained as a crystal (yield 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][C:13]=2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C.C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][C:13]=2[O:24][CH2:30][C:31]#[N:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCC#N)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a stirred solution of 9-benzyl-5-hydroxy-7-methoxycarbazole-4-carboxamide (0.75 g, 2.17 mmol) in DMF (76 ml) and THF (16 ml) and added 60% NaH (0.11 g, 2.71 mmol). After 15 min bromoacetonitrile (0.20 ml, 2.93 mmol) was added and the reaction was allowed to stir for 4 h. The reaction was diluted with EtOAc, extracted with water, then brine, dried (Na2SO4), and chromatographed on silica gel using a CH2Cl2-EtOAc-methanol gradient to give the titled compound (0.52 g, 63%). MS (ES+) 386
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+]>>[CH3:17][C:16]1[CH:18]=[CH:19][C:20]([C:18]2[C:16]3[CH2:17][CH:13]([CH2:12][N:23]=[N+:24]=[N-:25])[O:14][C:15]=3[CH:21]=[CH:20][CH:19]=2)=[CH:21][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc(-c2cccc3c2CC(CN=[N+]=[N-])O3)cc1
Yield: 187.1 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.0 mmol), o-tolylboronic acid (2.66 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.63 mmol) generally according to the procedure described for Intermediate 37 provided 4.0 g (77%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a yellow oil. Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.8 g, 9.63 mmol) with sodium azide (2.5 g, 38.53 mmol) generally according to the procedure described for Intermediate 98 gave 2.39 g (94%) of [4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.239 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.3 g (93%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 239-241° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69:36; H, 6.64; N, 4.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[N:12]1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[N:12]1)[C:5]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(-n2ncc3c2CCCC3)c(Cl)c1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1ccc(-n2ncc3c2CCCC3)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 10 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(4,5,6,7-tetrahydroindazol-1-yl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 10%; Rf value: 0.70 (silica gel: ethyl acetate); C23H21Cl2N5O (454.359); mass spectrum: (M+H)+=454/456/458 (chlorine isotope).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C)C=O.Br[CH:11]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][NH:13][C:12]1=[O:24]>C(OCC)(=O)C>[N:1]([C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][NH:13][C:12]1=[O:24])=[N+:2]=[N-:3]
Reactant: O=C1NCC(c2ccccc2)CCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CC[C@@H](c2ccccc2)CNC1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
2.0 g of sodium azide were added to 20 ml of dimethylformamide containing 1.6 g of 3-bromo-6-phenylperhydroazepin-2-one (Isomer A) [prepared as described in step (e) above]. The mixture was stirred for 6 hours at 60° C. and then diluted with ethyl acetate, washed with water three times and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The crystalline residue was triturated in a 1:1 by volume mixture of methylene chloride and diisopropyl ether and then collected by filtration, to give 1.14 g of the title compound melting at 150°-152° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:3]=1[C:29](=[O:31])[CH3:30].[CH3:32]I>CN(C=O)C>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][N:26]([CH3:32])[CH2:27][CH2:28]2)[C:3]=1[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: CI
Solvent: CN(C)C=O
Product: CC(=O)c1c(C2CCN(C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 1 h

Procedure:
To a solution of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (25 mg, 0.06 mmol), DEA (52 μL, 0.3 mmol) in DMF (1 mL) was added MeI (15 μL, 0.24 mmol). The reaction mixture was stirred for one hour and directly purified by HPLC to provide the title compound. LC/MS RT=2.76 min. Mass calculated for M+H 427.2, observed 427.3.