Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: Cc1nccn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 54.0 g of 2-methyl-1-(p-nitrophenyl)imidazole, 2.87 g of palladium black, 36.7 g of sodium formate and 47.4 ml of formic acid in 1100 ml of methyl alcohol is stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture is filtered and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is crystallized from ether:ethanol to give 34.9 g of the desired product as a solid, m.p. 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](OC)=O>>[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Nc1ccncc1S(N)(=O)=O
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)CC1=NS(=O)(=O)c2cnccc2N1
Temperature: 180 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
4-amino-pyridine-3-sulfonic acid amide (0.25 g, 1.44 mmol) was suspended in malonic acid dimethyl ester (5 mL, 43.75 mmol). The flask was purged with nitrogen and the mixture was stirred at 180° C. for 60 min. Upon cooling, the mixture was diluted with ethyl acetate (5 mL) causing immediate precipitation of an undesired side product. The solid was removed by vacuum filtration and rinsed with ethyl acetate (2 mL). The filtrate was passed through a plug of silica gel, eluting with ethyl acetate followed by 5% methanol in ethyl acetate. The fractions containing the 5% methanol in ethyl acetate were combined and concentrated in vacuo to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetic acid methyl ester (0.135 g, 0.529 mmol, 37%) as a yellow oil. LC-MS (ESI) calculated for C9H9N3O4S 255.03, found 256.0 [M+H+].
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][OH:24])[C@H:16]([OH:17])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
2-(Isopropylamino)-4,5,6-trichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.00 g, 1.86 mmol), sodium carbonate (0.26 g, 2.45 mmol), water (4 mL), methanol (6 mL) and ethanol (8mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.57 g (75%) of a white powder; m.p. 223-224° C. Anal. Calcd for C15H18Cl3N3O4: C, 43.87; H, 4.42; N, 10.23. Found: C, 43.63; H, 4.55; N, 9.98.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:14](O)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])(C)(C)C.OC1C=CC2C(=CC=CC=2)N=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.C(OC(NC[C@@H]1CN(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1)=O)(C)(C)C.C(OC([NH:67][CH2:68][C:69]([NH:71][C@H:72]1[CH2:76][N:75](C(OC(C)(C)C)=O)[C@H:74](C(O)=O)[CH2:73]1)=[O:70])=O)(C)(C)C>>[NH2:67][CH2:68][C:69]([NH:71][C@H:72]1[CH2:76][NH:75][C@H:74]([C:6]([NH:8][C@@H:9]([CH2:14][S:35][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH2:73]1)=[O:70]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)NC[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Oc1ccc2ccccc2n1
Product: CC(C)C[C@H](CSc1ccc(Cl)cc1)NC(=O)[C@@H]1C[C@@H](NC(=O)CN)CN1

Procedure:
This corpound was prepared as for Compound M48, replacing N-tert-butoxycarbonyl-D-homophenylalaine with N-tert-butoxycarbonyl-D-leucine, 2-hydroxyquinoline with 4-chlorothiophenol and trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline with trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:16][F:17])[C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[OH:5].[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].C(N(CC)CC)C>C(O)C>[C:18]([CH2:20][C:21]([NH:2][C@H:3]([CH2:16][F:17])[C@H:4]([OH:5])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)=[O:22])#[N:19]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc1

Procedure:
A mixture of (1R,2S)-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol hydrochloride (5.66 g; 20 mmol), absolute ethanol (27 ml), ethyl cyanoacetate (22.62 g; 200 mmol) and triethylamine (3.03 g; 30 mmol) was refluxed for 21 hours.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>CCO>[OH:10][N:9]=[C:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccccc1
Yield: 99.9 %

Procedure:
Benzonitrile (0.99 cm3, 1 g, 9.7 mmol) and hydroxylamine (50% in water, 0.89 cm3, 0.96 g, 14.55 mmol, 1.5 eq) were stirred under reflux in EtOH (10 cm3) for 48 hours. The solvent was evaporated under reduced pressure and water (10 cm3) was added to the residue. The mixture was extracted with dichloromethane (100 cm3) and the organic extract was evaporated under reduced pressure. The residue was purified by column chromatography to give the product N′-hydroxybenzimidamide (1.32 g, 100%) as a white crystalline solid, mp 79-81° C. (lit 79-80° C. This procedure is suitable for all starting materials bearing a benzene ring.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6].C(=O)([O-])O.[Na+]>O>[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6]
Reactant: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
12 ml of a 3:1 by volume mixture of acetic acid and water were added to 300 mg of 5-{4-(3-ethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), and the resulting mixture was stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 210-212° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:66]4[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]4)=[O:20])=[CH:21][CH:22]=3)[S:13][C:6]=12
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CC[C@@H](O)C5)cc4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
A capped vial was charged with 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzoic acid (0.100 g, 0.168 mmol), HOBT-H2O (0.103 g, 0.671 mmol), EDCI (0.129 g, 0.671 mmol), and DMF (2 mL). After stirring for 45 minutes, (R)-pyrrolidin-3-ol (0.0584 g, 0.671 mmol) and Hunig's base (0.175 ml, 1.01 mmol) were added. After stirring for 18 hours, water (20 mL) was added. The formed precipitate was isolated by filtration. After drying, (62 mg, 55%) of product was isolated as orange solid. LRMS (esi+) 666 m/z (M+1) detected. 1H NMR (CDCl3, 400 MHz) δ 11.84 (s, 1H), 8.47 (s, 1H), 8.39 (d, J=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.97 (m, 1H), 7.76 (m, 3H), 7.62 (m, 4H), 7.39 (d, J=9 Hz, 1H), 7.26 (m, 3H), 6.52 (d, J=6 Hz, 1H), 4.50 (br s, 1H), 3.72 (m, 5H), 2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:10]#[N:11].CO.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:10]#[N:11]
Reactant: Cc1ccccc1N=C(C#N)c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1NC(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a stirred mixture of 2.9 parts of 2,6-dichloro-α-[(2-methylphenyl)imino]benzeneacetonitrile in 50 parts of methanol are added portionwise 0.2 parts of sodium borohydride. Upon completion the mixture is stirred during 0.5 hours and 100 parts of water are added. The precipitated produce is filtered off and recrystallized from 30 parts of 2-propanol, yielding 2.4 parts (82.1%) of 2,6-dichloro-α-[(2-methylphenyl)amino]benzeneacetonitrile; mp. 107.7° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][SH:9].[CH3:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:8]([S:9][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCS
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCCCCCCCSCCC(=O)OC
Reaction time: 3 h
Yield: 143.6 %

Procedure:
Into the same type of equipment used in Example 1, 146 grams of 1-octylthiol was added over a 40 minute period with stirring to 0.7 grams of benzyl trimethyl ammonium hydroxide and 180.6 grams of methylacrylate. Over the 1/2 hour period, the temperature of the reaction went from 25° C. to 60° C. The reaction was stirred an extra 3.0 hours wherein the temperature went from 60° C. to 28° C. The reaction mixture was stripped at 102° C. and 15 mm pressure. 333 grams of product was obtained having a purity of approximately 96.4% as measured by GC analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]CC2C=CC=CC=2)(=[O:15])=[O:14])=[O:11])[N:3]=1.C(OCC1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OCc2ccccc2)n1
Solvent: CC(C)=O
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2O)n1

Procedure:
A stirred solution of 0.5 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-(benzyloxy)benzenesulfonamide (from b, above) in 20 ml of trifluoroacetic acid was boiled under reflux for 1.5 hours. The proton magnetic resonance spectrum indicated complete cleavage of the benzyl ether. The trifluoroacetic acid was evaporated in vacuum and the oily residue stirred with water and diethyl ether, providing white solid. The solid was dissolved in acetone and reprecipitated by dilution of the solution with hexane, yielding N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-hydroxybenzenesulfonamide as a white solid, m.p. ca. 180°. The mass spectrum showed a molecular ion, m/e 322; ##STR38## and no m/e 91 (no Ph--CH2+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:43]=1)=[O:8]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C=Cc2ccccc2Cl)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a mixture of 11.50 g. (63 mMol) o-chlorocinnamic acid, 200 ml. anhydrous tetrahydrofuran and 6.38 g. (63 mMol) anhydrous triethylamine, there are added dropwise at -15° C., 7.50 g. (69 mMol) ethyl chloroformate. The reaction mixture is then stirred for 15 minutes at -15° C. Subsequently, a solution of 15.80 g. (63 mMol) ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate in 50 ml. anhydrous tetrahydrofuran is added dropwise thereto and the reaction mixture is stirred for a further 2 hours at -10° C. and then left to stand for a day at ambient temperature. Thereafter, the tetrahydrofuran is distilled off in a vacuum and the residue is taken up in methylene chloride. The methylene chloride phase is extracted with 0.5 N aqueous sodium hydroxide solution, filtered, dried over anhydrous sodium sulphate and evaporated. After recrystallization of the residue from a mixture of ligroin and acetone (30:5 v/v), there is obtained, in a yield of 65% of theory, ethyl 2-{4-[2-(2-chlorocinnamoylamino)-ethyl]-phenoxy}-2-methylpropionate, which melts at 76° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.I[CH2:11][CH2:12][CH2:13][CH3:14].[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20])[CH2:12][CH2:13][CH3:14]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)NO
Reactant: CCCCI
Product: CCCCOc1ccccc1C=[N+]([O-])C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 28 using 2-hydroxybenzonitrile, 1-iodobutane and N-tert-butylhydroxylamine. The title compound was isolated in 77.4% overall yield as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[I-:37].[K+].[OH-].[K+].BrCCCCCCCCCC>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][C:9]([I:37])=[CH:8][CH:7]=3)[C:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:13]=2[CH:14]=1
Reactant: [I-]
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Agent: CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 24 h
Yield: 81 %

Procedure:
To a mechanically stirred mixture of 7-iodo-2-bromofluorene (example 2; 41.34 g, 0.1 114 mol), DMSO (100 mL), potassium iodide (1.79 g), and powdered potassium hydroxide (28 g) cooled in a cold water bath, 1-bromodecane (53 mL) was added dropwise, and the mixture was stirred for 24 hours. The oil that separated on dilution with water, was extracted with toluene. Toluene extract was washed with water, dried and concentrated. The residual oil was passed through a column of 300 g alumina. Elution with 900 mL hexanes gave the product as an oil, 65 g. This was left in 200 mL of isopropanola when the product solidified, 58.63 g (81% yield), m.p. 43-45° C. Mass Spec. (m/z): 698 (M+ diiodo), 650, 652 (M+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:24])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:25](O)(=[O:27])[CH3:26]>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:24])[CH2:2][NH:1][C:25](=[O:27])[CH3:26])[N:10]=[CH:9][N:8]=2)=[CH:17][C:18]=1[CH3:23]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 90 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol (obtained as described in Example 82, preparation of starting materials) to give N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide as a ginger solid in 90% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.76 (s, 3H), 2.17 (s, 3H), 3.41 (dt, 1H), 3.62 (dt, 1H), 4.96 (m, 1H), 6.85 (d, 1H), 7.31 (d, 1H), 7.36 (m, 2H), 7.49 (d, 1H), 7.96 (t, 1H), 8.24 (t, 1H), 8.77 (s, 1H), 9.57 (s, 1H), 10.77 (s, 1H); Mass spectrum MH+ 367.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].Cl[C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1.Cl.C([C:34](CC)([C:38]([O-:40])=[O:39])C([O-])=O)C>>[CH2:1]([O:40][C:38](=[O:39])[CH2:34][C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.25 h

Procedure:
To 20 ml of diethylmalonate was added 1.9 g (16.8 mmol) of potassium tertiary butoxide with stirring under nitrogen, and after 15 min, 2.0 g (5.59 mmol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine was added. The reaction was kept at 110° C. for 2 hr and 140° C. for 4 hr. Ice was added to the reaction mixture which was then acidified with concentrated hydrochloric acid, and extracted with 100 ml of ether. The ether layer was extracted with 25 ml of 3N hydrochloric acid, and the combined acid layers were made basic with ammonium hydroxide and extracted with ether (2×100 ml). The solution was dried, charcoal filtered and concentrated to a small volume. Petroleum ether was added and the product was filtered and recrystallized from the same solvents to give white rods, mp 98°-103° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[C:29](Cl)[N:28]=1>>[CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:29]3[C:30]([Cl:34])=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[N:28]=3)[CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2]
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)c(F)c1
Yield: 84.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (387 mg) described in Preparation Example 160 and 2,3,5,6-tetrachloropyridine (358 mg), the title compound (495 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH2:7]CO)[CH2:4][O:3]1.[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([S:20][CH3:21])[N:17]=[C:16]2[NH:22][N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:15]=12.[OH2:32]>O1CCOCC1.C(OCC)(=O)C>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:15]2[C:16](=[N:17][C:18]([S:20][CH3:21])=[N:19][C:14]=2[O:32][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:6]2)[NH:22][N:23]=1
Reactant: CC1(C)OC[C@@H](CCO)O1
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1nc(OCC2COC(C)(C)O2)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (R)-2,2-dimethyl-1,3-dioxolane-4-ethanol (2.12 g) in 10 mL dioxane was added sodium hydride (0.656 g) at 0° C. The resulting mixture was stirred for 10 minutes, and then 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.213 mmol) was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. Water (150 mL) and ethyl acetate (300 mL) was added, and the layers separated. The aqueous layer was washed four times with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes) to yield 1.03 g of 3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=407. Mp.=119.5-122.3° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CO>>[CH3:27][N:19]([CH2:18][CH2:17][N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-methyl-5-nitro-1H-isochromen-1-one (270 mg, 0.0012 mol), tert-butyl 2-aminoethylmethylcarbamate (400 mg, 0.002 mol), triethylamine (0.6 mL, 0.005 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 100° C. for 1.5 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product as a brown oil.