Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5](/[C:9](=[CH:12]/[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)/[CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([O:11][CH2:10]/[C:9](/[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:30])[F:1])[CH:4]=1)=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)(=[O:33])[CH3:32]
Reactant: CC1(C)CCC(C)(C)c2cc(CC/C=C(\CO)c3cccc(C(F)(F)F)c3)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC/C(=C\CCc1ccc2c(c1)C(C)(C)CCC2(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of (Z)-2-(3-trifluoromethylphenyl)-5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-pentenol 5r (0.99 g, 2.4 mmol) in anhydrous pyridine (25 mL) at room temperature under argon was treated with 4-dimethylaminopyridine (0.01 g) and acetic anhydride (0.32 g, 3.1 mmol). The reaction mixture was stirred for 2 h and then partitioned between diethyl ether (100 mL) and 1N HCl solution (50 mL). The ether layer was washed further with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1.09 g (100%) of the product as a colorless oil. The acetate was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ7.50 (d, J=8 Hz, 1H, 2-ArH), 7.36-7.41 (m, 2H, 2-ArH), 7.17 (d, J=8 Hz, 1H, 2-ArH), 7.11 (d, J=8 Hz, 1H, 5-ArH), 6.98 (d, J=2 Hz, 1H, 5-ArH), 6.82 (dd, J=2, 8 Hz, 1 Hz, 5-ArH), 5.89 (t, J=7.5 Hz, 1H, C=CH), 4.73 (s, 2H, CH2OAc), 2.61 (t, J=7 Hz, 2H, ArCH2), 2.24 (q, J=7 Hz, 2H, ArCH2CH2), 1.99 (s, 3H, CH3C=O), 1.64 (s, 4H, CH2CH2), 1.24 (s, 6H, 2'CH3), and 1.22 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ170.66 (C=O), 144.70, 142.52, 138.81, 137.91, 134.89, 133.09, 131.95, 128.67, 126.48, 126.45, 125.73, 125.36, 125.31, 124.02, 68.68 (CH2OAc), 35.33, 35.14, 35.09, 34.12, 31.87, 31.81, 30.67, and 20.89; IR (film) 2960, 2925, 2860, 1745 (C=O), 1325, 1225, 1165, and 1130 cm-1 ; MS (DCI) m/e 399 (M+ --OAc).
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:9]2)[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:8]2([CH2:13][CH2:12][CH:11]([CH3:14])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:9]2)[O:24]1
Reactant: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Reactant: OCCCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC2(CC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of n-butyl lithium (1.8 ml) was added dropwise to a solution of 560 mg of 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane in 5 ml of THF under an argon stream at −78° C. The resulting mixture was stirred for 10 minutes and then reacted at room temperature for 1 hour. HMPA (1 ml) was added and the resulting mixture was recooled to −78° C., followed by the dropwise addition of a solution of 166 mg of 10-bromo-1-decanol in 2 ml of THF. After stirring the reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ethyl ether. The organic layer was washed with water and saturated saline and then, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil. Yield: 97%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:31])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (123 mg, 0.280 mmol) and DIPEA (0.490 mL, 2.80 mmol) in DCM (3.0 mL) was added MeI (0.175 mL, 2.80 mmol) dropwise. The reaction mixture was stirred at rt for 3 h. Purification via MDAP then afforded the title compound (40 mg, 29.9% yield). LCMS: rt=3.60 min, [M+H+]=453
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)nc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(-c3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide, monohydrate (0.016 g, 037 mmol) was added to ethyl 1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate (50.0 mg, 0.19 mmol) in methanol (1.5 mL) and water (0.5 mL). The mixture was stirred at room temperature for overnight, then was adjusted to be acidic (pH=5) with 1N HCl aqueous solution, and then was concentrated to give a crude product which was directly used in the reaction of the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]([C:17]1[N:18]=[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:21]=1)=[O:16])(=O)C.[BH4-].[Na+].CC(C)=O>C1COCC1.O>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:19]1[N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:21]=[C:17]([C:15]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[O:7][CH2:6][CH2:5][OH:4])=[O:16])[N:18]=1
Reactant: CC(=O)OCCO[C@@H]1CCCC[C@H]1NC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@@H]1OCCO)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of 2-{[trans-2-({[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}amino)cyclohexyl]oxy}-ethyl acetate (Table entry 286) (31 mg, 0.06 mmol) in THF (7 mL) and water (0.7 mL) was added NaBH4 (5 mg, 0.13 mmol) portionwise over 1 h with the temperature kept below 20° C. The mixture was stirred at rt overnight, cooled to 5° C., treated with acetone (1 mL), and then concentrated. The residue was dissolved in CH2Cl2 and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (2.5% methanol in EtOAc) to give the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1R, 2S)-2-(2-hydroxyethoxy)cyclohexyl]-1H-imidazole-4-carboxamide (7.5 mg, 26% yield): LC-MS m/z (474.8 MH+), retention time 2.91 min (method 1); Rf=0.17 (EtOAc).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CCO.ClCCl>[CH2:19]([N:21]([C:2]1[N:7]=[C:6]([N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CCNCC
Reactant: Cc1ncc[nH]1
Solvent: CCO
Solvent: ClCCl
Product: CCN(CC)c1nc(C)c([N+](=O)[O-])c(-n2ccnc2C)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (208 mg, 1.0 mmol, 1.0 eq. in 2 mL each of EtOH and THF) was added 2-methylimidazole (164 mg, 2.0 mmol, 2.0 eq.) in 2 mL of EtOH. The resulting mixture was stirred for 1 hour at −78° C., then for 2 hours at 0° C. Diethylamine (0.413 mL, 4.0 eq.) was added dropwise and the reaction was stirred overnight. The resulting mixture was diluted with dichloromethane, washed with 0.1N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent was removed by evaporation and the residue was purified by silica gel chromatography to provide 35 mg of the target compound k as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:34][C:35]([OH:37])=[O:36])C=1)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][N:11]2[CH2:34][C:35]([OH:37])=[O:36])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Product: COC(=O)c1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from 3-acetyl-1H-indole-6-carboxylic acid methyl ester [106896-61-1] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Colored solid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.80 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>ClCCl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NCCN(C)C)c1)N2
Reaction time: 0.67 h
Yield: 106 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then N1,N1-dimethylethane-1,2-diamine (42.7 mg, 0.48 mmol, 1.1 eq.) was added to the flask and the reaction mixture was stirred for an additional 40 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 191 mg of methyl 2-(3-(2-(dimethylamino)ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a off-white solid, which was washed with hexane and collected by filtration to afford 162 mg product as a white solid. Yield: 89.5%.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[O:22])[C@@H:17]2[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[O:22])[C@@H:17]2[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH:12]=[CH:11][N:10]=1
Reactant: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)[C@H]1C(=O)NS(C)(=O)=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N)c2)[C@H]1C(=O)NS(C)(=O)=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 95 in 1 mL dichloromethane was added 300 uL of TFA. The reaction was stirred for 1 hour and then concentrated in vacuo. The crude material was purified via reverse phase HPLC (C18, acetonitrile/water with 0.1% TFA) to yield 0.75 mg of 96. MS [M+H]+=446.0
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl[C:29]1[CH:69]=[CH:68][C:32]([CH2:33][O:34][CH:35]2[CH:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[O:59][CH3:60])=[CH:43][CH:42]=3)[CH2:39][CH2:38][N:37]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:36]2)=[CH:31][C:30]=1[O:70][CH2:71][CH2:72][CH2:73][O:74][CH3:75].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1>[CH3:60][O:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:52][O:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH:40]2[CH2:39][CH2:38][N:37]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:36][CH:35]2[O:34][CH2:33][C:32]2[CH:68]=[CH:69][C:29]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[C:30]([O:70][CH2:71][CH2:72][CH2:73][O:74][CH3:75])[CH:31]=2)=[CH:42][CH:43]=1
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Reactant: C1COCCN1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCOCC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
The mixture of 0.0074 g of 2-(di-t-butylphosphino)biphenyl, 0.017 g of dipalladiumtris (dibenzylidenacetone)-chloroform complex and 0.055 g of sodium tert-butoxide is admixed under argon with the solution of 0.280 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a) and 0.043 ml of morpholine in 2.0 ml of toluene. The reaction mixture is stirred at 110° C. over 16 hours, subsequently cooled, poured onto water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (2:1 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=4)[N:24]=3)[CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]=[C:8]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[N:24]=1)[CH:9]=[C:10]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCO)CC4)c4cc(OC)ccc4c3)n2)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCN5CCCCC5)CC4)c4cc(OC)ccc4c3)n2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A solution of 3-(4-(7-methoxy-3-(2-((3-methoxybenzyl)amino)pyrimidin-4-yl)naphthalen-1-yl)piperazin-1-yl)propan-1-ol (65 mg, 0.127 mmol) and triethlyamine (35 μl, 0.254 mmol) in dichloromethane (2 ml) was treated with methanesulfonyl chloride (10 μl, 0.133 mmol) and stirred for one hour. The mixture was diluted with water (2 ml), the organic layer removed and the aqueous layer extracted with dichloromethane (2 ml). The organic layer was concentrated under reduced pressure. The product was treated with acetonitrile (2 ml) and treated with piperidine (38 μl, 0.381 mmol) and heated to 50° C. for 1 hour then concentrated under reduced pressure. The mixture was diluted with saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash column chromatography using a gradient of methanol-dichloromethane as eluent to afford 4-(6-methoxy-4-(4-(3-(piperidin-1-yl)propyl)piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxybenzyl)pyrimidin-2-amine (194) (18 mg). M.p.=63-75° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 8.35 (d, J=5.2 Hz, 1H), 8.30 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.81 (bm, 2H), 7.42 (s, 1H), 7.23 (m, 3H), 6.99 (bm, 2H), 6.78 (dd, J=2.0 and 8.4 Hz, 1H), 4.55 (d, J=6.4 Hz, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 3.40-2.40 (m, 16H), 1.73 (bm, 2H), 1.57 (bm, 4H), 1.44 (bm, 2H); LCMS: 581 [M+H+].
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:20]([NH:4][CH2:1][C:2]#[CH:3])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propargylamine (20 g) and triethylamine (60.7 mL) in ethyl acetate (500 mL) was added benzyloxycarbonyl chloride (71.7 g) slowly while maintaining the reaction temperature between −5° C. and +5° C. The mixture was then stirred at room temperature overnight. The mixture was washed sequentially with 1.5 M HCl (200 mL), 5% NaHCO3 in water (200 mL), and saturated aqueous sodium chloride (100 mL). The solvent was switched to hexane while the desired product precipitated as colorless crystals (60.1 g).
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[CH:6]([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[N:5]1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(O)=[O:2].C(Cl)(=O)[C:35]([Cl:37])=O.[N+](=CC(C1OC2C(C(=O)N2C(=C(C)C)C(OCC2C=CC=CC=2)=O)N1C(=O)C1C=CC=CC=1)=O)=[N-].Cl>C1C=CC=CC=1.CN(C)C=O.CCOCC>[Cl:37][CH2:35][C:1]([CH:4]1[O:10][CH:9]2[CH:6]([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:23])[CH3:24])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[N:5]1[C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:2]
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2C(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)C=[N+]=[N-])N2C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5.8 g of benzyl α-(3ξ-carboxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 70 ml of benzene and 0.14 ml of N,N-dimethylformamide is added 1.33 ml of oxalyl chloride at room temperature under nitrogen atmosphere, and the mixture allowed to stand for 30 minutes, and concentrated to 1/2 volume. The resulting solution of benzyl α-(3ξ-chlorocarbonyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is mixed under ice-cooling with an ether solution of diazomethane prepared from 4 g of N-nitrosomethylurea. The resulting solution of benzyl α-(3ξ-diazoacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is mixed with 2.1 ml of ether containing 0.47 g of hydrogen chloride at 0° C., and after 2 hours, evaporated to yield 6.3 g of benzyl α-(3ξ-chloroacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as an yellow-brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)[CH3:4].[CH3:14]OC(C)=C.N1C=CC=CC=1.ClS(O)(=O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([CH3:14])([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH2:11])=[CH:12][CH:13]=1)[CH3:4].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1
Reactant: C=Cc1ccc(OC(C)OC)cc1
Reactant: C=C(C)OC
Agent: O=S(=O)(O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)(C)OC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) obtained in the same manner as described in Synthesis Example 3, (2) and 2-methoxy-1-propene (4.8 g) in a mixed solvent (35 ml) of pyridine and 1,4-dioxane, a catalytic amount of chlorosulfonic acid was added and then reacted with stirring at room temperature for 20 hours. After reaction, the reaction was carried out in the same manner as described in Synthesis Example 2, (3) to give 4.1 g of poly[p-(1-methoxy-1-methylethoxy)styrene/p-hydroxystyrene as a white powder having Mw 10000 (GPC with polystyrene calibration). The composition of the polymer was found to be p-(1-methoxy-1-methylethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of ca. 1:1 based on 1 HNMR.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1[N:19]=[CH:20]OC)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[NH2:27]>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:19]=[CH:20][N:2]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: COC=Nc1oc2c(c1C#N)CCN(C(=O)OC(C)(C)C)C2
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1

Procedure:
tert-Butyl 3-cyano-2-[(1-methoxymethylidene)amino]-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 47A (134 mg, 0.44 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (221 mg, 0.88 mmol) were heated in methanol (3.0 mL) in a microwave oven for 1 h at 160° C. The title compound was isolated by preparative HPLC to yield 18 mg (8%).