Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[Br:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=[NH:18])[NH:14][CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1>>[Br:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13]3[N:14]([CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:18]=3)[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: N=C1NCCOc2cc(Br)ccc21
Reactant: O=C(O)C(=O)CBr
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2

Procedure:
Reaction of 3-bromo-2-oxopropanoic acid and 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 33 gives 28 (CAS Reg. No. 1282516-74-8).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:7]=1[F:16])(=O)C.[OH-].[Na+]>CO>[F:16][C:7]1[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: COc1ccc(COC(C)=O)c(F)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CO)c(F)c1OC

Procedure:
5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated to 80° for 1.5 hours together with 50 ml of methanol and 50 ml of 1N sodium hydroxide solution. After evaporation of the methanol the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 80 g of silica gel with methylene chloride/methanol (95:5). 2-fluoro-3,4-dimethoxybenzyl alcohol is obtained as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
2.0 g (0.01045 mol) of 1-benzyl-4-hydroxypiperidine were dissolved in 20 ml of dichlormethane and 5.1 ml (0.0366 mol) of triethylamine, cooled to 00 and treated with a solution of 1 ml (0.01255 mol) of methanesulfonyl chloride in 5 ml of dichloromethane. The mixture was stirred at 0° for 1/2 hr. Then, 10ml of 1N aqueous HCI were added, the mixture was stirred for 5 min. and the organic phase was washed with 1N aqueous HCI, with saturated bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. 0.97 g (35%) of 1-benzylpiperidin-4-yl methanesulfonate was obtained as yellow crystals. MS: me/e=270 (C13 H20NO3S+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 4.76 g, 12.6 mmol) in dichloromethane (40 ml) was treated with trifluoroacetic acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform: methanol, 95:5 spiked with acetic acid) to provide the title compound as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](OCC)=[O:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(CO)cc12
Temperature: -50 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a cooled (-50° C.) and stirred solution of the product from Step 3 (17.4 g, 52.4 mmol) in anhydrous tetrahydrofuran (650 ml) was added dropwise via cannula diisobutylaluminium hydride (1M in toluene; 168 ml) over 23 minutes, under a nitrogen atmosphere. After being stirred at -25° C. for 1 hour, additional diisobutylaluminium hydride (1M in toluene; 40 ml) was added dropwise over 15 minutes and stirring was continued at -25° C. for further 30 minutes. Methanol (65 ml) was added dropwise (CAUTION! H2 evolution) at -35° C. followed by aqueous citric acid (10%; 450 ml) and the organic phase was decanted off. The aqueous solution was extracted with ethyl acetate (500 ml) and the combined organic phases were washed with brine (1×200 ml), dried (Na2SO4) and concentrated. Flash chromatography (silica gel, dichloromethane-methanol, 97:3) of the remaining residue gave 13.8 g (90.8%) of the title compound as a white solid. A sample recrystallised from dichloromethane showed: mp 129°-130° C.; δH (360 MHz, DMSO-d6) 10.70 (1H, br s, indole N--H), 7.44 (1H, s, Ar--H), 7.26 (1H, d, J=8.3 Hz, Ar--H), 7.10 (1H, s, Ar--H), 7.03 (1H, d, J=8.3 Hz, Ar--H), 6.86 (1H, br t, --NH--), 4.95 (1H, t, J=5.6 Hz, --OH), 4.54 (2H, d, J=5.6 Hz, --CH2OH), 3.18 (2H, m, --CH2N--), 2.78 (2H, t, J=7.2 Hz, --CH2 --), 1.38 (9H, s, t-Bu); m/z (EI) 290 (M+). (Found: C, 65.95; H, 7.82; N, 9.37. C16H22N2O3 requires: C, 66.18; H, 7.64; N, 9.65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 69.6 %

Procedure:
1.80 g (5.0 mmol) of 4-[4-(tert-butoxycarbonylamino) butylamino]-3-nitroquinoline) was dissolved to a mixed solvent of 30 ml of methanol and 10 ml of ethyl acetate. 0.5 g of 10% palladium-carbon was added thereto and the mixture was stirred overnight under hydrogen atomosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1 (v/v)) to obtain 1.15 g (3.48 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]quinoline shown below as a brown amorphous substance. ##STR52## Its physicochemical properties were in agreement with those of the compound of Example 22.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][C:13]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C([O-])([O-])=O.[K+].[K+].C([O:14][C:15](=O)[CH:16](Br)[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)C.O>CCO>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]2[S:5][CH2:4][CH2:3][NH:2][C:15]2=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1NCCSC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanethiol hydrochloride (6.93 g; 61 mmol) in EtOH (400 mL) was added K2CO3 (16.86 g; 122 mmol), at RT, followed after 15 minutes by bromo-(4-bromo-phenyl)-acetic acid ethyl ester (12 mL; 61 mmol). The resulting mixture was stirred at RT for two days, subsequently, water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from EtOH to afford 2-(4-bromo-phenyl)-thiomorpholin-3-one (12.8 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:13]2[CH:12]=[C:11]3[CH2:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[CH2:7][C:6]1=[O:17])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:7]2[C:8]3[CH:9]=[C:10]4[O:16][CH2:15][CH2:14][C:11]4=[CH:12][C:13]=3[N:5]([CH2:3][CH3:4])[C:6]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CCO3
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)Nc2ccc(Cl)cc2)c2cc3c(cc21)CCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a slurry of 18 mg. (0.803 mmole) of sodium hydride in 740 ul. of dimethylformamide cooled to -10° C. was added 150 mg. (0.739 mmole) of 5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole. After the evolution of gas ceased, 125 mg. (0.813 mmole) of 4-chlorophenylisocyanate was added and the reaction mixture allowed to warm to 25° C. and stir for 16 hours. The reaction mixture was poured into a saturated solution of sodium chloride--1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to dryness in vacuo. The residue was purified by chromatographing on 20 g. of silica gel using ethyl acetate-hexane (1:2, v:v) as the eluant. The final product was recrystallized from diethyl etherdichloromethane, 15 mg. (6% yield), m.p. 175°-176° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.[CH3:19][S:20]C.O>CCOCC>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CSC
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Reaction time: 1 h

Procedure:
A solution of 5,6,7 or 8-bromo-2-(di-n-propylamino)tetralin (1.4 g; 4.5 mmol) in dry ether (20 ml) was cooled to -78° C. under nitrogen atmosphere. S-BuLi (7 ml, 10 mmol) was added and the mixture was stirred for 1 hr. Methylsulphide (0.31 g; 5 mmol) was added and the mixture was stirred for 3 hr. When the temperature reached -10° C., water was added. Workup afforded the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[O:13][CH2:14][CH2:15][C@@:11]2([C:17]([OH:19])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[CH2:35][NH2:36])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=1[CH2:35][NH:36][C:17]([C@:11]12[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:16][C@H:12]1[O:13][CH2:14][CH2:15]2)=[O:19])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C1

Procedure:
The product of Step A was prepared from the reaction of the product of Example 23, Step E and (2-(tert-butoxy)-5-(trifluoromethyl)phenyl)methanamine prepared according to procedures in ACS Med. Chem. Letters 2010, 1, 14 following the procedure from Example 1, Step C. Calculated for C25H35F3N2O5: 523.2 (M+23). found: 523.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:22]4[CH:21]=[CH:20][N:19]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:23]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: FC(F)(F)c1cc(Nc2ccccn2)ccn1
Solvent: c1ccncc1
Product: O=C(N(c1ccnc(C(F)(F)F)c1)c1ccccn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added N-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2-amine (48 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 427.4, found 428.1 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>ClCCl>[NH2:13][C@H:10]([CH2:11][O:12][CH3:28])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
Accordingly to a solution of the compound tert-butyl [(R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethyl]carbamate of Formula-XXI in dichloromethane, charged the phase transfer catalyst and cooled the reaction mass to −10° C. and charged dilute solution of sodium hydroxide. Maintaining the temperature at −10° C.-0° C. charged dimethyl sulfate and maintained the reaction under stirring for 3-5 hours. Charged water at the end of the reaction, stirred, separated the organic layer and extracted the aqueous layer with the dichloromethane. Combined the organic layer and acidified with concentrated hydrochloric acid. Charged water to the clear solution and stirred. Separated the aqueous layer and extracted the organic layer further with water. Combined the entire aqueous layer and adjusted the pH to 12 with aqueous sodium hydroxide solution. Extracted the aqueous layer with dichloromethane and separated the organic layer. Extracted the aqueous layer further with dichloromethane to ensure the complete extraction of the desired product. The organic layer is washed and concentrated to isolate the compound (2R)-2-amino-N-benzyl-3-methoxypropanamide of Formula-VIII.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@@:20]([O:24]C(C1C(C(O)=O)=CC=CC=1)=O)([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@@:20]([CH3:21])([OH:24])[C:22]#[CH:23])(=[O:3])[CH3:2]
Reactant: C#C[C@@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: C#C[C@](C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O

Procedure:
By the same procedure as described above (example 11), this compound was prepared from (R)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester, as white crystals =mp 100°-103 C., [α]D25 -17.38° (CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(-c4cccc(OC)c4)cc3)cnc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A mixture of 60 mg (0.126 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 5 mg (0.0063 mmol, 5 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 10 mg (0.012 mmol, 10 mol %) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 5% ethyl acetate in dichloromethane) to afford 47 mg (82% yield) of desired 7-cyclohexyl-6-(3′-methoxy-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR; LC-MS—calcd for C28H29N3O3 [M++H]+: 456.22, found: 456.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-chloropicolinic acid (160 mg, 1.04 mmol) and BOP-Cl (332 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (2 N, 3 mL) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide (240 mg, 73% yield) as a solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15].CO.[BH4-].[Na+].[ClH:20]>C(O)C>[ClH:20].[ClH:20].[CH3:14][NH:15][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][CH:9]=1
Reactant: CN
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNCc1c[nH]c(-c2ccccc2)n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in ethanol (30 mL) was added 40% methylamine-methanol solution (2.36 g) and the mixture was stirred at 65° C. for 1 hr. The mixture was allowed to cool to room temperature, sodium borohydride (571 mg) was added and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→4:1) and dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 1.06 g, yield 41%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[N:26]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:12])[F:13]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
To a stirred solution of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746] (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzene sulphonyl chloride (220 mg, 1.1 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (280 mg, 0.56 mmol). Mp: 186-187° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.2 (m, 3H), 4.75 (s, 1H), 7.8 (d, 2H), 7.9 (d, 2H); m/z 418.