Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C(N(CC)CC)C.[C:17](=[S:19])=S.C[Si]([Cl:24])(C)C>O1CCCC1>[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:24])=[O:9])=[C:17]=[S:19]
Reactant: NCCCCCC(=O)O
Reactant: C[Si](C)(C)Cl
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)CCCCCN=C=S
Reaction time: 0.33 h

Procedure:
An over-dried and nitrogen-cooled two liter round bottom flask was equipped with a nitrogen inlet, a pressure-equalizing dropping funnel, and mechanical stirrer. A mixture of 6-aminocaproic acid (66.02 g, 0.5 moles) in 500 ml of tetrahydrofuran (dried over Linde 4A Molecular Sieves) was added to the flask. After stirring the mixture for 20 minutes under nitrogen, 240 ml of triethylamine (1.7 moles, dried over Linde 4A molecular sieves) was added with stirring. After stirring for 20 minutes, 36 ml of carbon disulfide (0.6 moles) was added dropwise over a 45 minute period. The reaction mixture was stirred overnight and diluted with 250 ml of tetrahydrofuran. Then 225 ml of trimethylsilyl chloride was added dropwise over a 2.5 hour period. A white precipitate formed. The reaction mixture was gently refluxed with stirring for 7 hours. After cooling, the reaction mixture was filtered in the absence of air. The precipitate was washed with dry tetrahydrofuran, and a red-gold filtrate collected. This tetrahydrofuran solution was concentrated in vacuo at room temperature to remove the solvent. The residue was placed in a 500 ml round bottom flask and dissolved in 250 ml of methylene chloride. Thionyl chloride (70 ml) was then added with stirring over a 20 minute period. After stirring overnight, the solvent was removed on a rotary evaporator to give the crude product. This was distilled twice at 110°-115° (0.2 Torr) to give 31 g of 6-isothiocyanatocaproyl chloride having infrared adsorption bands at 4.6-4.8 u (N=C=S) and at 5.5 u (COCl), and n.m.r. resonances (CDCl3 solvent) at 3.4, 2.8 and 1.5 ppm. in structurally consistent area ratios.
Reaction SMILES: Cl[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:2][CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(CCl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(CN1CCOCC1)c1ccccc1
Temperature: 110 °C
Yield: 53.1 %

Procedure:
A mixture of ethyl 3-chloro-2-phenylpropionate (1 g, 4.72 mmol) prepared in the above (1) and morpholine (470 mg, 5.4 mmol) was stirred to cause reaction for 6 hours under heating at 110° C. To the resulting solution, saturated aqueous sodium bicarbonate was added. After the prepared solution was extracted with ethyl ether, the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/6 to obtain 660 mg of the titled compound as a colorless oil (yield: 53.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:30]([C:28]1[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=1)(=[O:32])=[O:31])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1cn(C)cn1

Procedure:
The title compound of Step B was prepared from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester of Step A and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H), 7.85 (d, 1H), 7.49 (s, 1H), 7.43 (m, 3H), 7.32 (d, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 3.20 (t, 2H), 2.20 (t, 2H), 1.48 (m, 2H), 1.40 (m, 2H), 1.15 (m, 4H); MS 477 (M+1).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>O1CCCC1.[Zn]>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mmol) of zinc (powder) in 10 cm3 of tetrahydrofuran and the mixture was stirred at 50° C. for one hour. To the reaction mixture was added dropwise 170 mg (9.43 mmol) of water. The mixture was stirred, and the organic layer was filtered. The filtrate was concentrated under reduced pressure to give 526 mg (2.82 mmol) of diphenylphosphine in 60% yield.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].CON(C)[C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:14]2[C@H:13]([C:11](=[O:12])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][S:16][C:15]2=[O:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Reactant: COP(C)(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)CP(=O)(OC)OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with dimethyl methylphosphonate (36.7 mL, 0.338 mol) and 0.5 L of THF. The solution was purged with nitrogen and cooled to −70° C. 126 mL of a 2.55 M solution of n-butyllithium was added dropwise maintaining an internal reaction temperature less than −60° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (50.0 g, 0.161 mol) was dissolved in 300 mL of dry THF. The resulting solution was added to the solution of dimethyl methylphosphonate anion at a rate maintaining an internal reaction temperature less than −60° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 50 mL of a 10% citric acid solution at a rate that maintained a temperature of less than 5° C. The mixture was diluted with 0.35 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 300 mL of ethyl acetate. The organic phase was separated and a suspension was formed by the addition of 250 mL of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 57 g of (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate was obtained (94% yield). 1H NMR (300 MHz, DMSO) δ 7.16 (d, 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 4.78 (d, J=15.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.79-3.55 (m, 11H), 3.51-3.27 (m, 3H). 13C NMR (75 MHz, DMSO) δ 36.3, 38.0, 46.9, 53.5, 55.08, 66.1, 114.7, 129.0, 129.9, 159.4, 171.9, 199.0; [α]25.0D-29.60 (c=1.00, EtOH).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1(SC)C=CC=CC=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.ClS(O)(=O)=O.[Br:62]Br>C(Cl)Cl>[Br:62][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: BrBr
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: O=S(=O)(O)Cl
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
149.2 g (0.77 mol) of 2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one, prepared by acylating thioanisol (as is described in EP-A-3002), are dissolved in 770 ml of methylene chloride. 0.2 ml of chlorosulfonic acid and 123.0 g (0.77 mol) of bromine are added dropwise slowly to this solution, with cooling, at room temperature. After stirring overnight, the solution is concentrated and is then reacted further as described below.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C2C=CC=CC=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: OCC(CO)OCc1ccccc1
Yield: 81.1 %

Procedure:
A mixture of about 338 g of 5-(benzyloxy)-2-phenyl-m-dioxane, about 1500 ml of ethanol, about 500 ml of water and about 20 ml of sulfuric acid was refluxed for about 2 hours. The ethanol was removed, the acid neutralized with solid sodium bicarbonate, the mixture steam distilled to remove benzaldehyde and then saturated with potassium carbonate. This mixture was extracted three times with ether. The ether extracts were combined, dried and evaporated. Toluene was added and evaporated. The residue was distilled via a Kugelrohr (about 0.1 mm, 170° C.) giving an oil. This oil was dissolved in about 300 ml of toluene, cooled and diluted with two volumes of petroleum ether. Refrigeration produced about 184.69 g of the desired title compound as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:4].[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([C:3](=[O:4])[CH2:2][Cl:1])[CH3:15])=[CH:14][CH:13]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1N
Reactant: CN(C(=O)CCl)c1ccc(C(=O)O)cc1
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: CN(C)C=O
Product: CN(C(=O)CCl)c1ccc(C(=O)NC2CCCCC2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Part A. 4-[(2-Chloro-acetyl)-methyl-amino]-benzoic acid (0.23 g, 1.0 mmol.) was stirred in DMF (2 mL) at RT under N2. (2-Amino-cyclohexyl)-carbamic acid tert-butyl ester (0.21 g, 1.0 mmol), HATU (0.57 g, 1.5 eq) and DIEA (0.5 mL, 2.9 eq) were added. The mixture was stirred at RT for 30 min. It was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give (2-{4-[(2-chloro-acetyl)-methyl-amino]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, yield: 95%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=2)=[CH:17][CH:16]=1.[CH2:36]([P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25](/[CH:26]=[CH:36]/[P:45](=[O:52])([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])=[CH:24][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 66 %

Procedure:
To a mixture of 3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.51 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[C:4]1=[O:11].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:18]=O.[OH-].[Na+]>C(O)(=O)C.O1CCOCC1>[CH3:1][O:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][CH2:18][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4]1=[O:11]
Reactant: C1CCNCC1
Reactant: C=O
Reactant: C#CCN1CC[C@H](OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CO[C@H]1CCN(CC#CCN2CCCCC2)C1=O

Procedure:
A mixture of 250 mg of (S)-3-methoxy-1-(2-propynyl)-2-pyrrolidinone, 3.0 ml of dioxane, 0.3 ml of acetic acid, 0.15 g of piperidine, 75 mg of paraformaldehyde and 10 mg of cuprous chloride was heated at reflux for 1 hour then cooled to 0° C. and basified with 1N sodium hydroxide. This mixture was extracted with dichloromethane. The dichloromethane solution was washed with brine, dried and concentrated, giving the desired product, [α]D26 =-43° (dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19]C2.ClC1C=CC(C2CCNCC2)=CC=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Clc1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, and then by a conventional treatment using hydrochloric acid, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazole hydrochloride was obtained, m.p. 228-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:38]2[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=2)OCCCO1>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1cncc(B2OCCCO2)c1
Solvent: O
Product: CCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 59.2 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (9.24 g, 18.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (3.39 g, 20.8 mmol) were coupled according to the method described in Examples 118-121. Additional reagents were added after the reaction was heated for 16 hours, and the reaction was continued for 16 hours. Water (20 mL) was added, and the n-propanol was removed under reduced pressure. The remaining mixture was extracted with chloroform (2×200 mL), and the combined organic fractions were purified by column chromatography on silica gel (eluting with chloroform and chloroform:CMA). The resulting solid was recrystallized from acetonitrile to provide 5.44 g of tert-butyl 4-{[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as a white, fluffy solid, mp 229-231° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CCCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Under a nitrogen atmosphere, add 3,3-dimethylcyclohexanol (1 g, 9.75 mmol), DMAP (238 mg, 1.95 mmol), triethylamine (2.70 mL, 19.5 mmol), and p-toluenesulfonyl chloride (2.045 g, 10.72 mmol) to DCM (25 mL) at 0° C. Stir the mixture for 1 h at 0° C. and warm to room temperature overnight. Add saturated aqueous NaHCO3 (20 mL) and separate the layers. Extract the aqueous layer with DCM (3×20 mL). Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a clear oil (1.93 g, 70%). MS (APCI+) m/z: 283 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1ccccc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and phenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.8 Hz), 8.21 (1H, d, J=7.3 Hz), 8.13 (1H, d, J=2.6 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.50–7.41 (4H, m), 7.34–7.29 (1H, m), 7.20–7.15 (2H, m), 5.42–5.33 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 411 (M+H)+, 409 (M−H)−.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Br:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:20])=O)[C:14]=1[CH3:21].[NH2:22][C:23]1[C:24](=[O:36])[N:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:26]([CH3:29])[C:27]=1[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[O:17][N:16]=[C:15]([C:18]([NH:22][C:23]2[C:24](=[O:36])[N:25]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:20])[C:14]=1[CH3:21]
Reactant: Cc1c(C(=O)O)noc1Br
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1Br
Reaction time: 0.17 h

Procedure:
A solution of DMF (5.33 mL, 68.8 mmol) in DCM (200 mL) was cooled to 0° C. and treated with oxalyl chloride (3.31 ml, 37.9 mmol). 5-bromo-4-methylisoxazole-3-carboxylic acid (7.09 g, 34.4 mmol) was added and stirred under ice cooling for 10 mins. 4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (7.92 g, 37.9 mmol) and triethylamine (14.39 ml, 103 mmol) were added at 0° C. and the mixture stirred at this temperature for 30 mins. The resulting mixture was diluted with DCM and washed with a saturated NaHCO3 (aq) solution. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 100% TBME afforded the title compound;
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1([NH:2][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 2.0 g, 6.01 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 1.21 g, 6.61 mmol) and DIPEA (3.15 ml, 18.02 mmol) in dry DMSO (15 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was partitioned between ethyl acetate and brine. The aqueous layer was extracted further with ethyl acetate (2×100 ml). The combined organics were washed with brine (3×125 ml), dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-30% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([CH:12]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:13][CH:14]=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.O>[CH:7]1([CH:12]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:13][C:14]#[CH:1])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) at 0° C. was added a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol (1.0 mL), followed by a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient temperature and stirred for 16 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, saturated ammonium chloride, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used without further purification (52 mg, 86%).