Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][F:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO.Cl>[CH3:21][O:22][N:23]=[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][F:12]
Reactant: CON
Reactant: O=C(CF)CCc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(CF)CCc1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one (0.13 g; 0.62 mmol) in methanol (1.3 ml) was added pyridine (80 μl; 0.99 mmol) followed by a portion wise addition of methoxyamine hydrochloride (78 mg; 0.93 mmol). The reaction mixture was stirred for 16 h at 23° C. The mixture was poured in 1 N hydrochloric acid (5 ml), extracted with dichloromethane (3×3 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.13 g (94% of theory) of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one O-methyl-oxime (mixture of E/Z-isomers) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].Cl[Si](C)(C)C.CN1CCOCC1.Cl[CH2:25][CH2:26][O:27][C:28](Cl)=[O:29].[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>ClCCl>[C:31]([O:35][CH2:25][CH2:26][O:27][C:28]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:29])(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCCCl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)OCCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general procedure for the one pot synthesis, tranexamic acid (786 mg, 5.0 mmol) was reacted with chlorotrimethylsilane (1.396 mL, 1.195 g, 11.0 mmol) in anhydrous dichloromethane (10 mL) and in the presence of N-methylmorpholine (1.374 mL, 1.264 g, 12.5 mmol). Subsequent reaction of the intermediate with chloroethylchloroformate (0.82 mL, 1.07 g, 7.5 mmol) followed by a mixture of NMM (2.75 mL, 2.53 g, 25 mmol) and propionic acid (3.73 mL, 3.70 g, 50 mmol) yielded the title compound 9 (103 mg, 7% yield) as colorless, very viscous oil after aqueous work-up and two mass-guided preparative HPLC purifications. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.03 (t, J=7.6 Hz, 3H), 1.17-1.35 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.65-1.73 (br. m, 2H), 1.83-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.26-2.33 (m, 2H), 2.74-2.90 (m, 2H), 6.64 (q, J=5.6 Hz, 1H), 7.44 (t, J=5.6 Hz, 1H), 11.99 (br. s, 1H). MS (ESI) m/z 324.14 (M+Na)+; 300.10 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[CH:29][C:26]=1[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([O:33][CH3:34])[C:25]=4[O:24][CH3:23])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c(OC)c1OC

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 2,3,4-trimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(2,3,4-trimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 168-169° C.; HPLC: TRet (Grad5-40)=20.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[CH:17][CH:18]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C=O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzaldehyde (Example 8B) (2.10 g, 3.72 mmol) in tetrahydrofuran (33.8 mL) was added sequentially acetic acid (0.426 mL, 7.45 mmol), sodium sulfate (1.058 g, 7.45 mmol), and pyrrolidine (0.466 ml, 5.58 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (1.578 g, 7.45 mmol) was added in a single portion. The reaction was stirred for 1 hour and was then quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL), ethyl acetate (20 mL), and solid sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane with 1% v/v aqueous ammonium hydroxide solution, to give the title compound. MS ESI(+) m/z 619.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:21])[NH:19][NH2:20])[CH3:16]>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:20][NH:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)NN
Reactant: O=C(c1ccccc1)c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)NN=C(c1ccccc1)c1ccncc1
Temperature: 100 °C
Yield: 42.8 %

Procedure:
A mixture of 9.16 gm (0.05 mole) of phenyl 4-pyridyl ketone, 5.21 gm (0.05 mole) of ethylcarbazate and 75 ml of glacial acetic acid is heated at 100° C. for 8 hr. The acetic acid is removed in vacuo. The residue is slurried with ethyl ether and collected to yield 5.76 gm (39%) of the title compound having a melting point of 188.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[CH3:14].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[ClH:13].[Cl:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=2[Cl:18])[N:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Solvent: CC(=O)O
Product: COc1ccc2nc(Cl)cc(C)c2c1Cl
Product: Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 162.2 %

Procedure:
A 10-liter, four-necked reactor equipped with a mechanical stirrer, condenser, thermowatch, addition funnel and a condenser was charged with 6-methoxy-4-methyl-2-chloroquinoline (3) (900 g, 4.33 moles) and glacial acetic acid (3.06 liters). The slurry was heated to 60° C. and a solution of sulfuryl chloride (646 g, 4.77 moles) in glacial acetic acid (0.902 liters) was added over 2 hours while maintaining the temperature between 60 and 65° C. The resulting slurry was stirred for 1 hour at 60-65° C., then cooled to 15-20° C. and stirred at this temperature for 2 hours. The product was removed by suction filtration, washed with cold (10° C.) acetic acid (0.550 liters), and air dried. to yield the title compound 978.4 g (81.2%); mp 159-160° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(C)C=CC=CC=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(N)[C@H](N)C(C)C)=CC=1>CC(O)(C)C.CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([OH:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(N)(c2ccc(OC)cc2)[C@H](N)C(C)C)cc1
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (Example 9B, Step A; 85.0 g, 406 mmol) and 1.0 M KOtBu (8.11 mL, 8.11 mmol) in t-BuOH in IPA (200 mL) and toluene (50 mL) in a autoclave was added dichloro{(R)-(+)-2,2′-bis[di(3,5-xylyl)-phosphino-1,1′-binaphthyl}[(2R)-(−)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine (0.991 g, 0.81 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 520 psi with hydrogen. The reaction mixture was vigorously stirred at ambient temperature for 2 days (pressure was recharged to 520 psi when the internal pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (83.5 g, 97.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 77.2% e.e. (R)-enantiomer). (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoro ethanol (171 g, 808 mmol, 77.2% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (3410 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight. The resulting solid was collected by filtration, washed with hexane and dried to give (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (97.1 g, 56.8%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.9% e.e. (R)-enantiomer).
Reaction SMILES: I[CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4].CCN(C(C)C)C(C)C.[SH:33][C:34]([CH3:52])([CH3:51])[CH2:35][N:36]([CH3:50])[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[C:44]([CH2:46][OH:47])[N:43]=[C:42]([CH2:48][OH:49])[CH:41]=1>CN(C=O)C>[OH:47][CH2:46][C:44]1[CH:45]=[C:40]([O:39][CH2:38][CH2:37][N:36]([CH3:50])[CH2:35][C:34]([S:33][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4])([CH3:52])[CH3:51])[CH:41]=[C:42]([CH2:48][OH:49])[N:43]=1
Reactant: COC(=O)CCOCCOCCOCCOCCNC(=O)CI
Reactant: CN(CCOc1cc(CO)nc(CO)c1)CC(C)(C)S
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCNC(=O)CSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Reaction time: 24 h
Yield: 57.1 %

Procedure:
73.7 mg of methyl 3-[2-(2-{2-[2-(2-iodoacetylamino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate in solution in 1 ml of DMF and 39 μl of DIPEA are added to 45 mg of 4-{2-[(2-mercapto-2-methylpropyl)(methyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine in solution in 1 ml of DMF. After 24 h at AT, the mixture is concentrated under RP and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-8 g), using a gradient from 0 to 10% of methanol in DCM. 53 mg of methyl 3-{2-[2-(2-{2-[2-(2-{[2-(2,6-bis(hydroxymethyl)pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}ethoxy)ethoxy]ethoxy}propanoate are thus obtained.
Reaction SMILES: [C:1]([C:5]1([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1C(=O)N([Br:33])C(=O)C1.[Cl-].[Na+]>O>[Br:33][C:15]1[CH:16]=[CH:17][C:12]([CH:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7]2)=[CH:13][C:14]=1[O:18][CH3:19]
Reactant: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C2OCC(C)(C)C2(O)C(C)(C)C)ccc1Br
Temperature: 0 °C
Yield: 47.7 %

Procedure:
Adding 2.16 g (7.77 mmol) of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (Compound [50]) to the mixture of 20 ml of THF and 2 ml of H2O, the mixture was stirred at the temperature of 0° C. After adding 1.54 g (8.65 mmol) of NBS, the mixture was stirred over night with increasing the temperature to a room temperature gradually, 140 mg (0.787 mmol) of NBS was added and the mixture was stirred for 6 hours. The mixture was added to saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with a solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride in this order, then dried with magnesium sulfate anhydride and concentrated. The concentrate was crystallized with the mixture of hexane and ethyl acetate to obtain 1.323 g of 2-(4-bromo-3-methoxyphenyl)-3-t-butyl-3-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydrofuran (Compound [51]). Yield 47.7%
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: NCC(F)(F)F
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
In an argon atmosphere, 5.63 g (24.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding 5.38 g (54.3 mmol) of 2,2,2-trifluoroethylamine, the mixture was stirred at room temperature for 15 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./4.7×102 Pa) to obtain 1,3-di-tert-butyl-2-(2,2,2-trifluoroethyl)amino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHCH2CF3) as a pale yellow liquid (yielded amount: 4.74 g, yield: 66%).
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Li+:23].P([O-])([O-:27])([S-])=S.[S]>>[OH:27][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:23]
Reactant: [O-]P([O-])(=S)[S-]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Agent: [S]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]
Temperature: 98.88888888888889 °C

Procedure:
A lithium hydroxystearate grease thickener was prepared by saponification of a mixture containing 12-hydroxystearic acid (8%) and the glyceride thereof (9%) with lithium hydroxide in a mineral oil vehicle (ISO 150 viscosity grade of a 70/30 mixture of naphthenic and paraffinic stocks) at about 350° F. in a closed contactor. After depressuring and dehydration of the thickener in an open kettle sufficient mineral oil was added to reduce the thickener content to about 9.0%. After cooling to 210° F., a typical grease additive package, consisting of an amine antioxidant, phenolic antioxidant, metallic dithiophosphate, sulfur-containing metal deactivator and nitrogen containing antirust additives, was added. The dropping point of this base grease was 201° C.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1.[OH-].[Na+]>C1COCC1.O>[C:3]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:6]=[CH:5]\[C:4]([OH:13])=[O:21])#[N:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Nc1c(O)ccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1/C=C\C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 1-nitrosonaphthalen-2-ol (5 g) dissolved in THF (30 mL) was treated with p-toluenesulfonyl chloride (6.61 g) under nitrogen. The resulting mixture was stirred at 20° C. for 1 h. The mixture was treated with a solution of sodium hydroxide (4.04 g) in water (30 mL) dropwise over 30 min to keep temperature below 25° C. The reaction mixture was diluted with water (200 mL), and extracted with diethyl ether (200 mL) (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate (200 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with 50% diethyl ether in isohexane to give the subtitle compound as a solid (4.75 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:26]=[O:27].O>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[N:3][CH:4]=1
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C2OCCO2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 2-bromo-5-(1,3-dioxolan-2-yl)pyridine (9.60 g) in tetrahydrofuran (150 mL) was slowly added a 1.6M n-butyllithium hexane solution (28.7 mL) at −78° C. The reaction mixture was stirred for 30 min, N,N-dimethylformamide (3.9 mL) in tetrahydrofuran (50 mL) was added, and the mixture was warmed to room temperature and stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate solution. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.70 g, yield 36%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). MS: 180 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 16 h

Procedure:
2-Chloro-5-nitropyridine (25 g) is dissolved in acetonitrile (150 ml) and the mixture is added dropwise over 30 min to a stirred suspension of piperizine (61.3 g) and potassium carbonate (26.2 g) in acetonitrile (550 ml). The reaction mixture is stirred at 20°-25° for 16 hr. The solvent is removed on a rotary evaporator and the residue is diluted with methylene chloride/water. The organic layer is separated and washed with water (twice) and saline, dried over potassium carbonate and concentrated to give 1-(5-nitro-2-pyridinyl)-piperazine, IR 3338, 3102, 3068, 1603, 1570, 1482, 1347, 1340, 1320, 1306 and 1253 cm-1.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[H][H].BrBr.[OH-:10].[Na+].OO>O1CCCC1.CO>[CH:2]1([C:1]2([OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:1][CH2:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C1=CCC=C1
Reactant: [H][H]
Agent: BrBr
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1(C2CCCC2)CCCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a 1000-mL 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 172 mL (1.72 mol) of a 10M solution of BH3-Me2S in tetrahydrofuran and 300 mL of dry tetrahydrofuran. The addition funnel was charged with 116.8 g (1.72 mol) of cyclopentadiene dissolved in 100 mL of dry tetrahydrofuran. The flask was immersed in an ice-water bath and the cyclopentadiene solution slowly added over 2 hours at 0-5° C. Stirring was continued for an additional 90 min at this temperature at which time 130 mL of methanol was cautiously added over 1 hour with vigorous evolution of hydrogen. The solvent was then removed under reduced pressure and the remaining oil transferred to a 5 L 3-necked round bottom flask equipped with a thermocouple inlet, overhead stirrer and a 500-mL addition funnel. Dichloromethane (2 L) and water (500 mL) were added and the mixture cooled to 5° C. The addition funnel was charged with 100 mL (1.95 mol) of bromine which was then added slowly over 1 hr. The resulting dark mixture was exposed to a long wave UV lamp with stifling at room temperature overnight by which time the bromine color had largely disappeared. The reaction mixture was recooled to 5° C. and 1.3 L of 6N NaOH was added slowly via the addition funnel followed by 400 mL of 30% hydrogen peroxide. After stirring overnight at room temperature the organic layer was separated, washed several times with water, once with brine and then dried over anhydrous magnesium sulfate for 1 hour. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled from Na2CO3 through a short Vigreux (bp 63° C.@ 1 mmHg) to yield 72 g (55%) the title alcohol as a clear, colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[CH4:3].[Cl:21][CH2:20][CH2:19][CH2:18][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C
Product: ClCCCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.2 %

Procedure:
To a suspension of sodium hydride (60%, 2.0 g, 49 mmol) in dimethylformamide (200 mL) was added 4-benzylphenol (6.0 g, 33 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, then 1-bromo-3-chloropropane (5.1 mL, 49 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (10 mL) and filtered through Celite®. The filtrate was taken up in ether (300 mL), washed thrice with water (150 mL) and dried over sodium sulfate. The solution was concentrated to give 7.5 g (79%) of 4-chloropropoxyphenyl-1-phenyl-methane methane as an amber oil. 1H NMR (CDCl3): δ7.44-6.78 (m,9H), 4.01(t,2H), 3.99(s,2H), 3.55(t,2H), 1.98(m,4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:23]1([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[N:23]1([C:29]2[CH:30]=[CH:31][C:32]([NH:33][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14][C:15]#[N:16])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cn1

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (20 mg, 0.00008 mol), 4-morpholin-4-ylaniline (20.1 mg, 0.000113 mol), and p-toluenesulfonic acid (11 mg, 0.000064 mol) in dry 1,4-dioxane (0.5 mL, 0.006 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to provide the desired product as a racemic mixture (free base). LCMS (M+H) 460.4.