Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[CH2:7]([O:14][CH2:15][C:16](=[O:38])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][C:16]([OH:38])([CH2:5][CH2:4][CH:3]=[CH2:2])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCOCCC(=O)COCc1ccccc1
Reactant: C=CCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)(CCOCCCCCCCCCCCCCCCCCC)COCc1ccccc1
Reaction time: 1 h

Procedure:
1.12 g (8 mmol) of 4-bromo-1-butene in 15 ml of dry ether was reacted with 200 mg of magnesium turnings at reflux under a nitrogen atmosphere for 1 hour. The resulting Grignard reagent was cooled to -60° C. and then treated with 2.22 g (5 mmol) of the compound prepared in (b) above in 30 ml of ether. After 1 hour at -60° C., the mixture was warmed overnight to room temperature and then quenched with a saturated aqueous ammonium acetate solution and partitioned. The organic layer was then washed twice with ammonium acetate, washed with a saturated sodium chloride solution and dried over magnesium sulfate, after which time the solvent was removed under reduced pressure. Purification of the crude product was effected on silica gel employing a mixture of petroleum ether and diethyl ether as the eluent to yield a low melting solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 67.5 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate (35 mg, 0.13 mmol) and 1-(3-methoxy phenyl) piperazine (50 mg, 0.26 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (40 mg, 0.26 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 37 mg of the titled compound (yield, 68%). NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.22-3.30 (m, 4H), 3.75 (m, 4H), 3.80 (s, 3H), 4.13 (s, 3H), 6.46-6.49 (m, 2H), 6.55-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.52 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S(=O)(N[C@@H]1CCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A suspension of 4-chloro-N-(trans-2-hydroxymethylcyclopentyl)benzenesulfonamide (290 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and α-bromo-p-tolunitrile (253 mg, 1.2 mmol) in 2 mL dimethylformamide was stirred for 2 h. The reaction was diluted into 50 mL ethyl acetate and extracted with brine. The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 20 to 70% ethyl acetate in hexane over 25 min. to give 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (327 mg, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (2H, d, J=8.56 Hz), 7.57-7.63 (2H, m), 7.49 (3H, dd, J=10.83, 8.31 Hz), 4.64 (1H, d, J=16.62 Hz), 4.16 (1H, d, J=16.62 Hz), 3.99-4.12 (1H, m), 3.37-3.62 (2H, m), 1.99 (1H, t, J=6.17 Hz), 1.32-1.71 (7H, m). LC/MS R.T.=2.77 min; [M+H]+=404.12. HRMS [M+H]+ calc'd 405.1040, found 405.1054.
Reaction SMILES: C[Si](C)(C)C1C=C(Br)C=C([Si](C)(C)C)C=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].S(Cl)([Cl:33])=O>CN(C)C=O.C(Cl)Cl.C(C1C=CC(CCC(O)=O)=CC=1)(C)(C)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([Cl:33])=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Agent: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCC(=O)Cl)cc1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A 2 L 3 neck round bottom flask fit with a condenser, thermometer, nitrogen inlet, and overhead stirrer was charged with 3-(4-t-butylphenyl)propionic acid (118.7 g, 0.576 mol),thionyl chloride (210 mL, 2.88 mol), dimethylformamide (3 drops), and methylene chloride solvent. The reaction was refluxed for 3 hours and additional 3-(4-t-butylphenyl)propionic acid (8.17 g, 0.040 mol) was added to the reactor and refluxed for an additional hour. After allowing to stand overnight, the reaction was stripped of volatiles to yield the crude 3-(4-t-butylphenyl)propionyl chloride (99.0 g). 1HNMR (CDCl3, 500 MHz) δ7.33 (d, JAB=8 Hz, 2H); 7.12 (d, JAB=8 Hz, 2H); 3.20 (t, J=7.5 Hz, 2H); 2.98 (t, J=7.5, 2H); 1.31 (s, 9H).
Reaction SMILES: [CH3:1][O:2][P:3]([O-:5])[O-:4].[CH2:6]([Sn+2:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>>[CH2:1]([O:2][P:3]([O-:5])[O-:4])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19].[CH2:15]([Sn+2:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: COP([O-])[O-]
Reactant: CCCCCCCCCCCCO
Agent: CCCC[Sn+2](CCCC)CCCC
Product: CCCCCCCCCCCCOP([O-])[O-]
Temperature: 140 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
In a 500 ml four-neck round-bottom flask, as described in Example 1, 148.85 g of tributyltin oxide and 110 g dimethyl phosphite are heated with stirring to about 120° C. The reaction mixture is kept at this temperature for about 2 hours, dimethyl ether being split off. The reaction mixture is then heated with stirring under a vacuum of 20 to 5 mm Hg at 145° C, until the excess dimethyl phosphite has been distilled off. 193.3 g of tributyltin methyl phosphite are obtained. 128.5 g of tributyltin methyl phosphite and 68.7 g of lauryl alcohol are heated with stirring in a 500 ml four-neck round-bottom flask equipped with a stirrer, thermometer, standard taper glass stopper, stillhead with condenser, cooled distillate receiver and cold trap at 140° C for 5 hours, for one hour of which a vacuum (30 - 5 mm HG) is applied. Methanol is distilled off. 178 g tributyltin lauryl phosphite are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH:1]([O:4][C:5]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(OC(C)C)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC(C)C)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.61 g portion of 4-isopropoxy-2-methoxybenzoic acid was dissolved in 20 ml of acetic anhydride, 0.38 ml of concentrated nitric acid and a small amount of acetic acid were added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured on crushed ice, extracted with chloroform and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was dissolved in 5 ml of tetrahydrofuran and 5 ml of 1N sodium hydroxide aqueous solution, followed by stirring for 1 hour. The reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 0.43 g of 4-isopropoxy-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[N:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([OH:29])[C:27]=2[N:28]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:20]=[N:21][C:22]2[C:27](=[C:26]([O:29][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)[CH:25]=[CH:24][CH:23]=2)[N:28]=1
Reactant: Cc1cnc2cccc(O)c2n1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Temperature: 60 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol) and 3-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, prepared according to J. Med. Chem. 1988, 41, 4062-4079.) in DMF (3 mL) was added sodium hydride (0.040 g, 1.0 mmol, 60% dispersion in mineral oil, Aldrich). The reaction was heated at 60° C. for 24 h, allowed to cool to room temperature and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (4 x). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuum. The residue was purified by flash chromatography (0→75% EtOAc/hexanes) to give the title compound as an ivory powder. Mp: 139-141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][O:19]2.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][C@@H:18]3[CH2:24][C@H:21]2[CH2:20][O:19]3)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Reactant: C1O[C@@H]2CN[C@H]1C2
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc1c(N3C[C@@H]4C[C@H]3CO4)nc(Cl)nc12
Temperature: 140 °C
Yield: 97.6 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane (73 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in pentane) affording 3-chloro-8,8-dimethyl-1-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-5,6-dihydro-8H-7-oxa-2,4,4b, 9-tetraaza-fluorene as a yellow solid (120 mg, 98%). LCMS (method A): RT=2.81 min, [M+H]+=336.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([N:24]2[CH2:25][CH2:26][N:21]([C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH2:22][CH2:23]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 49 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 49%). MS (m/e): 475.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:15]([C:14]1[C:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:23])[CH3:22])[CH2:20][C:6]=2[C:7]2[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 0.5 mmol), acetic anhydride (0.1 g, 1 mmol) and triethylamine (0.2 g, 2 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 3 h. The solvent was removed by rotoevaporation, and the residue suspended in water and 2N HCl. The solid which formed was collected by filtration, washed with diethyl ether and dried to give the acetamide (0.14 g) in 88% yield. Anal. calc'd for C14H14N4O5.H2O: C, 50.00; H, 4.80; N, 16.66; found-C, 49.92; H, 4.77; N, 16.04.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19]C(N)=O.CS(C)=O.[OH-].[Na+]>O>[CH3:17][CH:16]([CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1)[CH3:18]
Reactant: NC(N)=O
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (4 g, 0.0154 mol), urea (18.5 g, 0.308 mol, 20 equiv.) and DMSO (26 ml) was heated under stirring at 145-150+C for 24 hours. Then, the reaction mixture was cooled to 80° C. and water (52 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (25 ml) at 70-80° C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80° C. under reduced pressure overnight to yield 3.13 g of crude imiquimod in 84.8% yield, having a purity of 99.4% by HPLC, (containing 0.6% of the compound II). The crude imiquimod was purified by the method presented in Example 1 to obtain 2.75 g of imiquimod in 87.8% yield; total yield: 74.4%; having a purity of 99.93% (by HPLC).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:4])[CH3:3].OS(O)(=O)=O.[CH2:40](O)[CH2:41][OH:42]>O>[OH:42][CH2:41][CH2:40][O:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reactant: OCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(OCCO)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 60 °C
Yield: 21 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.086 mmol, example 147) in ethylene glycol (4.93 mL) was added concentrated H2SO4 (0.5 mL, 9.38 mmol) at RT and heated at 60° C. overnight. The reaction mixture was cooled to RT, diluted with water, and extracted 5×DCM. The combined DCM layers were washed with brine, concentrated, and purified by reverse phase HPLC (Waters Sunfire 30×150 mm column, acetonitrile:water 0.1% TFA long 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (121 mg, 21%). MS (m/z) 505.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH2:29][CH:26]1[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]=2[F:24])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To the crude tert-butyl 2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate (800 mg, 1.63 mmol) dissolved in DCM (4 mL) in ice bath, was dropwise added TFA (2 mL) slowly, stirring for 10 min at which point nostarting material remained by TLC analysis. The solvent was removed and EtOAc added, which was washed with 2M HCl. The combined aq. solution was adjusted with NaOH to pH around 10, and the aq. layer extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent removed to get 450 mg of 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine, which was used in the next step directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][C:26]=3[Cl:27])[CH2:17][NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:26]1[CH:25]=[CH:24][C:16]([CH2:17][NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])=[C:3]([O:28][CH3:29])[CH:4]=2)[N:9]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1NC(=O)C1CC1
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using N-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-37, 0.050 g, 0.120 mmol), cyclopropylcarbonyl chloride (0.018 g, 0.180 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 0.77 (s, 4H), 1.60 (m, 1H), 2.08 (m, 1H), 3.88 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45 (m, 2H), 7.62 (s, 2H), 7.96 (d, J=8.4 Hz, 1H), 8.69 (m, 1H), 9.49 (s, 1H), 12.54 (s, 1H); MS (m/z): 482.10 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC1NCC2(CCN(C)CC2)S1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 0 °C

Procedure:
2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (982 mg, 5.28 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.10 ml, 7.92 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (910 mg, 5.60 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 150/10/1) to give AF717 (521 mg, 99.2% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 5.53, 5.26 (2q, J=6.12 and J=6.3 Hz, 1H, CHCH3), 4.67, 3.90 (2d, J=12.0 and J=11.35 Hz, 1H, CHHNCO), 3.48, 3.09 (2d, J=11.35 and J=12.0 Hz, 1H, CHHNCO), 2.78-2.59 (m, 2H, CH2N), 2.53-2.47 (m, 1H, CHCO), 2.30, 2.19 (2s, 3H, NCH3), 2.15-2.05 (m, 2H, CH2N), 2.02-1.84 (m, 2H, CH2CS), 1.74-1.61 (m, 4H, CH2CHCO), 1.55, 1.50 (2d, J=6.3 and J=6.12 Hz, 3H, CH3CH), 1.44-1.36 (m, 2H, CH2CS), 1.34-1.21 (m, 4H, CH2CH3), 0.93-0.87 (m, 6H, CH3CH2) ppm; 13C NMR (CDCl3, 300 MHz) δ 174.35, 174.04 (C), 59.13 (C), 57.35, 57.19 (CH), 54.52, 54.06 (CH2), 53.13, 52.77 (CH2), 46.09 (CH3), 43.77, 42.55 (CH), 38.37, 37.58 (CH2), 37.04, 36.20 (CH2), 35.76, 35.35 (CH2), 35.08, 34.77 (CH2), 26.01, 23.01 (CH3), 21.08, 20.98 (CH2), 20.73, 20.56 (CH2), 14.27, 14.22 (CH3) ppm.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15].[OH-].[Na+]>>[CH2:1]([O:8][CH:9]1[CH2:12][N:15]([CH3:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OCc1ccccc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 47 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane and 77.5 parts of monomethylamine (40% aqueous solution) were added to an autoclave and they were heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and 120 parts of 2 N-NaOH aqueous solution were added thereto. Then the mixture was heated to distill off excessive monomethylamine. The remaining liquor was extracted twice with 200 parts of ether, and the extract was washed with 100 parts of water, extracted with 100 parts of 2 N-HCl aqueous solution and further extracted with 50 parts of 2 N-HCl aqueous solution. The water layers were combined, washed with 50 parts of ether and made sufficiently alkaline with 2 N-NaOH aqueous solution. The liquor was extracted twice with 100 parts of ether, and the ether extract was washed in 50 parts of water and dried over anhydrous soduim sulfate. The solvent was distilled off and the residue was subjected to distillation to yield 8.3 parts of 3-benzyloxy-1-methylazetidine boiling at 80°-82° C. The yield was 47%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows: