Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19])([CH3:7])([CH3:6])[CH3:5].CC[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:14]1[CH:13]=[C:12]2[C:26](=[CH:27][CH:15]=1)[N:23]([CH2:24][CH:25]1[CH2:6][CH2:4][CH2:5]1)[N:10]=[CH:11]2)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1cc(F)ccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(F)ccc1Nc1ccc2c(cnn2CC2CCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
To a flask containing boronic acid (0.175 g, 0.76 mmol), amine (6q) (0.22 g, 0.915 mmol), Cu(OAc)2 (0.135 g, 0.76 mmol) and 4 Å sieves (0.2 g) in DCM, Et3N (0.52 mL, 3.7 mmol) was slowly added. The mixture was stirred at room temperature for 3 days. DCM was added to the reaction mixture and filtered. The filtrate was washed with H2O (2×), brine and dried over Na2SO4. After concentration, the residue was purified by chromatography (Sep-Pak; 10 g) with hexane/Et2O (3:1). The fractions containing the product were combined to afford (7q-2) (0.12 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.24 (br s, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.94-6.84 (m, 3H), 5.02 (br s, NH), 4.35 (d, J=7.8 Hz, 2H), 4.29 (d, j=6.2 Hz, 2H), 2.98-2.85 (m, 1H), 2.10-1.98 (m, 2H), 1.95-1.79 (m, 4H), 1.44 (s, 9H); MS (APCI+) m/z 425 (M+H) was detected.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]2[C:15](=[O:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)[O:18][C:13]=2[C:12]([F:30])=[CH:11][C:10]=1[F:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>O1CCCC1>[F:31][C:10]1[CH:11]=[C:12]([F:30])[C:13]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([F:28])[CH:20]=3)=[CH:16][C:15](=[O:29])[C:14]=2[C:9]=1[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCBr)c(F)cc(F)c3o2)cc1F
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCN4CCCC4)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h

Procedure:
500 mg (1.01 mmol) of Compound 59 obtained in Example 59 was dissolved in 5 ml of tetrahydrofuran, 0.17 ml of pyrrolidine was added and the mixture was heated at reflux for 5.5 hours. At 1 hour and 1.7 hours after the reaction was started, each 0.17 ml of pyrrolidine was added. At 3.5 hours and 4.5 hours, each 0.17 ml of pyrrolidine was added. At 3.5 hours and 4.5 hours, each 0.08 ml of pyrrolidine was added. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine=90:10:1) and triturated with n-hexane to give Compound 63 which was converted into hydrochloride according to the same manner as that in Example 62 to give 465 mg (83%).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:27])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:26])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:3][C:4]([OH:6])=O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:27])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:26])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:3][C:4]([NH:31][CH2:30][CH2:28][OH:29])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: NCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 93 %

Procedure:
The procedure of Example 1 was repeated except that 7.4 g of 3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenoic acid and 1.8 ml of ethanolamine were used as starting materials. 7.7 g (yield 93%) of the title compound as a colorless oil was obtained.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH:10]=[C:9]([CH3:12])[CH2:8][CH:7]1[C:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=O)C.[OH-].[Na+].C(O)COCCO>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]([CH:7]2[CH2:8][C:9]([CH3:12])=[CH:10][CH2:11][NH:6]2)([CH3:15])[CH3:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CC=C(C)CC1C(C)(C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC1=CCNC(C(C)(C)c2ccc(Cl)cc2)C1

Procedure:
A mixture of 1-ethoxycarbonyl-1,2,3,6-tetrahydro-2-[1-(4-chlorophenyl)-1-methylethyl]-4-methylpyridine (14.5 g), sodium hydroxide (15 g) and diethylene glycol (150 ml) was refluxed for 5 hours. After cooling, water was added to the reaction mixture and the resulting mixture was extracted with benzene. The extract was washed with water and dried over potassium carbonate. After removal of benzene, the residue was distilled under reduced pressure to obtain 10.7 g of a colorless viscous mass of 2-[1-(4-chlorophenyl)-1-methylethyl]-1,2,3,6-tetrahydro-4-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=O>C(O)(=O)C>[CH3:7][C:6]1[CH:5]=[N:4][N:3]2[C:12]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-amino-4-methylpyrazole and 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone in glacial acetic acid is refluxed for 6 hours. The solvent is removed and the residue dissolved in methylene chloride and passed through a column of hydrous magnesium silicate. Concentration of the eluent and addition of hexane gives the product of the example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:24]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:23]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
A solution of 6-(2,6-dimethoxyphenyl)piperidin-2-one (70 mg; 0.29 mmol; 1.0 equiv.) in anh. DMF (3 ml) was treated at rt with NaH (60% dispersion in mineral oil; 71 mg; 1.78 mmol; 6.0 equiv.), and 3-(bromomethyl)-1,1′-biphenyl (110 mg; 0.44 mmol; 1.5 equiv.). The resulting mixture was then heated to 60° C., under nitrogen, for 1 h. The reaction mixture was allowed to cool to rt, and a solution of aq. sat. NaHCO3 (10 ml) was added. After extractions with AcOEt (2×20 ml), the mixed organic layers were further washed with brine (10 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 1-([1,1′-biphenyl]-3-ylmethyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one as a colorless oil. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 402.16 g/mol.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Yield: 35.2 %

Procedure:
In a manner similar to that described in part A of Example 1 hereinabove, 7.4 g (0.05 mole) of phthalic anhydride, 16.0 g (0.053 mole) of 76.5 percent active 1-n-octyl-2-methylindole, and 13.3 g (0.1 mole) of aluminum chloride were interacted in 50 ml of benzene to obtain 6.9 g of 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)7CH3), as a pink-colored powder which melted at 121°-123° C. The nuclear magnetic spectrum was in agreement with the structure and a significant maxima occurred at 1717 cm-1 (C=O; s).
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1)[C:2]#[N:3].[NH2:23][OH:24]>CCO>[OH:24]/[N:23]=[C:2](\[NH2:3])/[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: NO
Reactant: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Solvent: CCO
Product: Cc1ccc(N/C(N)=N/O)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NH2OH (50 wt % in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1H), 9.46 (dd, J=6.8, 0.8 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.76 (dd, J=7.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.52-7.43 (m, 2H), 7.18-7.06 (m, 2H), 2.13 (s, 3H). MS m/z 325.1 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=[O:21])[CH3:20].[Na+].C(Cl)(=O)C>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][O:15][C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 67.1 %

Procedure:
1.27 g (5 mmol) of N-benzyloxycarbonyl-L-homoserine are dissolved in 5 ml of acetic acid, and 0.41 g (5 mmol) of sodium acetate is added. 1.19 g (15 mmol) of acetyl chloride are then added and stirring is carried out for one hour. The acetic acid and the excess acetyl chloride are removed in vacuo, the residue is taken up in 30 ml of methyl isobutyl ketone and 30 ml of water, and the pH is adjusted to 8 using 50% sodium hydroxide solution. The aqueous phase is separated off, adjusted to pH=2 using hydrochloric acid and extracted using 30 ml of methyl iso-butyl ketone. Concentration of the organic phase in vacuo yields 0.99 g (67%) of N-benzyloxycarbonyl-O-acetyl-L-homoserine in the form of a colourless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:18][CH2:17][C:5]2=[N:6][C:7]3[CH:8]=[N:9][C:10]4[C:15]([C:16]=3[N:4]2[NH:3]1)=[CH:14][CH:13]=[CH:12][CH:11]=4.ClC1C=C(C=CC=1)C(OO)=O.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O.CO>[CH3:1][CH:2]1[CH2:18][CH2:17][C:5]2=[N:6][C:7]3[C:8]([NH2:30])=[N:9][C:10]4[C:15]([C:16]=3[N:4]2[NH:3]1)=[CH:14][CH:13]=[CH:12][CH:11]=4
Reactant: [NH4+]
Reactant: CC1CCc2nc3cnc4ccccc4c3n2N1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1CCc2nc3c(N)nc4ccccc4c3n2N1
Reaction time: 0.5 h

Procedure:
A solution of 10-methyl-8,9,10,11-tetrahydropyridazino[1′,6′:1,2]imidazo[4,5-c]quinoline (1.56 g, 6.55 mmol) in chloroform (50 mL) was chilled in a cold water bath and treated with 3-chloroperoxybenzoic acid (2.35 g, 8.18 mmol, 70%). After 30 min, the reaction mixture was treated with concentrated NH4OH (25 mL), stirred rapidly to homogenize, and then treated with p-toluenesulfonyl chloride (1.31 g, 6.88 mmol). After 20 min, the mixture was diluted with chloroform (25 mL) and water (25 mL) transferred to a separatory funnel and separated. The organic portion was washed with 10% Na2CO3 aqueous solution (25 mL), water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a tan solid. The solid was purified by column chromatography (50 g silica gel eluted with 95:5 chloroform:methanol) to give an off white solid. The solid then was dissolved in 85:15 chloroform:methanol, stirred with activated carbon (0.100 g, Darco G-60), filtered through layer of CELITE filter agent, and concentrated under reduced pressure to yield 0.079 g of 10-methyl-8,9,10,11-tetrahydropyridazino[1′,6′:1,2]imidazo[4,5-c]quinolin-6-amine as an off white solid, mp 241-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (dd, J=8.1, 1.3 Hz, 1H), 7.53 (dd, J=8.3, 1.5 Hz, 1H), 7.39-7.34 (m, 1H), 7.21-7.15 (m, 1H), 6.68 (d, J=10.5 Hz, 1H), 6.46 (s, 2H), 3.44-3.31 (m, 1H), 3.14-3.08 (m, 2H), 2.14-2.07 (m, 1H), 1.79-1.66 (m, 1 H), 1.27 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 151.4, 144.3, 143.9, 129.9, 126.1, 125.2, 123.3, 121.1, 120.2, 114.8, 50.4, 27.3, 22.2, 18.2; MS (APCI) m/z 254 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.N#N.C(N(CC)CC)C.[C:32]([CH:34]1[CH2:36][CH2:35]1)#[CH:33]>O1CCOCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:34]1([C:32]#[C:33][C:2]2[C:3]([NH2:22])=[N:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[N:7]=2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Reactant: C#CC1CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N)c(C#CC3CC3)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (step 3) (440 mg, 1.24 mmol) in dioxane (5 ml) was degassed with N2 and treated with triethylamine (1.558 ml, 11.18 mmol), ethynylcyclopropane (0.210 ml, 2.484 mmol), copper(I) iodide (71.0 mg, 0.373 mmol) and PdCl2(dppf)-CH2Cl2-adduct (101 mg, 0.124 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure and dry loaded onto silica using DCM (10 ml). Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the titled compound as a beige coloured solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(C)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.103 g, 0.123 mmol) and 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.025 ml, 0.025 mmol) in toluene (5 mL) at −35 C was added dropwise 1M catecholoborane/THF (0.245 ml, 0.245 mmol) over 5 min. After 30 min, the reaction mixture was warmed to −15° C., diluted with EtOAc (10 ml) and quenched with sat. Na2CO3 (5 mL). The resulting mixture was vigorously stirred for 30 min, aqueous layer removed and organic layer washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated to yellow residue which was purified by prep-HPLC to afford (S)-methyl 2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as white solid. To a stirred solution above solid (18 mg) in CH2Cl2 (3 mL) and tert-BuOAc (1 mL) was added 70% perchloric acid (0.025 mL) at rt and sealed for 1.5 h. Then, the reaction was diluted with Et2O (25 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.01 g, 0.021 mmol, 17.06% yield) as pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.86-7.83 (m, 1H), 7.73 (dt, J=6.6, 1.7 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.40 (dd, J=12.5, 7.9 Hz, 2H), 7.32-7.27 (m, 2H), 6.86 (s, 1H), 5.14 (s, 1H), 3.80 (s, 3H), 2.65 (s, 3H), 2.51 (s, 3H), 0.95 (s, 9H). LCMS (M+H) calcd for C27H29ClN3O3: 478.19. found: 480.3.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([C:14]([N:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH3:17])=[O:15])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:24]#[C:25][NH2:26]>C(O)C>[ClH:1].[CH:18]1([N:16]([CH3:17])[C:14]([N:12]2[CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:25]([NH2:26])=[NH:24])[CH:4]=3)[N:10]=[CH:11]2)=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#CN
Reactant: CN(C(=O)n1cnc(-c2cccc(N)c2)c1)C1CCCCC1
Agent: Cl
Solvent: CCO
Product: CN(C(=O)n1cnc(-c2cccc(NC(=N)N)c2)c1)C1CCCCC1
Yield: 68.4 %

Procedure:
Gaseous anhydrous hydrogen chloride (0.096 mL, 1.156 mmol) was added to a stirred suspension of 4-(3-aminophenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (0.345 g, 1.156 mmol) and cyanamide (0.135 mL, 1.734 mmol) in ethanol (1.2 mL) at room temperature. The clear solution was allowed to stir at reflux for 1 h and a colourless solid formed. The reaction mixture was allowed to stir at reflux for further 7 h, whereupon the mixture was allowed to cool. The solid was separated by filtration and washed with ethanol to give the product as a colourless solid, (298 mg, 68%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
2-mercaptopyridine (10 g) was dissolved in DMF (100 ml), 60% sodium hydride (3.6 g) was added to the mixture at 0° C., and then, the mixture was stirred for 15 minutes at room temperature. 4-fluoronitrobenzene (9.75 g) was added dropwise to the mixture at 0° C. and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added, and the precipitated crystals were collected by filtration, and washed with hexane/diethylether, to give 2-[(4-nitrophenyl)sulfanyl]pyridine (12.6 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:12][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ncccn1)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
NaH (300 mg, 60%, 7.5 mmol) was suspended in N,N-dimethylformamide. 1-(4-bromophenyl)ethanol was added to the above mixture and stirred at 40° C. for 0.5 hour. Then 2-chloropyrimidine was added to the above mixture and stirred at 100° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=3:1) to give 2-(1-(4-bromophenyl)ethoxy)pyrimidine as a white solid (2.6 g, 94%). LRMS (M+H+) m/z: calcd 278.01. found 278.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:8][C:3]([CH3:9])([CH:2]=[O:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
Add methyl 3-hydroxy-2,2-dimethylpropanoate (33 g, 250 mmol) to Dess-Martin periodinane (106 g, 250 mmol) suspended in DCM (1000 mL) at 0° C. and stir at room temperature for 18 h. Filter the reaction mixture through a celite bed and concentrate the filtrate. Wash the concentrated filtrate with pentane (2×200 mL). Separate the pentane layer and concentrate in vacuo to give methyl 2,2-dimethyl-3-oxo-propanoate (31.93 g, quantitative). 1H NMR (d6-DMSO) δ 9.59 (s, 1H), 3.67 (s, 3H), 1.26 (s, 6H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:40])[CH3:41])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: COC(=O)C1CCC(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCC2CCC(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.2 %

Procedure:
To a solution of rac 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (54.3 mg, 0.0875 mmol, example XC-1) in THF (5 mL) was added a solution of LiOH (27.8 mg, 0.662 mmol, Aldrich) in water (2.5 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (52.1 mg, 98%). HRMS (ES+) m/z Calcd C31H35Cl2F2N3O3+H [(M+H): 606.2097. Found: 606.2097.