Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@H:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].N[C@H]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CC([O-])=O.C(O)(=O)C.C([O-])(=O)C.[Na+].C(=O)C1C=CC=CC=1>CO.C(O)C>[CH2:26]([NH:5][C@H:6]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](CC(=O)[O-])Cc1ccccc1
Reactant: CCOC(=O)C[C@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C[C@@H](Cc1ccccc1)NCc1ccccc1
Reaction time: 1 h

Procedure:
A total of 19.1 g of sodium cyanoborohydride (0.304 mol) is added in portions to a solution of 42.2 g (0.203 mol) of ethyl (R)-3-amino-4-phenylbutyrate obtainable by esterification of the known (R)-3-amino-4-phenylbutyrate with ethanol, 11.6 ml (0.203 mol) of glacial acetic acid, 33.3 g (0.406 mol) of sodium acetate and 20.9 ml ((0.207 mol) of benzaldehyde in 400 ml of methanol at -5° to 5°. After the addition is complete, reaction is allowed to go to completion at room temperature for 1 hour. The yellow suspension is almost completely concentrated in a rotary evaporator, and the pasty residue is partitioned between ethyl acetate and water which is adjusted to about pH 8 with ammonia solution. The organic phases are washed with water and brine until neutral, dried over magnesium sulfate and evaporated to dryness, resulting in a yellow oil. This is chromatographed on silica gel with methylene chloride/methanol 99:1, resulting in the title compound of the formula as a pale yellow oil. The oxolate is obtained by adding oxalic acid to an ethereal solution of the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:23]([CH2:30][CH2:31][CH3:32])[CH2:24][C:25]([O:27]CC)=[O:26].[O-]CC.[Na+].Cl>C(O)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:23]([CH2:30][CH2:31][CH3:32])=[C:24]([C:25]([OH:27])=[O:26])[N:3]=[N:2]3)=[CH:21][CH:20]=2)=[O:9])[CH2:14][CH2:15]1
Reactant: CN1CCN(CCNC(=O)c2ccc(N=[N+]=[N-])cc2)CC1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCN(C)CC2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 98.2 %

Procedure:
4-Azido-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide obtained in Example 63b) and ethyl 3-oxohexanoate (0.503 ml, 2.99 mmol, 1.25 eq.) were dissolved in ethanol (15 ml), sodium ethoxide (226 mg, 2.99 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. 1N hydrochloric acid (3.0 ml) was added to the reaction mixture, and the mixture was concentrated. The residue was diluted with acetonitrile (20 ml) and ethanol (40 ml), and the mixture was concentrated. Ethanol (15 ml), THF (20 ml) and ethyl acetate (20 ml) were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, containing sodium chloride, 1.04 g, 2.33 mmol, 98.2%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]=[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[N:17]([CH3:18])[C:13]=2[CH:12]=1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:27]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:22][CH2:21][CH2:20][CH2:19][C:16]1[N:17]([CH3:18])[C:13]2[CH:12]=[C:11]([CH2:9][OH:8])[CH:31]=[CH:30][C:14]=2[N:15]=1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCc1nc2ccc(C(=O)OC)cc2n1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)CCCCc1nc2ccc(CO)cc2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Lithium aluminum hydride (120 mg) was suspended in THF (3.0 ml) and then cooled to 0° C. After that, a solution of the compound (305 mg) obtained in Example 13-3 in THF (4.5 ml) was dropped in the suspension. The whole was warmed back to room temperature and stirred for 2 hours. After completion of the reaction, sodium sulfate decahydrate was gradually added to the solution until bubbling was stopped, and a 1 mol/l sodium hydroxide aqueous solution was then added to the mixture until a white precipitate was generated. Solid matter was separated by filtration and the solvent was then distilled off from the filtrate under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (246 mg) as a brown oily substance.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=3)=[N:22][CH:23]=[C:24]([F:26])[CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)=O.CO.[Pd]>[F:26][C:24]1[CH:25]=[C:20]([C:18]([NH:17][C@@H:14]2[CH2:15][CH2:16][C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]2)=[O:19])[C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[N:22][CH:23]=1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)c1
Reaction time: 2 h
Yield: 48.3 %

Procedure:
cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (1.75 g, 3.54 mmol) was dissolved in a solution of 4.4% formic acid in methanol (40 ml) and this was added dropwise to a suspension of palladium black (2 g) in 4.4% formic acid in methanol (120 ml) at room temperature under nitrogen. The mixture was stirred for 2 h, then filtered through arbocel washing with methanol (5×50 ml). The filtrates were concentrated under reduced pressure and basified to pH10 with 1M sodium hydroxide solution (50 ml). The aqueous phase was extracted with diethylether (3×50 ml) then acidified to pH1 with concentrated hydrochloric acid. After extraction with diethylether (3×50 ml) the combined organic extracts were washed with water (10 ml), dried over MgSO4 and the solvent removed under reduced pressure to give cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid (691 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].F[C:6]1[N:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[N:7]=1>C(OCC)C>[F:13][C:8]1[CH:9]=[C:10]([F:12])[N:11]=[C:6]([NH:4][CH2:1][CH2:2][CH3:3])[N:7]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: CCCN
Solvent: CCOCC
Product: CCCNc1nc(F)cc(F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.0 g (0.22 mol) of n-propylamine were added at -20° C. to a mixture of 13.4 g (0.1 mol) of 2,4,6-trifluoropyrimidine in 150 ml of diethyl ether within 20 minutes. After stirring at -20° C. for 1 hour and at 25° C. for 1 hour, the precipitate was filtered off, and the organic phase was washed with water, dried and concentrated under reduced pressure. 15.8 g (91.3% of theory) of the title compound were obtained as an oil (nD23 =1.4965).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[CH:11][C:10]=1[O:17][CH2:18][C:19]1[C:20]([C:25](=[O:28])[CH2:26]C)=[N:21][CH:22]=[CH:23][CH:24]=1>C1COCC1>[O:6]1[CH2:7][CH2:8][O:4][CH:5]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[CH:11][C:10]=1[O:17][CH2:18][C:19]1[C:20]([C:25]([OH:28])([CH3:1])[CH3:26])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)c1ncccc1COc1cnc(OC)cc1C1OCCO1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C2OCCO2)c(OCc2cccnc2C(C)(C)O)cn1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
Methylmagnesium bromide (3M/ether, 0.25 mL, 0.75 mmol, 3.0 eq.) was added to a stirred solution of 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (82 mg, 0.25 mmol, 1 eq.) in THF (5.0 mL) at −78° C. After addition, the reaction mixture was warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (38 mg, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=7.7, 1.6 Hz, 1H), 7.84 (dd, J=7.7, 1.5 Hz, 1H), 7.74 (s, 1H), 7.18 (dd, J=7.7, 4.7 Hz, 1H), 6.84 (s, 1H), 6.01 (s, 1H), 5.27 (s, 2H), 4.07-3.88 (m, 4H), 3.82 (s, 3H), 1.55 (s, 6H). LRMS (M+H+) m/z 347.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH2:15])[C:7]([C:16]([O:18]CC)=O)=[CH:6]2.Cl.[C:22]([C:27](=[NH:31])OCC)([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.C(O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:27]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:31][C:16](=[O:18])[C:7]1=[CH:6]2
Reactant: CCOC(=N)C(=O)OCC
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2nc1N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1

Procedure:
An alternative route to this product comprises heating a mixture of ethyl 6,7-dimethoxy-2-aminoquinoline-3-carboxylate (1.38 g., 5.0 mM), ethyl 1-carbethoxyformimidate hydrochloride (1.82 g., 10 mM), triethylamine (5.1 g., 5.0 mM), ethanol (50 ml.) and N,N-dimethylformamide (20 ml.) on a steam bath for 17 hours. The reaction mixture is cooled and the solid which separates filtered off, triturated with hot chloroform and then recrystallized from chloroform to give 0.170 g. of product. M.P. 273°-274° C. (dec.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Three drops of phosphoryl chloride were added to a stirred mixture of 5-bromopentanol (34.3 g, 205 mmol) and dihydropyran (19.0 g, 226 mmol). After standing for one hour, the mixture was fractionated. Yield 34.7 g, b.p. 102° C. (0.2 bar). Chromatography on alumina eluted with petroleum ether gave the pure title compound (25.1 g, 52% of theory) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[S:24])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=S)Nc2ccc(Br)cc21

Procedure:
The product was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and Lawesson's reagent using the procedure of Example 9, as a white solid: mp 221-222.5° C.; 1H-NMR (CDCl3) δ9.38 (s, 1H, D2O exchangeable), 7.42 (dd, 1H, J=8.5, 2.1 Hz), 7.29 (d, 1H, J=2.0 Hz), 6.76 (d, 1H, J=8.4 Hz), 1.76 (s, 6H); MS (EI) m/z 272 ([M+H]+, 94%), 274 ([M+H]+, 100%).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:12][N:13]([CH2:18][CH:19]=[CH2:20])[CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:4].[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH2:18]([N:13]([CH:14]1[CH2:15][CH2:16][CH2:17]1)[N:12]1[C:37](=[O:38])[C:36]([C:31]2[NH:30][C:29]3[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=3[S:33](=[O:35])(=[O:34])[N:32]=2)=[C:3]([OH:4])[CH:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]12)[CH:19]=[CH2:20]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: C=CCN(NC1CCCCCC1C(=O)OC)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCN(C1CCC1)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Yield: 31.9 %

Procedure:
2-(N′-Allyl-N′-cyclobutyl-hydrazino)-cycloheptanecarboxylic acid methyl ester (0.60 g, 2.16 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.72 mg, 2.16 mmol) was added followed by N-methylmorpholine (0.50 mL, 4.54 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.44 mg, 2.27 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with brine (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (20 mL). A 21% w/w solution of sodium ethoxide in ethanol (2.42 mL, 6.48 mmol) was added. The reaction was heated at reflux for 16 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (40 mL). The mixture was extracted with ethyl acetate (3×40 mL). The organic layer was further washed with saturated sodium bicarbonate solution (2×20 mL), aqueous saturated brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-5% methanol in dichloromethane) afford the desired product, N-{3-[1-(allyl-cyclobutyl-amino)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.39 g, 0.69 mmol, 32%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.38-2.14 (17H, m), 2.90-3.05 (3H, m), 3.14-3.97 (4H, m), 5.09-5.95 (3H, m), 7.16-8.02 (3H, m). LC-MS (ESI) calcd for C25H33N5O6S2 563.69, found 564.5 [M+H+].
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[CH3:3].B(Br)(Br)[Br:24].O>ClCCl>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:24])[C:13]=1[O:20][CH3:21])[CH3:3]
Reactant: CCN1CCCC1CNC(=O)c1c(OC)cccc1OC
Reactant: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1c(O)ccc(Br)c1OC
Yield: 80 %

Procedure:
To a solution of N-ethyl-2-(2,6-dimethoxybenzamidomethyl)pyrrolidine hydrochloride (23.0 g, 0.07 mole) in 300 ml of dry dichloromethane was added dropwise with stirring a solution of boron tribromide (17.5 g, 0.07 mole) in 25 ml of dry dichloromethane at 0° C. After the addition was completed the solution was allowed to reach room temperature over night. Water was added and pH adjusted to 7. The organic layer was washed with water and dried (MgSO4). The solvent was evaporated in vacuo affording the title compound as a viscous oil (20 g) which was judged by TLC and GC analysis to be sufficiently pure for use in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([F:13])[C:8]([CH2:9][OH:10])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=[CH2:3].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([F:13])[C:8]([CH2:9][O:10][C:28]([N:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]2[CH2:31][CH3:32])=[O:29])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: C=CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 87 %

Procedure:
This compound was prepared from 4-allyloxy-2-chloro-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (405 mg; 87%); MS (ISP): 474.4 (M+NH4)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].C([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)(=O)C>O>[CH:8]([C:29]1[N:25]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=2[OH:14])[C:19]([O:21][CH3:22])=[O:20])[CH:26]=[CH:27][CH:28]=1)=[O:9]
Reactant: COC(=O)c1ccc(OC(C)=O)c(-n2cccc2)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(O)c(-n2cccc2C=O)c1
Reaction time: 20 h

Procedure:
To a solution of phosphorus oxychloride (8.3 ml) and N,N-dimethylformamide (70 ml) was added methyl 4-acetoxy-3-(pyrrol-1-yl)benzoate (11.7 g) at ambient temperature and the mixture was stirred for 20 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tetrahydrofuran. To the solution was added 28% methanolic sodium methoxide (9.7 ml) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added acetic acid (6 ml) and evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 7 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from toluene, collected by filtration and the precipitate was washed with ether to give methyl 3-(2-formylpyrrol-1-yl)-4-hydroxybenzoate (7.89 g).
Reaction SMILES: [NH2:1][NH2:2].Cl.[C:4]([CH:6]1[C:10](=O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:5]>C(O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:5][C:4]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]=2[NH:1][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of anhydrous hydrazine (0.082 mL) in ethanol (6.5 mL) was added hydrogen chloride (1.43 mL, 2N solution in diethyl ether). The reaction mixture was stirred for 5 min, then tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate was added and the mixture heated to reflux. After 1 h the mixture was cooled to ambient temperature and diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution (1:1, 20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes followed by 0 to 20% methanol/ethyl acetate gradient) to give the title compound. LC/MS 225.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C>>[OH:23][CH2:22][CH2:21][CH2:20][N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=1
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1B from 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile and [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane: MS (APCI) m/z 327 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Reactant: Cc1cccc(CO)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(C)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
This compound was prepared by reacting 333 mg (1.295 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate with 0.31 mL (2.59 mmol) of 3-methylphenylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)tributylphosphorane (CMBP). The reaction mixture is stirred at 110° C. for 15 hours and then concentrated to dryness. The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate, to give 376 mg of the expected product in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-])=[O:2].[NH4+].[Cl-]>C(O)C.[Zn]>[OH:8][CH2:7][C:6]1[CH:5]=[C:4]([NH:1][OH:2])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: OCc1cccc(NO)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 3-nitrobenzyl alcohol (90) (1.53 g, 10 mmol) and NH4Cl (1.3 g, 24.3 mmol) in 86% aqueous ethanol (88 mL) was added zinc powder (2.6 g, 39.8 mmol). The resulting mixture was stirred vigorously at room temperature for 50 min. The mixture was filtered, and the solvent was poured into dichloromethane (450 mL). The solution was washed with water (10 mL) and dried (MgSO4), and the solvent was concentrated to about 15 mL with a rotary evaporator. The resulting solution was used in subsequent reactions without further purifications.
Reaction SMILES: BrC1C=CC(N(C)C(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=O)=CC=1.CN1CCNCC1.[CH3:59][N:60]([C:103]1[CH:108]=[CH:107][C:106]([N:109]2[CH2:114][CH2:113][N:112]([CH3:115])[CH2:111][CH2:110]2)=[CH:105][CH:104]=1)[C:61]([N:63]1[C:67]2[N:68]=[C:69]([N:97]3[CH2:102][CH2:101][O:100][CH2:99][CH2:98]3)[N:70]=[C:71]([C:72]3[CH:73]=[N:74][C:75]([N:78](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:76][CH:77]=3)[C:66]=2[CH2:65][CH2:64]1)=[O:62]>>[CH3:59][N:60]([C:103]1[CH:104]=[CH:105][C:106]([N:109]2[CH2:110][CH2:111][N:112]([CH3:115])[CH2:113][CH2:114]2)=[CH:107][CH:108]=1)[C:61]([N:63]1[C:67]2[N:68]=[C:69]([N:97]3[CH2:102][CH2:101][O:100][CH2:99][CH2:98]3)[N:70]=[C:71]([C:72]3[CH:73]=[N:74][C:75]([NH2:78])=[N:76][CH:77]=3)[C:66]=2[CH2:65][CH2:64]1)=[O:62]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(N4CCN(C)CC4)cc3)cn2)cc1
Agent: CN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(Br)cc3)cn2)cc1
Product: CN1CCN(c2ccc(N(C)C(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)cc2)CC1
Yield: 63 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-bromo-phenyl)-methyl-amide (121 mg) obtained in Step B instead of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide, and 1-methyl-piperazine (35.7 μl) instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid methyl-[4-(4-methyl-piperazin-1-yl)-phenyl]-amide was obtained. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-160) as a brown solid (54 mg, 63%).