Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:34][CH3:35])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2cccs2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccs1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(2-thienylmethylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.8 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.26 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(2-thienylmethyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].C(OC(O)C)C>N1C=CC=CC=1>[OH:23][CH2:22][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3)c2cc1OC
Yield: 86 %

Procedure:
A mixture of 1.0 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.98 g of 3-aminobenzyl alcohol, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 3 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was washed with hot methanol to give 1.16 g of 4-[(3-(hydroxymethyl)phenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 250-255° C.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[ClH:18]>[Pd]>[ClH:18].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[CH:11][N:10]=[CH:9]2)=[CH:16][CH:17]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Product: N#Cc1ccc(Cn2cncc2N)cc1

Procedure:
A solution of 1-(4 cyanobenzyl)-5-nitro-1H-imidazole (100 mg, 0.438 mmol) and 10% palladium on carbon was hydrogenated in the presence of 1 equivalent of HCl under Parr conditions for 1 hr. Removal of the catalyst by filtration and evaporation of solvent in vacuo afforded the title compound.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:34]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH2:30][CH:31]([CH3:32])[CH3:33])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=2[CH3:34])[CH:11]=1)#[N:16]
Reactant: Cc1ccc(S(=O)(=O)CC(C)C)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CC(C)C)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-4-(isobutylsulfonyl)-1-methylbenzene (Intermediate 66), the title compound was obtained as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][O:16][C:17]=3[CH:18]3[CH2:20][CH2:19]3)=[N:11][N:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>>[CH:18]1([C:17]2[O:16][N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][C:4]=3[O:27][CH3:28])=[N:12][N:11]=2)[CH2:20][CH2:19]1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Yield: 34.6 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.53 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 4-aminotetrahydropyran (161 mg, 1.59 mmol) and N,N-diisopropylethylamine (137 mg, 1.06 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 84 mg, 35%) which was obtained as a white solid. MS: m/e=459.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.CCCCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(COCCO)cc1
Agent: c1c[nH]cn1
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
To a solution of the product of Example 8A (500 mg, 2.334 mmol) in DMF (23 mL) was added tert-butyldimethylsilyl chloride (528 mg, 3.501 mmol) and imidazole (238 mg, 3.501). The reaction was stirred at room temperature for 5 hours under nitrogen atmosphere, monitoring by TLC (3:1 pentane:ethyl acetate). Another 0.5 eq. portion of tert-butyldimethylsilyl chloride (176 mg) and imidazole (79 mg) were added and the resultant mixture stirred at room temperature overnight. The majority of the starting material was consumed in 16 hours, as indicated by thin layer chromatography. The reaction was diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil which was purified by passage through thick pad of silica gel (3:1 pentane:ethyl acetate) to obtain the product as a clear oil (602 mg). 1H NMR (600 MHz, CDCl3): 8.00 (d, 2H, J=8.3 Hz), 7.40 (d, 2H, J=8.5 Hz), 4.62 (s, 2H), 3.90 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]([NH:17]C(=O)C(Cl)(Cl)Cl)=[O:16])=[C:11]([C:24]([O:26]C)=O)[CH:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][C@H:41]([NH2:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O.O>[NH2:17][C:15]([NH:14][C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[C:24]([NH:45][C@H:41]1[CH2:42][CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]1)=[O:26])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c(NC(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of methyl 5-(4-methoxyphenyl)-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (1.0 g, 2.2 mmol) in dry THF (20 mL) was added a solution of [Me2Al-3-Boc-(S)-3-aminopiperidine] in THF (which was preformed by the addition of Me3Al (2.0 M in hexanes, 2.2 nL, 4.4 mmol) to a solution of (S)-3-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 4.4 mmol) in 10 mL THF at −78° C. followed by warming to room temperature for an additional 15 min). The resulting orange-colored solution was stirred overnight at room temperature. The reaction mixture was cooled with ice and a 10% aqueous solution of Rochelle's salt was added slowly to quench the reaction. The resulting biphasic solution was warmed to room temperature and stirred for an additional 1 h. The mixture was diluted with EtOAc and H2O, the aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with H2O, brine and dried (Na2SO4). Evaporation gave a pale orange solid. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave 0.70 g (67%) of a light yellow solid. LC/MS (APCI, ES, M+H=475).
Reaction SMILES: [Cl-].[C:2]([C@@H:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH3+:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([OH:4])=[O:3].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C:44](=[N:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])SC)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(O)(C)C>[C:51]([O:50][C:48]([NH:47][C:44]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([CH2:6][C@H:5]([O:24][CH2:25][CH3:26])[C:2]([OH:4])=[O:3])=[CH:8][CH:9]=2)=[CH:20][CH:19]=1)=[N:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCO[C@@H](Cc1ccc(OCCCc2ccc([NH3+])cc2)cc1)C(=O)O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.08 h
Yield: 26.9 %

Procedure:
4-(3-{4-[(2S)-2-Carboxy-2-ethoxyethyl]phenoxy}propyl)benzenaminium chloride (152 mg, 0.4 mmol) was in isopropyl alcohol (3 ml). N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) was added. The mixture was stirred for 5 minutes, then 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (290 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 7 days and thereafter evaporated in vacuum to dryness. Water and ethyl acetate were added into the residue. The mixture was acidified with 1% hydrochloric acid, pH˜5 and there was some precipitation. The two phase mixture was filtered and then separated. The pH of the water phase was further adjusted to ˜3 and the water phase was extracted with ethyl acetate (×2). All organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. Chromatography of the residue on an ISOLUTE column (SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and MeOH/DCM (0.5: 99.5) as eluant gave the desired product (63 mg), yield 27%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:38]2[C:39]([CH:44]=O)=[N:40][CH:41]=[CH:42][CH:43]=2)([CH3:37])[CH3:36])=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:44][C:39]2[C:38]([C:35]([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)([CH3:37])[CH3:36])=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)(C)c3ccc(F)cc3)c2)cc1
Yield: 39 %

Procedure:
Using General Procedure B: Reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine and 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-{2-[1-{toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine (87.3 mg, 39%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccnc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
To a solution of (2-fluoro-3-pyridinyl)methanol (ASYNCHEM, 505 mg, 3.97 mmol) in dry DCM (15 mL), under N2 atmosphere, were added triphenylphospine (ALDRICH, 1042 mg, 3.97 mmol) and carbon tetrabromide (ALDRICH, 1318 mg, 3.97 mmol) in an ice-water bath. Reaction mixture was stirred at room temperature overnight. 0.3 eq. of carbon tetrabromide (ALDRICH, 409 mg, 1.19 mmol) and 0.3 eq. of triphenylphospine (ALDRICH, 323 mg, 1.19 mmol) were added. Reaction mixture was stirred until starting material was not detected. Solvent was evaporated to dryness. Residue was purified by silica gel chromatography using a linear gradient of hexane-EtOAc. Collected fractions afforded title compound (812 mg, 4.27 mmol, quantitative yield) as yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.20-8.21 (m, 1H), 8.06-8.12 (m, 1H), 735-7.39 (m, 1H), 4.69 (s, 2H). [ES+MS] m/z 190 (M).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.Br[CH2:14][CH2:15][Cl:16].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:14][CH2:15][Cl:16])[C:4]=2[O:3]1
Reactant: ClCCBr
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Cc2cccc(OCCCl)c2O1
Reaction time: 7 h

Procedure:
To 200 ml. methylene-chloride 32.84 g. (0.2 mole) 2,3-dihydro-2,2-dimethyl-7-hydroxy-benzofuran, 57.37 g. (0.4 mole) 1-bromo-2-chloro-ethane 200 ml. 2N sodium hydroxide solution and 8 g. Adogen 464 phase transfer catalyst (tri-C8-10 -alkyl-methyl-ammonium-chloride) are added. The reaction mixture is heated under vigorous stirring for 7 hours and the reaction is monitored by gas chromatographic analysis.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:11][CH:12]=O>CCO>[N:1]1[CH:11]=[CH:12][N:9]2[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=12
Reactant: O=CCCl
Reactant: N#Cc1cccnc1N
Solvent: CCO
Product: N#Cc1cccn2ccnc12
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a solution of 2-aminonicotinonitrile (1.0 g, 8.39 mmol) in EtOH (10 ml) in a 20 ml sealed vial was added 2-chloroacetaldehyde (1.611 ml, 9.23 mmol) vial was then sealed and heated to 120° C. overnight. Reaction was cooled to RT and quenched with 2N Na2CO3, removed EtOH in vaccuo and extracted with DCM×3. Combined organics and washed with water then brine×2. Dired over sodium sulfate and removed solvent to give title compound as a yellow brown solid (1.2 g, 8.38 mmol, 100% yield) was verified by MS (ES+) C8H5N3 requires: 143 found: 144 [M+H]+
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O1CCCC1.[C:24](=[O:26])=[O:25]>CCCCCC>[O:18]=[C:16]1[O:15][N:14]=[C:13]([CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:24]([OH:26])=[O:25])[NH:17]1
Reactant: O=c1[nH]c(Cc2ccccc2)no1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C(c1ccccc1)c1noc(=O)[nH]1
Reaction time: 2 h

Procedure:
169.2 g. (0.328 moles + 20 percent) of a 15 percent solution of butyl lithium in hexane is cooled to -60° under a nitrogen atmosphere. At this temperature, a solution of 28.9 g. (0.164 moles) of 3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one in 360 ml. of anhydrous tetrahydrofuran is added dropwise with stirring over a period of about 2 hours. A proportionate stream of carbon dioxide is passed through the resulting suspension for a period of 2 hours. The cold bath is removed and the solution is permitted to come to room temperature. The solution is concentrated in a rotary evaporator, the residue is treated with water, the aqueous solution is extracted with ether and the aqueous phase is acidified with 2N hydrochloric acid. This acidified aqueous phase is extracted several times with ether. The combined ether phases are dried with magnesium sulfate and the ether is evaporated. The residue is crystallized by trituration with petroleum ether. 23.9 g. of 4,5-dihydro-5-oxo-α-phenyl-1,2,4-oxadiazole-3-acetic acid are obtained, m.p. 140°-141° (dec.). The product is purified by dissolving in a small amount of water with the addition of sodium bicarbonate and again precipitating with dilute hydrochloric acid. The precipitated product melts at 142°-143° (dec.).
Reaction SMILES: [Na].[C:2]([O:7][CH2:8][CH3:9])(=[O:6])[C:3]([O-:5])=O.[C:10]([NH:14][C:15]1[C:16]([CH3:28])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25](=[O:27])[CH3:26])[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11]>CCO.O>[C:10]([NH:14][C:15]1[C:16]([CH3:28])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25](=[O:27])[CH2:26][C:3](=[O:5])[C:2]([O:7][CH2:8][CH3:9])=[O:6])[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Temperature: -10 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a 25-mL round-bottomed flask was added EtOH (4 mL) and sodium ethoxyde (1.01 g of 21% in EtOH, 3.11 mmol). The reaction mixture was cooled to −10° C. and added ethyl oxalate (0.21 mL, 1.55 mmol, Sigma-Aldrich) and 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (0.4 g, 1.55 mmol) slowly. The reaction mixture was warmed to RT and stirred at RT for 18 h. The reaction mixture was diluted with water (10 mL) and partially concentrated under vacuum. The reaction mixture was diluted with HCl (1 N, 5 mL) and extracted with EtOAc (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate as an orange oil (135 mg, 24% yield). m/z (ESI, +ve) 358.1 (M+H)+. To a 15-mL glass tube was added ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate (135 mg, 0.38 mmol), hydrazine (12 μL, 0.38 mmol), and AcOH (2 mL). The tube was sealed and heated at 85° C. for 1 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The mixture was diluted with EtOAc (10 mL) and NaOH (1 N, 5 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (102 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.97 (m, 1H), 7.74 (d, J=7.82 Hz, 1H), 7.51-7.60 (m, 1H), 7.40 (t, J=8.90 Hz, 1H), 6.00-6.07 (m, 1H), 4.31 (q, J=7.11 Hz, 2H), 2.56 (s, 3H), 1.53 (s, 9H), 1.33 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 354.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:15][CH3:16])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O.N>C(Cl)(Cl)Cl>[Cl:19][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH2:15][CH3:16]
Reactant: CCc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CCc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.00 g (4.21 mmol) of the compound from Example 29A are dissolved in 15 ml of chloroform, and 1.4 ml (15.15 mmol) of phosphoryl chloride are added carefully. The mixture is heated to reflux and stirred at this temperature for 30 min. The mixture is then cooled to 0° C. and made slightly basic using ammonia. The reaction mixture is extracted three times with in each case 20 ml of ethyl acetate. The solvent is removed on a rotary evaporator and the residue is dried in a vacuum drying cabinet. The product is used without further purification in the subsequent reactions.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38](I)[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38]([N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CNCCCc1ccccc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)CCCc3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 70 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with methyl-(3-phenyl-propyl)-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 70% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.49 (s, 1H), 7.99 (s, 1H), 7.31-7.38 (m, 2H), 7.09-7.28 (m, 5H), 7.00-7.08 (m, 2H), 6.17 (bs, 1H), 4.56 (d, J=8.0 Hz, 2H), 3.57-3.64 (m, 2H), 3.10 (s, 3H), 2.69 (s, 3H), 2.64-2.71 (m, 2H), 1.91-2.01 (m, 2H); MS (ES+) m/z 476.2 (M+1), Rt=1.69 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH2:7][C:6]=2[CH:11]=1.[CH3:18]I.[H-].[Na+]>COCCOC>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([CH3:18])[C:6]=2[CH:11]=1
Reactant: CI
Reactant: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1C(=O)Oc2cc(N3CCCCC3)c(Cl)cc21

Procedure:
A solution of 2.5 g (10 mmoles) of 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one and 2.1 g (15 mmoles) of methyl iodide in 15 ml of absolute 1,2-dimethoxyethane is added dropwise in the course of 20 minutes to a suspension, boiling under nitrogen, of 530 mg (11 mmoles) of 50% strength sodium hydride-oil dispersion in 15 ml of absolute 1,2-dimethoxyethane. The mixture is then boiled under reflux for a further 3 hours, the solvent is removed in vacuo and the residue is cautiously acidified with dilute hydrochloric acid and extracted three times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Recrystallisation from ether/petroleum ether yields 5-chloro-3-methyl-6-(piperidin-1-yl)-benzofuran-2(3H)-one having a melting point of 112°-113°.