Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.ClCCl.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1cc(Br)cc2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylate (9 g, 25 mmol) was dissolved in trifluoroacetic acid (6 mL) and stirred at room temperature for 16 hours. Dichloromethane and sodium hydroxide solution (2 M) were added and the organic layer washed twice with sodium hydroxide solution until the aqueous layer pH>7. The organic layer was then concentrated in vacuo to give 6.5 g (100%) of the title compound as a brown solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:33][CH2:34][N:35]([C:9]([C:8]3[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:14])[CH:7]=3)=[O:11])[CH2:36][CH2:37]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)COC2(CCNCC2)CN1Cc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)C(C)(C)CO3)ccc1OC(C)C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
A solution of 4-isopropoxy-3-methylbenzoic acid (31.0 mg, 0.161 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (61.3 mg, 0.161 mmol) in acetonitrile was treated with triethylamine (67 μL, 0.48 mmol) and stirred for 5 min. 8-Benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (56.0 mg, 0.161 mmol) was added and the reaction mixture stirred for 3 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by chromatography (0-80% of ethyl acetate/hexanes) to provide (8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (51.0 mg, 70%) as colorless oil. ESI-MS m/z calc. 450.6. found 451.3 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH2:11][OH:12])([CH3:10])[CH2:7][C:6]=2[C:13]=1[CH3:14].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:10][C:8]1([CH2:11][OH:12])[CH2:7][C:6]2[C:13]([CH3:14])=[C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]=2[O:9]1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CO)O4)CC2)cc1
Yield: 6.8 %

Procedure:
By using (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (360 mg, 1.16 mmol) synthesized in Reference example 123 and 1-(4-methylphenyl)piperazine (668 mg, 3.79 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 30 mg (yield 6%). Melting point was 152 to 155° C. (ethyl acetate-hexane).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]([CH2:29][C:30]1[CH:31]=[C:32]([CH:36]([CH2:39]/[CH:40]=[C:41](/[C:43]2[CH:52]=[CH:51][C:50]3[C:49]([CH3:54])([CH3:53])[CH2:48][CH2:47][C:46]([CH3:56])([CH3:55])[C:45]=3[CH:44]=2)\[CH3:42])[C:37]#N)[CH:33]=[CH:34][CH:35]=1)[Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O:59]CC)C>>[O:11]([CH2:29][C:30]1[CH:31]=[C:32]([CH:36]([CH2:39]/[CH:40]=[C:41](/[C:43]2[CH:52]=[CH:51][C:50]3[C:49]([CH3:54])([CH3:53])[CH2:48][CH2:47][C:46]([CH3:56])([CH3:55])[C:45]=3[CH:44]=2)\[CH3:42])[CH:37]=[O:59])[CH:33]=[CH:34][CH:35]=1)[Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: C/C(=C\CC(C#N)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C/C(=C\CC(C=O)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Diisobutylaluminum hydride (1.0M in hexanes, 1.54 mL, 1.54 mmol) was added dropwise to a solution of 26 (0.74 g, 1.18 mmol) in anhydrous diethyl ether (22 mL) at 0° C. under argon. The reaction mixture was allowed to warm to room temperature over 2.5 h. The reaction was quenched with ethyl acetate (2.5 mL) and 1N H2SO4 solution (5 mL) and stirring was continued for 10 min. The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted again with diethyl ether. The organic layers were combined, washed sequentially with 1N NaOH solution and saturated sodium chloride solution, and concentrated in vacuo to give 0.72 g (97%) of 27 as a dark yellow oil. 1H NMR showed the presence of trace impurities, but the compound decomposed on silica gel. The material was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ9.73 (s, 1H, CHO), 7.61-7.77 (m, 4H, ArH), 7.03-7.42 (m, 13H, ArH), 5.62 (t, J=9 Hz, 1H, CH=C), 4.78 (s, 2H, CH2OSi), 3.66 (t, J=6 Hz, 1H, CHCHO), 2.92-3.01 (m, 1H, 1×CH2CH), 2.55-2.67 (m, 1H, 1×CH2CH), 1.95 (s, 3H, C=CCH3), 1.66 (s, 4H, CH2CH2), 1.28 (s, 12H, 4×CH3), and 1.07 (s, 9H, SiC(CH3)3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C(N)CN>>[Si:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12]
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: NCCN
Product: CO[Si](CCCNCCNCCC[Si](OC)(OC)OC)(OC)OC
Temperature: 140 °C
Yield: 972.3 %

Procedure:
A 2 liter, 3-necked reaction flask equipped with a magnetic stirrer, electric heating mantle, dropping funnel and water condenser, containing 22.0 grams of NH2CH2CH2NH(CH2)3Si(OCH3)3 was heated to 140° C. whereupon the addition thereto of 198.0 grams of 3-chloropropyltrimethoxy silane (Cl(CH2)3Si(OCH3)3) was commenced. Cl(CH2)3Si(OCH3)3 was introduced dropwise to the reaction flask over a period of 1 hour while maintaining a temperature of 145° C. to 150° C. by the occasional application of a water bath. The resultant mixture was cooled to 75° C., and 90 grams of anhydrous ethylenediamine was added to the cooled mixture. Thereafter, the mixture was allowed to separate into layers with the upper product containing layer being separated therefrom and stripped by vacuum distillation of lowboiling volatiles to yield 370 grams of (CH3O)3SiC3H6NHC2H4NHC3H6Si(OCH3)3. Amine titration and 13C NMR and 29Si NMR analysis verified the assigned structure of the resultant product.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.NC1C=C[O:71]N=1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:71])=[C:25]([NH:31][C:32]3[CH:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 40 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 3-aminoisoxazole instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (32) (the second stage yield: 40%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]=[N+]=[N-])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
To a mixed liquid of 5.16 g of t-butyl[3-(azidomethyl)phenoxy]acetate and 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml of water, followed by stirring at room temperature for 4 days. The solvent was evaporated and diisopropyl ether was added thereto. The precipitated solid was separated by filtration and the solvent was evaporated again. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g of t-butyl[3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][CH:22]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Reactant: II
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.14 g, 0.35 mmol) (from Example 17, Step E, supra) in dichloromethane (20 mL) was added I2 (0.23 g, 1.75 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow foam. (Yield 0.12 g, 66%).
Reaction SMILES: [Na].[CH2:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=2)=[C:6]([O:18][CH3:19])[CH:5]=1)[CH3:3].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([CH2:2][CH3:3])=[CH:5][C:6]=2[O:18][CH3:19])[N:10]=1)[CH3:21]
Reactant: CCc1ccc(Oc2cccc(F)n2)c(OC)c1
Reactant: CCO
Agent: [Na]
Product: CCOc1cccc(Oc2ccc(CC)cc2OC)n1
Temperature: 80 °C
Reaction time: 26 h

Procedure:
To a solution of sodium (55 mg; 2.39 mmol), under argon, in ethanol (2 mL), was added 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (82 mg; 0.33 mmol). The reaction was heated to 80° C. for 16 hours then to 90° C. for 26 hours. The mixture was concentrated in vacuo. After quenching with saturated NaHCO3 (10 mL), extractions with ethyl acetate (3*5 mL), the organic phase was dried over NaSO4, and concentrated in vacuo to give the desired product as a light brown oil used without further purification (82 mg; 0.30 mmol; 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][CH2:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc([C@H]2CO2)cc1
Product: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
Charge a 10 L round bottom flask with (S)-2-(4-fluorophenyl)oxirane (880 g, 6.38 mol) under a nitrogen atmosphere. Add benzylamine (2047 g, 19.13 mol) while the mixture is maintained at 20° C. Heat the mixture to 80° C. and stir it at that temperature for 5 h. Cool to 22° C. and stir for 16 h. Add H2O (3 L) to quench the reaction. Filter and wash the filter cake with water (2×1 L). Slurry the solid obtained with heptane (2 L) and filter to give the title compound (1216 g, 77%). MS (m/z): 246 (M+1); ee value: 99.0% (AD-H 250 mm×4.6 mm×5 μm column using 90:10 hexanes (with 0.02% diethylamine):EtOH at 25° C. with a flow rate of 1.0 mL/min).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)O1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([F:34])([F:35])[F:36])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CC1(C)OB(c2ccc(C3(C(F)(F)F)CC3)cc2)OC1(C)C
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4,4,5,5-tetramethyl-2-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]-1,3,2-dioxaborolane according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H15F3N4, 369. Found, 369.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:26]([O-:28])=[O:27])=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:8]=[C:9](F)[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 850 %

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-fluoro-2-nitrophenylmethanesulfonyl]-naphthalene (0.42 g, 0.1 mmoles) and N-methylpiperazine (0.168 g, 1.1 mmoles) in DMF was stirred under nitrogen at 40° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound (0.45 g, 0.85 mmoles), identified by HNMR and mass spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][CH:3]=1.[CH3:10][O:11]C(N(C)C)OC.C(N(CC)CC)C.Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:5]1[NH:6][C:2]([Cl:1])=[C:3]([CH:10]=[O:11])[N:4]=1)[CH2:8][CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCCc1ncc(Cl)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C=O)c(Cl)[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-propyl-1H-imidazole (1.45 g, 10 mmol), dimethoxymethyldimethylamine (1.55 g, approximately 92 percent pure, 12 mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (50 ml) was heated for 1 hour at 80° C. and 2.5 hours under reflux, cooled to room temperature and poured into 2M hydrochloric acid (100 ml). The pH was adjusted to pH 1.97 by addition of 30 percent strength sodium hydroxide solution (19 ml) and the mixture was extracted three times, each time with 50 ml of ethyl acetate. The combined organic phases were dried and concentrated on a rotavapor. The yield of the product was 1.27 g (approximately 90 percent pure according to H--NMR), 66 percent based on 5-chloro-2-propyl-1H-imidazole. Other data concerning the product was:
Reaction SMILES: Cl[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)Cl.[OH:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].N1C=CN=C1>O>[Si:2]([O:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
1.87 g of chloro t-butyl diphenylsilane was dropped into 10 ml of methylene chloride solution including 1.64 g of (E)-5-hydroxy-N-phenyl-2-(phenylthiomethylene)pentanamide and 0.82 g of imidazole at room temperature. After stirring at room temperature for 2 hours, the resulting solution was added with water and extracted with ethyl acetate. The organic layer was washed 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.81 g the title compound.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[CH2:25]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N(C(=O)c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.006M) in DMF (25 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.3 g, 0.007M). The mixture was stirred at room temperature for 0.5 hours, and then benzyl bromide (1.2 g, 0.007M) was added dropwise. The reaction mixture was warmed to 60° C. and allowed to stir for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-benzyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].C1N2CN3CN(C2)C[N:22]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Br-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
Reflux 1.76 g. (0.005 moles) of 2-(2-bromoacetamido)-5-chlorobenzophenone, 2.80 g. (0.02 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide in 14 ml. of 85% (v/v) aqueous isopropyl alcohol for 2 hours. Pour the reaction mixture into water and extract with benzene. Dry the benzene solution over anhydrous sodium sulfate. Filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. In thin layer chromatography the product shows a single spot (silica gel GF plates, benzene-ethyl acetate-acetic acid=18:3:1), m.p. 213°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 1 h
Yield: 253.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 140° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 80 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixture poured into 1 L of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the solid which formed on stirring was collected. The Celite pad was washed well with methylene chloride, the methylene chloride removed and the residue was combined with the solid obtained from basification of the aqueous phase. The combined material was dissolved in refluxing ethanol (175 mL), and treated hot with 125 mL of water. The brown solid obtaing on cooling was additionally recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) yielded the aniline as a white solid (5.45 g, 25%); mp 128°-130° C. 1H-NMR (250 MHz, d6-DMSO): 6.32 (s, 2H, NH2)6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic) 7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH4): 216 (M+1). Analysis for C13H10FNO: Calculated: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.46; H, 4.82; N, 6.21.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[C-:25]#[N:26].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:25]#[N:26])=[O:5]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 1.00 g (2.4 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in DMSO (10 ml) at RT, 012 g of sodium cyanide was added. The reaction mixture was stirred at RT for one hour, poured on a saturated aqueous ammonium chloride solution and the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, EtOAc/Hex 9/1) afforded 0.31 g (36%) of 5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as a light yellow oil.