Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.[CH3:21][NH:22][O:23][CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([O:23][CH3:24])[CH3:21])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A solution of 2-chloronicotinic acid (20.0 g, 127 mmol) in N,N-dimethylformamide (600 mL, 0.21M) was treated with N,N-diisopropylethylamine (66 mL, 379 mmol), N,O-dimethylhydroxylamine hydrochloride (13.63 g, 140 mmol), and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (84.25 g, 190 mmol). The reaction was stirred at 25° C. over 3 d. The resulting reaction was concentrated in vacuo, taken up in ethyl acetate (400 mL) and washed with a saturated aqueous ammonium chloride solution (2×250 mL), a saturated aqueous sodium bicarbonate solution (2×250 mL), and a saturated aqueous sodium chloride solution (250 mL). The organics were dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix IntelliFlash 280 column chromatography, 400 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 2-chloro-N-methoxy-N-methyl-nicotinamide (23.58 g, 93%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][N:25]([NH2:27])[CH3:26].CO.C(Cl)(Cl)Cl>CO.CN(C=O)C>[Cl:1][CH:2]1[C:10](=[C:11]=[N:27][N:25]([CH3:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CN(C)N
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)N=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 100 mg, 0.26 mmol) was dissolved in MeOH (5 mL) to which was added asym-dimethylhydrazine (0.5 mL). The resulting solution was stirred at room temperature for 16 h, then evaporated under vacuum to yield a yellow residue. The residue was dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield 87 mg (78%) of 4.35 as a white powder: mp dec >170° C.; Rf 0.4 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.36 (s, 1H), 7.35 (s, 1H), 5.91 (d, 1H), 5.36-5.31 (m, 2H, D2O exch.), 5.21 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.96 (d, 1H), 3.70 (b, 2H), 2.93 (s, 6H). 13C-NMR (125 MHz, DMSO-d6): δ 133.01, 125.64, 125.62, 125.37, 124.26, 124.04, 121.97, 114.85, 110.14, 88.58, 85.75, 71.18, 69.66, 61.14, 42.58. HRMS (ES) m/z calcd. for C16H18Cl3N3O4 □ Na 444.0261, found 444.0269. Anal calcd for C16H18Cl3N3O4: C, 45.46; H, 4.29; N, 9.94. Found: C, 45.79; H, 4.61; N, 10.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](O)(=O)[CH3:16]>C(O)C>[NH2:13][C:3]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:7]([C:15]2[CH:16]=[CH:8][CH:6]=[CH:5][CH:4]=2)[CH:2]=1
Reactant: CC(=O)O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (2 ml) was added to benzoylacetonotrile (0. 145 g) in ethanol (8 ml) and the solution heated at 80° C. for 6 hours. Glacial acetic acid (1 ml) was added and the mixture heated at 80° C. for 4 hours and then 90° C. for 2 hours. The reaction mixture was evaporated and the residue purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of appropriate fractions followed by further purification of their residue by reverse phase high performance liquid chromatography on C18 silica eluted with methanol: acetonitrile: water (1:5:4). Combination and evaporation of appropriate fractions gave the title compound as a white solid m.p. 141.5-142.5° C.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](C3C=CC=C(SC)C=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)(C)C.OOS([O-])=O.[K+]>CO.O.C([O-])(O)=O.[Na+]>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of the 6-isopropyl-8-(3-methylsulfanyl-phenyl)-quinoline from the previous Step 1 (0.84 g) in MeOH (0.35M) at 0° C. was added a solution of Oxone (0.5 eq) in water (0.18M). The resulting mixture was stirred for 30 min, then poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residual oil was dissolved in TFAA (0.2M), stirred at 40° C. for 30 min and finally concentrated. The residual oil was dissolved in excess NEt3:MeOH (1:1) and concentrated. The operation was repeated twice to afford the title compound as a yellow oil which was used as such.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.C[C:21](C)([O-:23])C.[K+]>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:23][CH3:21])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: O=C1NC(=O)C(c2c(F)cccc2F)O1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cccc(F)c1C1OC(=O)NC1=O
Temperature: 155 °C

Procedure:
5-(2,6-Difluorophenyl)oxazolidine-2,4-dione (2.0 g., 9.4 mmoles) was dissolved in 50 ml. of dimethylsulfoxide. Methanol (5 ml.) and then potassium tert-butoxide (2.11 g., 18.8 mmoles) were then added and the reaction mixture heated in an oil bath maintained at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 200 ml. of 1 N hydrochloric acid and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. The solids were taken up in 1 N sodium hydroxide, and the solution washed with three portions of ethyl acetate and then acidified with 1 N hydrochloric acid to precipitate purified 5-(2-fluoro-6-methoxyphenyl)oxazolidine-2,4-dione (1.32 g., 62%; m.p. 138°-142° C.). For analysis, the product was recrystallized from toluene (930 mg. recovered; m.p. 139°-141° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:27](=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27](=[O:36])[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)[N:15]2[CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nccc(C(=O)N(C)N(C(=O)Cc2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)n2C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a 0° C. solution of 4-{N-[2-(4-fluoro-phenyl)-acetyl]-N′-methyl-N′-(2-methylsulfanyl-pyrimidine-4-carbonyl)-hydrazino}-piperidine-1-carboxylic acid tert-butyl ester, 17, (26.7 g, 51.7 mmol) in DMF (50 mL) is slowly added NaH (3.1 g of a 60% dispersion in mineral oil, 77.55 mmol). The reaction mixture is stirred for 0.5 h at 0° C. and then quenched with 1.0 N HCl. The aqueous layer is extracted threee times with CH2Cl2. The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo. Purification over silica (100% EtOAc) affords 12 g (45% yield) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=4.9 Hz, 1H), 7.35-7.29 (m, 2H), 7.02 (t, J=6.8 Hz, 2H), 6.85 (d, J=5.1 Hz, 1H), 4.42-4.32 (m, 3H), 3.28 (s, 3H), 2.88 (t, 12.8 Hz, 2H), 2.58 (s, 3H), 2.79-2.39 (m, 2H), 1.94 (d, J=11.7 Hz, 2H), 1.50 (s, 9H); ESI/MS: 500.3 (M+H).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[CH3:3][CH:2]([O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)CCCC(C)Br
Product: COc1ccc(OC(C)CCCC(C)C)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-methoxy-phenol to obtain p-[(1,5-dimethyl-hexyl)-oxy]-anisole (boiling point =170°-172° C/1.0 mmHg);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:35].CO.C(=O)([O-])[O-].[NH4+:42].[NH4+]>ClCCl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 73 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 73% of theory, C2H25N7O3 (471.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=472; (M+H+Na)++=247.8.
Reaction SMILES: C1(CBr)CC1.[CH:6]1([CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=2)[CH2:8][CH2:7]1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.N1CCCCC1>O1CCCC1.[Pd]>[CH3:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:22][CH:24]1[O:26][CH2:25]1
Reactant: ClCC1CO1
Reactant: Cc1cc(OCCOCC2CC2)ccc1O
Agent: [Pd]
Agent: BrCC1CC1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1cc(OCCOCC2CC2)ccc1OCC1CO1

Procedure:
The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[S:9]1[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.O>CS(C)=O>[S:9]1[C:13]2[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: CCOC(=O)/C=C/c1cccc2nnsc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a suspension of 60% sodium hydride (1.34 g, 30.7 mmol) in dimethyl sulfoxide (20 mL) was added a solution of trimethylsulfoxonium iodide (6.76 g, 30.7 mmol) in dimethyl sulfoxide (50 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(1,2,3-benzothiadiazol-7-yl)acrylate (6.00 g, 25.6 mmol) in dimethyl sulfoxide (130 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.00 g, yield 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:22]=[C:21]([CH3:23])O[C:19](=[O:24])[C:18]=3[CH:25]=2)=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[NH3:27].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:12]([C:14]2[CH:25]=[C:18]3[C:17](=[CH:16][CH:15]=2)[N:22]=[C:21]([CH3:23])[NH:27][C:19]3=[O:24])=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1c(C)c(C(=O)c2ccc3nc(C)oc(=O)c3c2)n2ccccc12
Reactant: N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)c(C(=O)c2ccc3nc(C)[nH]c(=O)c3c2)n2ccccc12

Procedure:
0.100 g (0.29 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2-methyl-4H-3,1-benzoxazin-4-one in 2 ml of a 20% aqueous ammonia solution are heated for 2 hours at 50° C. and then hydrolysed with 3 ml of 10% aqueous sodium hydroxide solution and brought to 50° C. for 2 hours. The reaction medium is acidified with a 1N aqueous solution of hydrochloric acid, to pH=9. The precipitate obtained is filtered off, rinsed with water and then dried under reduced pressure at 40° C. overnight. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 67 mg of a yellow solid are obtained.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[F:29][C:30]1[CH:31]=[C:32]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]2[NH2:44])[CH:33]=[C:34]([F:36])[CH:35]=1>C(Cl)Cl.O>[C:10]([O:9][C:7](=[O:8])[NH:1][C@@H:2]([CH3:3])[C:4]([NH:43][C:39]1[C:38]([NH:37][C:32]2[CH:33]=[C:34]([F:36])[CH:35]=[C:30]([F:29])[CH:31]=2)=[N:44][CH:42]=[CH:41][CH:40]=1)=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1=CC=CN(c2cc(F)cc(F)c2)C1N
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
Boc-L-Ala-OH (2.05 g, 10.8 mmol) and isobutyl chloroformate (1.4 g, 10.8 mmol) were dissolved in DCM (20 mL) and N-methyl morpholine (1.14 g, 11.3 mmol) was added to at −10° C. and stirred for 30 min. To the mixture was added N1-(3,5-difluorophenyl)-pyridine-2,3-diamine (1.2 g, 5.42 mmol) dissolved in DCM (10 mL). The reaction mixture was stirred at −10° C. for 30 min and then at rt overnight. After completion of the reaction, water (100 mL) was added and the organic layer was extracted with DCM (200 mL), dried over sodium sulfate and concentrated to provide a crude product, which was purified by column chromatography using 100-200 mesh silica gel and 35% EtOAc in hexane to provide (S)-tert-butyl-1-(2-(3,5-difluorophenylamino)pyridine-3-ylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 393.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:11])=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[C:15]([CH3:18])[CH:16]=O>C(O)C.C(O)(=O)C>[C:1]([C:5]1[C:6]([NH2:11])=[N:7][N:8]2[CH:16]=[C:15]([CH3:18])[CH:14]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)=CN(C)C
Reactant: CC(C)(C)c1c(N)n[nH]c1N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture from Example 105A (1.56 g, 10.1 mmol), 3-dimethylamino-2-methyl-2-propenal (1.63 g, 14.4 mmol) and acetic acid (25 μL, 0.44 mmol) in ethanol (10 mL) was heated by microwave to 150° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.53) afforded 1.66 g (80%) of the title compound. MS (DCI) m/z 205 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[CH2:30]([N:29]([CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CNCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (86 mg, 0.236 mmol) was dissolved in EtOH (5 mL) and N-methylbenzylamine (0.027 mL, 0.283 mmol), sodium cyanoborohydride (30 mg, 0.472 mmol), and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 100% EtOAc.) The title compound was obtained as an oil. (Yield: 23 mg, 0.049 mmol, 20%) 1H NMR (400 MHz, CDCl3) 7.62, 7.37-7.23, 7.14, 7.08-7.02, 6.82, 6.57, 5.45, 4.60, 4.04, 3.44, 2.75, 2.16, 2.10, 1.83-1.59, 0.91, 0.51
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([N:23]([CH3:25])[CH3:24])=O)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)(=O)C>CCOCC.C1C=CC=CC=1>[CH3:24][N:23]([CH2:21][C:10]1[CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH3:25]
Reactant: CSc1ccc(-c2cc(C(=O)N(C)C)nn2-c2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cc(CN(C)C)nn2-c2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-N,N-dimethyl-5-[4-(methylthio)phenyl)pyrazole-3-carboxamide (1.6 g) and lithium aluminum hydride (0.34 g) in ether (8.5 ml) and benzene (13 ml) was stirred and refluxed for 2 hours. 4N Sodium hydroxide (10 ml) was added dropwise and ethyl acetate (20 ml) was added to the mixture. The insoluble was filtered and the filtrate was separated. The organic layer was washed with water, dried and concentrated. The residue (1.2 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of ethyl acetate and methanol (5:1) to give a pale brown oil of 3-(N,N-dimethylaminomethyl)-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (0.69 g).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH3:29][CH2:30][O:31][CH:32]=[C:33]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH2:17]([N:16]([CH2:20][CH2:21][CH3:22])[CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:23])[N:14]=1)[CH:32]([CH:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[O:31][CH2:30][CH3:29])[CH2:18][CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCN(CCC)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-[(6-mesitylpyridin-2-yl)methyl]-N-propylpropan-1-amine (0.71 g, 2.29 mmol), was dissolved in tetrahydrofuran (15 mL). The solution was cooled to −78° C. and n-butyllithium (2.5M, 1.0 mL, 2.51 mmol) was added drop wise. After 0.5 h, diethyl ethoxymethylene malonate (0.48 mL, 2.40 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. The mixture was quenched with water, extracted with ether, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 0.65 g (59% yield) of an isomeric mixture of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[OH:10][CH:11]([CH3:15])[C:12](=O)[CH3:13]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH:12]([CH3:13])[C:11](=[O:10])[CH3:15]
Reactant: CC(=O)C(C)O
Reactant: Cc1cccc(C)c1N
Solvent: c1ccccc1
Product: CC(=O)C(C)Nc1c(C)cccc1C
Yield: 94.4 %

Procedure:
A solution of 484.8 g (4 mols) 2,6-dimethylaniline and 422.8 g (4.8 mols) 3-hydroxy-2-butanone in 1200 ml benzene was heated under reflux for 21 hours in a reaction vessel equipped with a Dean-Stark trap. The reaction mixture was then cooled, washed with four 600-ml portions of water, slurried with silica gel, filtered and evaporated under reduced pressure to give 722 g of 3-(2,6-dimethylphenylamino)-2-butanone, as an orange oil. The infrared spectrum of the product showed strong carbonyl absorption at 6.3 microns.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:27][CH:26]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:16]=[C:17]([C:21]#[C:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)=[O:36]
Reactant: COC(=O)Cc1ccc(OCC#Cc2cccc(C#CCOc3ccc(CC(=O)OC)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)Cc1ccc(OCC#Cc2cccc(C#CCOc3ccc(CC(=O)O)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a solution of [4-(3-{3-[3-(4-methoxycarbonylmethyl-phenoxy)-prop-1-ynyl]-phenyl}-prop-2-ynyloxy)-phenyl]-acetic acid methyl ester (example 15) (200 mg, 0.42 mmol) in ethanol (3 mL) was added 1N sodium hydroxide (1.6 mmol, 1.6 mL). After stirring at room temperature for 16 h, the reaction mixture was added 1N hydrochloride acid to pH 1. The product was isolated by filtration and dried to give 100 mg (53%) of the title compound as a crystalline product.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[Si](C)(C)[O-].[Li+:16]>C1(C)C=CC=CC=1>[C:1]([O-:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li+:16]
Reactant: CCCCCCC(=O)OC
Agent: C[Si](C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)[O-]
Yield: 51.1 %

Procedure:
The procedure of Example 1 was followed using methyl heptanoate (5 mL, 30.2 mmol), lithium trimethylsilanolate (2.90 g, 30.2 mmol), dry toluene (50 mL) and 2.5 h of heating at reflux. Lithium heptanoate (2.1 g, 51% yield) was isolated as a white solid: 1H NMR (D2O) δ 0.7 (t, J=5.3 Hz, CH3, 3H), 0.9-1.7 (m, CH2, 8H), 2.1 ppm (t, --CH2CO2-Li+, J=7.2 Hz, 2H). Anal. Calcd. for C7H13LiO2 : C, 61.77; H, 9.63; Li, 5.10. Found: C, 59.84, 59.89; H, 9.47, 9.47; Li, 5.01.