Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C[Si](Cl)(C)C>C(O)CCC>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:2]3[N:3]=[C:4]([N:23]4[CH2:24][CH2:25][CH:26]([CH2:29][NH2:30])[CH2:27][CH2:28]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4c(C#N)c[nH]c4n3)cc2)CC1
Temperature: 135 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
A mixture of tert-butyl (1-(2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (180 mg, 0.330 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (137 mg, 0.625 mmol) and TMSCl (0.300 mL, 2.37 mmol) in nBuOH (5 mL) was stirred at 135° C. for 48 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 474.5 (M+H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([NH:15][C@@H:16]([CH3:30])[CH2:17][N:18]2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[CH:13][CH:12]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCCl>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([Br:10])[CH:20]=2)[N:15]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[C@@H:16]([CH3:30])[CH2:17]1
Reactant: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
N,N-Diisopropylethylamine (0.041 mL, 0.232 mmol) was added to a solution of (S)-2-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]oxazole (0.016 g, 0.046 mmol) and cyclopropanecarbonyl chloride (0.021 mL, 0.232 mmol) in 1,2-dichloroethane (1.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was partitioned between water and dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(4-(benzo[d]oxazol-2-yl)-6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (0.019 g, 99%) as a brown oil. MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:10][CH:11]=1
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cn1ccnc1)c1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
A solution of 7.8 g of 2-[2'-(1H-imidazol-1-yl)acetyl]-5-chloropyridine in 40 ml of methanol is charged at 0°, in portions, with 2.0 g of sodium borohydride. The mixture is stirred for one hour at 0°. For working-up the mixture is decomposed by careful addition of 1N hydrochloric acid at 0°, followed by 1N sodium hydroxide to reach a pH of 9. The solvents are evaporated in vacuo. The residue is stirred with water and dichloromethane, the aqueous phase is extracted twice with dichloromethane and the combined organic extracts are washed with brine, dried and evaporated. The compound is obtained as a cream coloured solid; m.p.: >210° (decomp.). Purification is possible by chromatography over silicagel.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][O:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1C[O:18]CC1>>[OH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:1]([OH:14])=[O:18]
Reactant: C1CCOC1
Reactant: O=C1OCCc2c1[nH]c1ccccc21
Product: O=C(O)c1[nH]c2ccccc2c1CCO
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4,9-dihydro-3H-pyrano[3,4-b]indol-1-one (Arch. Pharm., 1987, 320, 1202–1209, 5.225 g, 27.9 mmol) in THF (25 mL) was added deoxygenated 3 N KOH (25 mL). The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was washed with EtOAc, acidified with 1 N HCl, and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated to give 5.589 g of 3-(2-hydroxyethyl)-1H-indole-2-carboxylic acid as a solid. This material was used for the next reaction without further purification: 1H NMR (DMSO-d6) δ 3.26 (t, J=7.5 Hz, 2H), 3.63 (t, J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H). Anal. Calcd. for C11H11NO3.0.1 EtOAc: C., 63.98; H, 5.56; N, 6.54. Found: C, 63.90; H, 5.57; N, 6.46.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH:8]=[C:7]2[SH:15].[Si:16]([O:33][CH2:34][C@@H:35]1[CH2:40][C@H:39](OS(C)(=O)=O)[CH2:38][CH2:37][N:36]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH:8]=[C:7]2[S:15][C@H:39]1[CH2:38][CH2:37][N:36]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[C@H:35]([CH2:34][O:33][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=c1[nH]cc(S)c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2c[nH]c(=O)c3ccc(Br)cc23)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
Sodium borohydride (97 mg) was added to a degassed solution of 6-bromo-4-sulfanylisoquinolin-1(2H)-one (Example 58a, 0.54 g) in ethanol (20 mL) at room temperature with effervescence. The resulting mixture was stirred at room temperature for 10 min before being heating to 85° C. A degassed solution of tert-Butyl (2S,4R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(methylsulfonyl)-oxy]piperidine-1-carboxylate (Example 67d, 1.17 g) in ethanol (3 mL) and potassium carbonate (0.353 g) were added to the orange solution and the reaction was heated for 1 h, cooled to room temperature and concentrated in vacuo. Purification (SiO2 chromatography, elution gradient 25% to 40% ethyl acetate in isohexane) afforded the subtitle product (0.68 g) as a white foam.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7]1>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[CH2:7]1[C:8]2[C:13](=[C:12]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][CH:9]=2)[CH2:14][NH:6]1
Reactant: COc1ccc(CN2Cc3cccc(OCCN(C)C)c3C2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN(C)CCOc1cccc2c1CNC2
Yield: 242.4 %

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-4-(2-dimethylamino-ethoxy)-2,3-dihydro-1H-isoindole (170 mg, 0.48 mmol) in trifluoroacetic acid (0.5 mL) and anisole (0.5 mL) was heated at 150° C. under microwave irradiation for 10 minutes. The mixture was diluted with ethyl acetate and extracted twice with water. The combined aqueous extracts were concentrated to give the title compound as a purple oil (240 mg, including residual TFA and/or water). 1H NMR (methanol-d4) 7.42 (1H, t), 7.07 (1H, d), 7.04 (1H, d), 4.64 (4H, br.s), 4.47-4.44 (2H, m), 3.65-3.63 (2H, m), 3.01 (6H, s). MS: [M+H]+ 207.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=O)[C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1([NH2:61])[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1)=[O:51])[CH3:48]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:47]([O:49][C:50]([C:52]1([NH:61][C:9]([C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=3[S:6][CH:7]=2)=[O:11])[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1)=[O:51])[CH3:48]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1csc2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1(NC(=O)c2csc3ccc(Cl)cc23)Cc2ccccc2C1
Yield: 96.3 %

Procedure:
To a 40 mL vial containing a stirring bar, 5-chloro-benzo[b]thiophene-3-carboxylic acid (518 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8.0 mmol) are added. Then 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 20 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.64 g of off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 7 through 31 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.94 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[N+]([C:15]1C=CC=CC=1S(Cl)(=O)=O)([O-])=O.IC.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CS>C(N(CC)CC)C>[CH3:15][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CI
Product: CNc1cccc(NC(C)=O)c1

Procedure:
N-(3-Aminophenyl)acetamide was treated with 2-nitrophenylsulfonyl chloride in the presence of triethylamine and then the resulting compound was treated with iodomethane and potassium carbonate. Thereafter, the product was treated with thioglycolic acid to obtain N-[3-(methylamino)phenyl]acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([SH:13])[CH:6]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:23][C:24](=[O:26])[CH3:25].CCOC(C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][CH2:23][C:24](=[O:26])[CH3:25])[CH:6]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1ccc(OC)c(S)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC)c(SCC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Mercapto-4-methoxy-benzoic acid ethyl ester (1.29 g, 6.08 mmol) and triethylamine (2.12 mL, 15.19 mmol) were dissolved in THF (20 mL) at 0° C. Chloroacetone (0.58 mL, 7.29 mmol) was then added and the reaction stirred at room temperature for 30 minutes. It was then allowed to slowly warm to room temperature and stirred an additional 30 minutes. Standard aqueous workup followed by silica gel chromatography (0-70% EtOAc in hexanes) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=2)=[CH:8][C:7]=1[N+:25]([O-])=O)=O.[CH:30]([O:37][CH2:38][CH3:39])([O:34]CC)OCC.C(O)CO>C(OCC)(=O)C>[O:37]1[CH2:38][CH2:39][O:34][CH:30]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]3[NH:5][C:3]([C:2]([F:29])([F:28])[F:1])=[N:25][C:7]=3[CH:8]=2)=[CH:18][CH:19]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c(C(F)(F)F)c2)cc1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc2cc(Oc3ccc(C4OCCO4)cc3)cc(C(F)(F)F)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-[4-[(4-formylphenyl)oxy]-2-nitro-6-(trifluoromethyl)phenyl]acetamide (0.65 g, 1.54 mmol), triethyl orthoformate (0.282 mL, 1.69 mmol), and ethylene glycol (0.343 mL, 6.16 mmol) was added (butyl)4NBr3 (0.007 g, 0.015 mmol). The reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed 1×NaHCO3, 1× brine and then dried (Na2SO4), filtered and concentrated. The residue was dissolved in ethyl acetate (5 mL) and hydrogenated over 10% Palladium on carbon (0.13 g) under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through Celite and the filtrate concentrated. The residue was purified by silica gel column chromatography on using a gradient of 20-40% ethyl acetate:hexanes to give 5-{[4-(1,3-dioxolan-2-yl)phenyl]oxy}-2,7-bis(trifluoromethyl)-1H-benzimidazole.
Reaction SMILES: CC([C@]1(O)[C@@]2(C)[C@]3(O)[C@]45O[C@@]2(O)C[C@@](C)([C@@]4(O)CCC([C@H]5[OH:19])=C)[C@]3(O)[C@@H]1OC(C1NC=CC=1)=O)C.C(OC1C=CC(C(NCCC(O)=O)=O)=CC=1)CCC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:69]1([N:75]=[C:76]=[N:77][CH:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O1CCCC1.O>[C:76]([NH:75][CH:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74]1)([NH:77][CH:78]1[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1)=[O:19]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=C1CC[C@]2(O)[C@]3(C)C[C@]4(O)O[C@@]2([C@@H]1O)[C@]1(O)[C@@]3(O)[C@H](OC(=O)c2ccc[nH]2)[C@](O)(C(C)C)[C@@]14C
Agent: CCCCOc1ccc(C(=O)NCCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dehydro-ryanodine (60 mg., 0.125 mmol), N-(p-n-butoxybenzoyl)-β-alanine (40 mg. 0.15 mmol) and DMAP (2 mg., 0.02 mmol), dried over P2O5, were dissolved in a solvent mixture of CH2Cl2 (10 ml.) and tetrahydrofuran (0.1 ml) dried over Molecular Sieve. To the stirred solution dicyclohexylcarbodiimide (35 mg., 0.15 mmol) was added at once and the reaction mixture maintained at room temperature for 6 hours. Water (0.1 ml) was added and stirring continued for 30 minutes. The solids formed (dicyclohexylurea) were filtered and washed twice with CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][N:24]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1
Reactant: Clc1cnc(Nc2cnn(CC3CC3)c2)nc1NC1CC2CNCC2C1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CC2CC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 5-chloro-N2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (0.52 g, 1.40 mmol) and 2-cyanoacetic acid (136.9 mg, 1.61 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (821.4 mg, 2.16 mmol) and Et3N (0.33 g, 3.26 mmol). After addition, the reaction mixture was stirred at rt for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (357.2 mg, 58%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: OCC1CCNCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1C(=O)N(CC1CCNCC1)C2=O)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
At room temperature, 0.43 ml (2.73 mmol) of diethyl azodicarboxylate (DEAD) is added dropwise to a suspension of 670 mg (2.18 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 314 mg (2.73 mmol) of 4-hydroxymethylpiperidine and 716 mg (2.73 mmol) of triphenylphosphine in 8.7 ml of absolute THF. After 2 h at room temperature, the mixture is concentrated and the residue is separated by chromatography on silica gel (gradient: from dichloromethane/methanol 95:5 to dichloromethane/methanol/triethylamine 9:1:0.1). Yield: 430 mg (41.5% of theory); MS (ESI): m/z (%)=404 (M+H, 60), 145 (100); LC-MS (Method 4): rt (%)=3.02 (84).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1
Temperature: 130 °C

Procedure:
In a microwave reaction vial was placed (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 4-(4-bromophenyl)butanoic acid (49.6 mg, 0.204 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (2.63 mg, 3.71 μmol), and K2CO3 (51.3 mg, 0.371 mmol) in toluene (1.2 mL) and H2O (0.2 mL). The reaction was heated at 130° C. for 120 min under microwave irradiation. The aqueous layer was collected, acidified with 1M HCl, and purified by HPLC to give the title compound. LCMS m/z=352.4 [M+H]+; 1.26 (d, J=6.8 Hz, 0.4H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 1.87-1.94 (m, 2H), 2.01-2.10 (m, 2H), 2.21-2.30 (m, 1H), 2.33 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.7 Hz, 2H), 3.06-3.18 (m, 4H), 3.35-3.45 (m, 1H), 3.50-3.60 (m, 1H), 3.74-3.84 (m, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=1)=[CH:6][CH:5]=2.[CH3:30][O:31][CH2:32][CH:33]=O>>[CH3:30][O:31][CH2:32][CH2:33][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:22][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)=[N:13][CH:14]=[N:15]3)=[CH:20][CH:19]=2)[CH2:25][CH2:26]1
Reactant: COCC=O
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Product: COCCN1CCC(COc2ccc3c(Oc4ccc5[nH]c(C)cc5c4)ncnc3c2)CC1
Yield: 46.4 %

Procedure:
Using an analogous procedure to that described for Example 71, 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.386 mmol), (prepared as described in Example 122), was reacted with methoxyacetaldehyde (83 mg, 0.772 mmol), (prepared as described for the starting material in Example 71), to give 7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (80 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.Br[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])=[O:34])[CH3:37]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2sccc21
Yield: 82 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as solvent, the thienopyrimidine-2,4-dione (3.0 g, 7.76 mmol) from Example 19, and ethyl 5-bromovalerate was used as the alkylating agent. The title compound was isolated in 82% yield (3.3 g), after recrystallization from EtOH, mp 118°-119° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[P:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(N(CC)CC)C.C1C=CC=CC=1>[C:18]1([P:17]([O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 42.4 grams of 2,4-di-tert-butylphenol in 101 grams of triethylamine was added dropwise over a 15-minute period 17.9 grams of dichlorophenylphosphine. The reaction mixwas then heated for 6 hours at 65°-70° C. After cooling to room temperature, the reaction mixture was diluted with 50 ml of benzene and poured onto a rapidly stirred mixture of 70 grams of concentrated hydrochloric acid and 200 grams of chopped ice. The product was then isolated as in Example 17 with the product crystallized from acetonitrile as white crystals melting at 90°-93° C.