Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH2:5][CH2:4][CH:3]=1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19].C(C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2CCC=1)(=O)C.BrN1C(=O)CCC1=O>N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH2:5][CH:4]([CH2:19][C:18]([OH:21])=[O:20])[CH:3]=1
Reactant: O=C1C2=C(C(=O)c3ccccc31)C(O)=CCC2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)C1=CCCC2=C1C(=O)c1ccccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC1C=C(O)C2=C(C1)C(=O)c1ccccc1C2=O
Reaction time: 8 h

Procedure:
1-hydroxy-3,4-dihydroanthraquinone is reacted with 2 moles of acetic anhydride in pyridine for 15 hours. The mixture is poured into water, when 1-acetyl-3,4-dihydro-anthraquinone separates. It is collected, washed and dried at 80° C. and 2 Pa absolute (15 torr). The 1-acetyl-3,4-dihydroanthraquinone is reacted with 2 moles of N-bromosuccinimide while suspended in boiling carbon tetrachloride under reflux for 2 hours. 1-acetyl-3-bromo-3,4-dihydroanthraquinone is collected, dissolved in acetone and treated with ethyl 2-bromoacetate and excess copper powder, under reflux, for 2 hours. The ethyl ester of 1-acetoxy-3(carboxymethyl)-3,4-dihydroanthraquinone is collected and hydrolysed by standing overnight in N sodium hydroxide solution under nitrogen. The free acid, 1-hydroxy-3(carboxymethyl)-3,4-dihydroanthraquinone is then obtained on acidification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S([O-])(=O)=O)=CC=2)=CC=1)C.[Na+].Cl>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([OH:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1O

Procedure:
To a solution of 5.15 g (20 mmol) 4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert. butylester 3-ethylester in 30 ml methanol was added 1.88 g (30 mmol) sodium cyanoborohydride and a small amount of methylorange. With stirring the pH was adjusted to 3 by dropwise addition of 1N hydrochloric acid (color change from yellow to orange). After no more acid was consumed the mixture was stirred for one hour. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with water, then with brine, dried over magnesium sulfate and evaporated. The residual yellow oil was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.C([N:36](CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:36])=[O:32])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(N)=O)CC3)cc2)c2ccccc2C)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 131.3 %

Procedure:
A mixture of (R)-1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-piperidine-4-carboxylic acid (100 mg, 226 μmol), triethylamine (229 mg, 2.26 mmol) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (218 mg, 678 μmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 15 min, then treated with ammonium chloride (96.7 mg, 1.81 mmol), then after 20 h partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to produce the crude title compound (131 mg), which was directly used in the next step. Yellow oil, MS (ESI+): m/z=442.4 ([M+H]+).
Reaction SMILES: CN(C)CCN.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][O:13][N:14]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=O)[CH2:45][CH3:46])[CH:31]=1>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=[N:14][O:13][CH2:12][C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH2:45][CH3:46])[CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(=NOCc1cccs1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.3 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(thiophen-2-ylmethoxy)phthalimide (365 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (1 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-{4-chloro-2-[1-(thiophen-2-ylmethoxyimino)propyl]phenyl}trifluoromethanesulfonamide 207 (364 mg, 85%), as a white solid. M.p. 53-54° C. 1H n.m.r. (400 MHz, CDCl3) δ 11.49, br s, 1H, 7.64, d, J=8.8 Hz, 1H, 7.47, d, J=2.4 Hz, 1H, 7.33) m, 2H, 7.16, m, 1H, 7.01, m, 1H, 2.82, q, J=7.6 Hz, 2H, 1.17, t, J=7.6 Hz, 3H. HRMS (M+) 426.0065.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[Na+].[I-]>CN(C)C=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:12]([C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(Nc1ccc(-c2ccccc2)s1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N(Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
The amide of Example 53 (2.8 g, 0.01 mole) in dimethylformamide (25 ml.) was added to sodium hydride (0.0105 mole) (from 40-50% NaH in oil, 0.74 g) which was stirred in dimethylformamide (25 ml.) and cooled in ice. The mixture was stirred for 0.5 hr. and treated with a solution of p-chlorobenzyl chloride (3.22 g, 0.02 mole) in DMF (15 ml.) and a trace of NaI. The mixture was stirred, initially at ice-bath temperature and then at room temperature overnight and then refluxed for 3 hours to complete the reaction. The DMF was evaporated off, water was added, the product extracted with chloroform, which was dried (Na2SO4), filtered and evaporated to give the N-p-chlorobenzyl-benzamide (2.07 g.) as a viscous oil, b.p. 240°-245° C./0.35 mm.Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:18]2[C:19](O)=[CH:20][C:21]3[O:25][CH2:24][CH2:23][C:22]=3[CH:26]=2)([CH2:16][OH:17])[C:7]1=[O:28])[CH3:2].ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:16][O:17][C:19]3[CH:20]=[C:21]4[C:22](=[CH:26][C:18]2=3)[CH2:23][CH2:24][O:25]4)[C:7]1=[O:28])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Yield: 63 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl[4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 63% yield as a colorless solid: MS (ES+) m/z 400.8 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+].CC1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.C1(C)C=CC=CC=1.CCCCCC>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:17][CH:16]=1
Reactant: Brc1ccc(Br)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
4.30 g (25.7 mmole) of carbazole, 18.19 g (77.1 mmole) of p-dibromobenzene, 0.14 g of palladium acetate and 0.33 g of 1,1′-bisdiphenyl phosphinoferrocene, 3.46 g of (36.0 mmole) sodium t-butoxide and 43 ml o-xylene were put in a 200 ml three-necked flask, and refluxed under stirring for 15 hours and 30 minutes under argon flow. The reaction mixture was filtered using a filter packed with alumina to remove insoluble matter, the filter was washed with toluene and tetrahydrofuran successively. The filtrate and wash liquid were combined and condensed under reduced pressure. Hexane was added to the residue, followed by heating and stirring, then insoluble matter was removed by filtration, and the filtrate was vacuum dried. Hexane was added to the residue and deposited crystal was filtered off. The filtrate was condensed, and refined by silica gel column chromatography (eluent:hexane/toluene:3/1), recrystallized with hexane to give 3.68 g of a white crystal of 9-(4-bromophenyl)carbazole (yield: 44.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:3]=1.[CH3:23][O-:24].[Na+].[Na]>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:22])([CH3:21])[CH2:10][CH:9]([C:4]3[CH:3]=[C:2]([O:24][CH3:23])[CH:7]=[CH:6][N+:5]=3[O-:8])[C:14]=2[CH:15]=1)#[N:20]
Reactant: CC1(C)CC(c2cc(Cl)cc[n+]2[O-])c2cc(C#N)ccc2O1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C2CC(C)(C)Oc3ccc(C#N)cc32)c1
Temperature: 25 °C

Procedure:
250 mg of 4-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide were dissolved in 6 ml of methanol and added to a solution of sodium methoxide prepared from 0.5 g of metallic sodium in 50 ml of methanol. The mixture was heated at reflux for 2 hours under a nitrogen atmosphere and then allowed to cool to room temperature. The solution was evaporated and the residue was taken up in ethyl acetate and water, the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 20% (v/v) methanol/ethyl acetate for the elution to give a solid which was recrystallized from ethyl acetate. There were obtained 65 mg of 2-(6-cyano-3,4 -dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-4-methoxypyridine N-oxide of melting point 196°-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.C([Li])(C)(C)C.[C:21](=[O:23])=[O:22].O>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([OH:23])=[O:22])[CH:8]=2)[S:3]1
Reactant: O=C=O
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCCCC
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2S1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 240 mg (0.84 minol) of 2,2,4,4-tetramethyl-6-bromothiochroman in 1 ml of dry ether at -78° C. was added, dropwise under nitrogen, 1 ml of 1.7M (1.7 mmol) tert-butyl lithium in pentane. The reaction mixture was stirred at -78° C. for a further 2 h and then treated quickly with an excess of dry ice. The reaction mixture was warmed to room temperature and treated with 1 ml of water and 1 ml of ether. The aqueous layer was separated and the organic layer was extracted with 4×5 ml of water. The aqueous extracts were combined, acidified with HCl to a pH of 2 and then extracted with 2×15 ml of ether. The ether extracts were combined, washed with water and saturated NaCl solution and then dried (MgSO4). The ether solution was filtered and the solvent removed in-vacuo to give the title compound as a white solid. PMR (CDCl3): δ1.42 (6H, s), 1.43 (6H, s), 2.03 (2H, s), 7.50 (1H, d, J~8.4 Hz), 7.81 (1H, dd, J~8.4 Hz, 1.8 Hz), 7.89 (1H, d, J~1.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[H-].[Na+].CC1C=CC(S(O[CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])(=O)=O)=CC=1.O>CS(C)=O>[CH3:41][N:40]([CH2:39][CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:16]=1)[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47]
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 44; 200 mg, 0.62 mmol) in dimethylsulfoxide (8 ml) was added sodium hydride (17.98 mg, 0.75 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. 2-[{[(1,1-Dimethylethyl)oxy]carbonyl}(methyl)amino]ethyl 4-methylbenzenesulfonate (247 mg, 0.75 mmol) in dimethylsulfoxide (8 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to yield the title compound as a yellow oil. 140 mg.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[C:33]=1[OH:40].[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4OC5C=CC=C(C)C=5N=4)=[CH:53][CH:52]=3)[C:43]=12>>[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:75][CH2:76][N:77]([CH3:80])[CH2:78][CH2:79]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4[O:40][C:33]5[C:34]([Cl:39])=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=5[N:31]=4)=[CH:53][CH:52]=3)[C:43]=12
Reactant: Nc1cc(Cl)cc(Cl)c1O
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(Cl)cc(Cl)c6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dichloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-4,6-dichlorophenol (0.044 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4042235). The compound was formed as an off-white solid (0.008 g, 6%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=8.93 min., 95%; m/z 594 (MH+).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][C:8]([Cl:19])=[CH:7][CH:6]=2.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([NH:3][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1)=[C:17]1[C:12]([CH2:13][CH2:14][CH2:15][C:16]1=[O:18])=[N:11]2
Reactant: Nc1c2c(nc3cc(Cl)ccc13)CCCC2=O
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3cc(Cl)ccc3c(NCc3ccc(F)cc3)c21
Temperature: 0 °C

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were added 9.00 g of 9-amino-6-chloro-3,4-dihydroacridin-1(2H)-one and 3.10 g of tetrabutylammonium hydrogen sulfate catalyst. The mechanically stirred solution was warmed to reflux (90° C.) and 9.54 ml of 4fluorobenzyl bromide in 50 ml of toluene was added dropwise over 0.5 hours. After refluxing 3 hours the reaction was complete by TLC. It was poured into 500 ml of ice. The aqueous phase was separated and extracted with dichloromethane (DCM hereafter). The organic layers were combined and washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was purified by preparative HPLC (1:1 ethyl acetate/hexane) and the product-containing fractions were combined and evaporated to a solid. The solid was crystallized from 1:1 DCM/pentane to yield 6.10 g of solid, mp 156°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12](O)([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C-]#[N:17].[K+].C(OCCCC)CCC.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH2:17])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC(C)(C)O)cc1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(CCCC(C)(C)N)cc1
Yield: 23.3 %

Procedure:
To a stirred mixture of 52.5 g. (0.253 mole) of 4-(4-methoxyphenyl)-1,1-dimethylbutyl alcohol, and 44.5 g. (0.685 mole) of powdered potassium cyanide in 200 ml. of n-butyl ether at 60° C. was added dropwise over 1 hour 80 ml. of concentrated sulfuric acid. The temperature was maintained at 60°-65° C. throughout the addition and stirring was continued at 50°-55° C. an additional hour after the addition was complete. The reaction mixture was then poured into 850 ml. of ice, made basic with 35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts were evaporated to dryness and the residual oil heated under reflux 3 hours in 125 ml. of 12N hydrochloric acid. The resulting mixture was diluted with 300 ml. of water and washed with a mixture of ether and benzene. The aqueous layer was made basic with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The organic layer was then extracted with 1N hydrochloric acid, the acidic aqueous layer made basic with 35% aqueous sodium hydroxide and extracted with an etherbenzene mixture. The extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo affording 12.2 g of 4-(4-methoxyphenyl)-1,1-dimethylbutylamine as a straw-colored oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:23])[N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:6][CH:7]=1.[C:24]([NH:31][CH2:32][C:33](O)=[O:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33](=[O:34])[NH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:23])[S:6][CH:7]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: NCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 29 %

Procedure:
Prepared in 29% yield (40 mg) as described in general procedure (K) from 3-(4-aminomethylthiazol-2-yl)-1,1-dicyclohexyl-urea (96 mg, 0.28 mmol) and Boc-glycine (60 mg, 0.30 mmol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@:5]12[CH2:17][CH2:16][CH2:15][N:6]1[C@@H](C(Cl)(Cl)Cl)[O:8][C:9]2=O)[CH3:3].[NH3:18]>CO>[CH3:1][N:2]([CH2:4][C@@:5]1([C:9]([NH2:18])=[O:8])[CH2:17][CH2:16][CH2:15][NH:6]1)[CH3:3]
Reactant: N
Reactant: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Solvent: CO
Product: CN(C)C[C@@]1(C(N)=O)CCCN1
Temperature: 50 °C

Procedure:
A mixture of (3R,7aR)-7a-dimethylaminomethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (0.26 g) and 7M ammonia in methanol (4 ml) is heated at 50° C. for 3 days in a sealed vessel. The cooled reaction mixture is then evaporated to give the title compound as a brown oil which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([CH:13]([CH:16]=O)[CH:14]=[O:15])([O-:12])=[O:11]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:16]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: O
Product: COc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To the HCl salt of 3-methoxy-phenylamine (4.6 g, 289 mmol) in 1N HCl (300 mL) was added a solution of 2-nitro-malonaldehyde (2.7 g, 19.3 mmol) in 150 mL water. After 30 min, the precipitate was filtered and rinsed with 0.1 N HCl. Air-drying in a Büchner funnel for 18 h gave 3.36 g (78%) of a light yellow/green powder. LC/MS (m/z): 245.1 (MH++Na), Rt 2.21 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:24]([C:25](OC)=[O:26])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([C:13]2[C:24]([CH2:25][OH:26])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a suspension of 80% lithium aluminum hydride (100 mg, 2.16 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 2-phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (160 mg, 0.544 mmol) in tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred for 30 min. Sodium sulfate decahydrate (1.7 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate), and further washed with diisopropyl ether to give the title compound (132 mg, yield 90%).