Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:37][CH:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][N:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.185 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF and at 0° C. was added TEA (0.094 g, 0.930 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was warmed to RT, and stirring was continued at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by prep HPLC. Yield: 0.058 g (58.0%). 1H NMR (400 MHz, CD3OD): δ 9.03 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.97-7.79 (m., 2H), 7.76 (s, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.88-1.85 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.58 (TFA), −112.32, −122.76. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1nc(Br)cc(Br)c1OC

Procedure:
To methyl 4,6-dibromo-3-hydroxypyridine-2-carboxylate 3.98 g (3.98 g, 12.81 mmol) in 40 mL of acetone was added K2CO3 (2.0 g, 14.47 mmol) and dimethyl sulfate (1.20 mL, 12.37 mmol). The reaction mixture was refluxed overnight and concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness. The residue was purified by chromatography (silica gel). Elution with 15% ethyl acetate/hexane gave 0.980 g, of a white solid. 1H NMR(CDCl3): δ 3.95 (s, 3H); 3.90 (s, 3H); 7.80 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[CH:9]([CH:13](OC)OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC(C)C
Reactant: COC(OC)C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.6 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 22.8 g (0.108 mol) of 3-bromo-4,4-dimethoxy-2-butanone and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 20 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 9.63 g (yield: 54%) of 5-acetyl-1-isopropyl-2-methylimidazol as pale yellow liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH3:12])[C:8](=[O:11])[CH2:9][CH3:10])[CH2:3][CH2:2]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(O)C>[CH2:18]([O:17][C:13]([CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH3:12])[C:8](=[O:11])[CH2:9][CH3:10])[CH2:3][CH2:2]1)=[O:16])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: CCC(=O)N(C)C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N(C)C(=O)CC)CC1

Procedure:
7.4 g of the compound obtained in Stage C of Example 1 are dissolved in 10 ml of ethanol, then 4.73 ml of ethyl acrylate dissolved in 12 ml of ethanol are poured onto the solution. The mixture is left at room temperature for one night, and then concentrated in a rotary evaporator and distilled in a Kugelrohr to yield the compound in the form of an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[CH2:40][OH:41]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:39][CH2:38][CH2:37][C@@H:36]4[CH2:40][OH:41])[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: OC[C@H]1CCCN1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCC[C@@H]4CO)c23)ccc1OCc1cccc(F)c1
Yield: 14 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and (R)-2-pyrrolidinemethanol to give the title compound in 14% yield; NMR Spectrum: 1.51 (m, 1H), 1.66 (m, 2H), 1.80 (m, 1H), 2.23 (s, 3H), 2.32 (q, 1H), 2.57 (m, 1H), 2.75 (dt, 1H), 3.14 (td, 1H), 3.24 (m, 1H), 3.40 (m, 2H), 4.39 (t, 2H), 4.44 (s, 1H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.31 (m, 2H), 7.48 (m, 3H), 8.16 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 493 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]([Cl:18])=[O:7])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)O)C1CCCCC1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)Cl)C1CCCCC1

Procedure:
A solution of 2-cyclohexyl-malonic acid monoethyl ester (2.9 g, 14 mmol; CAS Reg. No. 147596-63-2) in thionyl chloride (29 ml) was heated under reflux conditions for 2 h. The solvent was removed under reduced pressure to give chlorocarbonyl-cyclohexyl-acetic acid ethyl ester. 1,2,3-Benzotriazole (1.47 g, 12 mmol) was dissolved at ambient temperature under an argon atmosphere in CH2Cl2 (45 ml). Et3N (1.86 ml, 13 mmol) and a solution of chlorocarbonyl-cyclohexyl-acetic acid ethyl ester in CH2Cl2 (4 ml) was added. The reaction mixture was stirred at ambient temperature for 14 h, quenched with ice cold aqueous 2 N HCl and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.05 g, 3.3 mmol; 25%) as yellow oil. MS: m/e=316.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[CH:32]([Mg]Br)=[CH2:33]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])[CH:32]=[CH2:33])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: Cc1c(C=NS(=O)(=O)C=Cc2ccccc2)c2ccccc2n1CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: C=CC(NS(=O)(=O)C=Cc1ccccc1)c1c(C)n(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C

Procedure:
The product of step b) (2.2 g, 5 mmol) was treated with 100 mL toluene. The slurry was stirred at 0° C. and treated with Me3AI (3.8 mL of 2 M in toluene) followed by vinyl magnesium bromide (10 mL of 1 M). The reaction was warmed to rt and stirred for 10 minutes. The reaction was cooled to 0° C., quenched with aqueous acetic acid, and partitioned between water and EtOAc (200 mL each). The organic layer was washed with 1 M NaOH, dried over MgSO4 and purified over silica gel (30% EtOAc/Hex) to give 1.25 g of the sub-title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH2:12]1COCC1.C[Mg]Br.[NH4+].[Cl-]>C(OCCCC)CCC.C(OCC)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: O=Cc1c(F)ccc(F)c1Cl
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCOCCCC
Solvent: CCOCC
Product: CC(O)c1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry 18×250 mm test tube, 2-Chloro-3,6-difluorobenzaldehyde (1.00 g, 5.66 mmol) and THF (10.0 mL, 123 mmol) were added. The reaction tube was evacuated and filled with N2 3 times. Methylmagnesium bromide (0.810 g, 6.80 mmol) 1.0 M in butyl ether was added slowly at 0° C. The reaction mixture was stirred at room temperature overnight. 5 mL of sat. aq. NH4Cl was added to quench the reaction at 0° C. Diethyl ether was added and aq. layer was extracted with ether 3 times. The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The material was not further purified and ready for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) and 4-bromophenylboronic acid (80 mg) were dissolved in a mixed solution composed of dichloromethane (5 ml) and triethylamine (0.07 ml) to prepare a solution. Copper(II) acetate (50 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The stirred mixture was filtered, and the filtrate was then concentrated. The crude thus obtained was purified by chromatography on silica gel to give (4-bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (70 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]([C:30]([O:32][CH3:33])=[O:31])[C:30]([O:32][CH3:33])=[O:31])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by methyl chloroformate (0.033 mL, 0.43 mmol). The mixture was stirred at room temperature for 30 min. To the reaction mixture was added a catalytic amount of DMAP and another equivalent of methyl chloroformate. The reaction was stirred at room temperature over a weekend, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the bis-acylated product (67 mg, 50%). LCMS calculated for C19H18ClFNO5 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:3]1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:23](=[O:24])[CH2:22][C:20]#[N:21])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: N#CCC(=O)O
Reactant: c1cc2c(ncc3nnc([C@@H]4CCCNC4)n32)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a suspension of (R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.074 g, 0.265 mmol; Example #I1.1) and 2-cyanoacetic acid (0.034 g, 0.398 mmol) in DMF (3 mL) was added HOBt (0.041 g, 0.265 mmol), EDC.HCl (0.051 g, 0.265 mmol) and DIEA (0.093 mL, 0.531 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by RP-HPLC (Table 2, Method f). The appropriate fractions were concentrated in vacuo and lyophilized to afford (R)-3-(3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a white solid (0.052 g, 63%): LC/MS (Table 2, Method a) Rt=1.30 min; MS m/z: 310 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(S(O)(=O)=O)(F)(F)F.C1C(=O)N([Br:26])C(=O)C1>CC#N>[Br:26][C:7]1[C:8]([OH:10])=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzonitrile (10 g, 65.1 mmol) in CH3CN (200 mL) was added CF3SO3H (6.33 g, 71.6 mmol) and NBS (16.2 g, 94.1 mmol) at −30° C. After being stirred for 18 hours at room temperature, the mixture was quenched with aq. saturated NaHSO4 solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 37 (10.5 g, 66%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16]C#N)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.C(P(CC)CC)C>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylthiocyanate (5513 g, 0.209 mole) was dissolved in acetone (200 ml) under an argon atmosphere. Water (7.6 g, 0.42 mole) was added and the reaction cooled to 0° C. Triethylphosphine (24.7 g, 0.209 mole) was added dropwise over a period of 1 hour and the reaction was then allowed to warm to room temperature with stirring. The solution was concentrated, solvents removed, and the resulting oil purified by chromatography on silica. The fractions containing the thiol were combined and the solvents removed to yield a white powder. Recrystallization from methanol/water yielded, upon drying, 43.3 g of the title compound. The NMR spectrum confirmed the identify of the product.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:60]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:67][CH:60]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NC1CCCCCC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NC2CCCCCC2)cc1Cl
Reaction time: 8 h
Yield: 38.6 %

Procedure:
In THF (30 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3-chloro-4-methoxybenzylamino)-pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol) and DIEA (0.3 mL, 1.78 mmol). The reaction mixture was cooled in an ice bath, then HATU (250 mg, 0.65 mmol) and cycloheptanyl amine (67 mg, 0.60 mmol) were added. The react ion was conducted at ambient temperature overnight. The reaction mixture was concentrated, quenched with water and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=3/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-meth oxybenzyl)amino)-N-cycloheptanylpyrimidine-5-formamide (98 mg, 38.6% yield).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[C:15]([OH:18])=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[C:14]([OH:19])[C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: Oc1ccc(Cl)cc1O
Reactant: Cc1ccc(S(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)c2c(Cl)ccc(O)c2O)cc1

Procedure:
In a manner analogous to that described in Example 5a), p-toluenesulphinic acid is oxidatively condensed with 4-chloro-1,2-benzenediol. On recrystallisation from 1,2-dichloroethane, 4-chloro-(4-methylphenylsulphonyl)-1,2-benzenediol is obtained in the form of colourless crystals having a melting point of 162°-164°.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[CH3:43]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[CH3:43]
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
5.54 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 53 ml of anhydrous ether and 18.4 ml of phenyllithium (0.88 M) was dropped thereto and the resulting mixture was stirred at a room temperature for 15 minutes. 35 ml of ether solution of 3.01 g of (4-chloro-3-methyl-2-pyridyl)cyclopropylketone (X) was dropped thereto and the resulting mixture was stirred at a room temperature for 2 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.66 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropyl-1-methoxyethene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[CH:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2NC(=O)CCl)[CH2:14][CH2:13][CH:12]=[CH:11]1>>[CH:10]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:9])[CH2:7][Cl:8])[CH2:14][CH2:13][CH:12]=[CH:11]1
Reactant: O=C(CCl)Nc1ccccc1C1C=CCC1
Reactant: COCCNC(=O)CCl
Product: COCCN(C(=O)CCl)c1ccccc1C1C=CCC1

Procedure:
The preparation of N-[2-(cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide was conducted in a fashion analogous to example 2. Reaction of 30.00 g (188.4 mmol) of 2-(cyclopent-2-enyl)aniline, 75.75 g (750 mmol}of triethylamine, and 70.91 g (750 mmol) of 2-chloroethyl methyl ether at 100° C. in a closed, 500 mL flask for 56 hr. afforded ca. 40 g of a crude product consisting of, in part, 90.05 wt % of N-(2-methoxyethyl)-2-(cyclopent-2-enyl)aniline and 7.24 wt % of 2-(cyclopent-2-enyl)aniline. Acylation of this material with 2-chloroacetyl chloride provided ca. 50 g of a product consisting of, in part, 89.35 wt % of N-[2- cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide and 8.84 wt % of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide. This material was purified by column chromatograph then bulb-to-bulb distillation (bp 165-175°C/1 mm/Hg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[Cl:20][C:21]1[CH:22]=[N+:23]([O-:41])[CH:24]=[C:25]([Cl:40])[C:26]=1[CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:40][C:25]1[CH:24]=[N+:23]([O-:41])[CH:22]=[C:21]([Cl:20])[C:26]=1[CH2:27][C@H:28]([O:18][C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)(=[O:10])=[O:11])=[O:19])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C=O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a stirred solution of (2S)-1-(4-formylphenyl)sulfonylpyrrolidine-2-carboxylic acid (283 mg, 1 mmol) in DMF (15 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (344 mg, 1 mmol), followed by DMAP (60 mg, 0.5 mmol) and EDC (385 mg, 2 mmol). The mixture was allowed to stir at room temperature for 18 hours and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in isohexane followed by 10% methanol in DCM, to afford the title compound as an off-white solid (333 mg, 55%).