Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][C:25]#[CH:26])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH2:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:25]#[CH:26]
Reactant: C#CCOc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 60.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.5 g), N,N'-carbonyldiimidazole (12 g) and 2-amino-7-propargyloxy-1,8-naphthyridine (10 g). The product produced by precipitation in water (15.3 g; m.p. 140° C.) is dissolved in boiling ethanol (190 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-propargyloxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (10.1 g) is produced, m.p. 140° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccccc1C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
The above general procedure was followed using 2-bromotoluene (171 mg, 1.00 mmol) and dibutylamine (129 mg, 1.00 mmol) with 2 mol % Pd(OAc)2 and 1.6 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 2% ethyl acetate/hexanes to give 181 mg (83%) of N,N-dibutyl-o-toluidine. 1H NMR (500 MHz, CDCl3) δ 7.18 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 2.91 (t, J=7.5 Hz, 4H), 2.30 (s, 3H), 1.41-1.37 (m, 4H), 1.27 (sept, J=7.3 Hz, 4H), 0.87 (t, J=7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 150.7, 135.0, 130.9, 126.0, 123.1, 122.3, 53.9, 29.6, 20.5, 18.3, 14.0.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.[C:36]([O:40][C:41]([NH:43][C@@H:44]([C:53](O)=[O:54])[CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([NH:25][C:53](=[O:54])[C@@H:44]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])[CH:27]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 73.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (829 mg) and N,N-diisopropylethylamine (1.13 mL) were added to a solution of 3-aminoquinoline (391 mg) and N-tert-butoxycarbonyl-D-homophenylalanine (1.13 g) in dichloromethane (15 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 19 hr, the solvent was removed in vacuo. The residue was diluted with 10% citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform: methanol=50:1, v/v) to afford the title compound (813 mg) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.00-2.10 (m, 1H), 2.27-2.39 (m, 1H), 2.80 (t, J=7.8 Hz, 2H), 4.20-4.29 (m, 1H), 4.98-5.07 (m, 1H), 7.19-7.33 (m, 5H), 7.51-7.55 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), and 8.68-8.80 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(F)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of the product of Step 1 (252 mg, 1.18 mmol) in isopropyl alcohol (5 ml) was added 2,6-lutidine (197 mg, 214 uL, 1.84 mmol) and potassium iodide (few mg). The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (221 mg, 0.591 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (methylene chloride to methylene/methanol 95:5 gradient) to afford the title compound (160 mg, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.79) (0.43 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.13 g, 33%). MS (ISP) 401.3 [(M+H)+]; mp 249.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNOCc1ccccc1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Product: CCCNc1nc(NCCC)nc(N(C)OCc2ccccc2)n1
Yield: 29 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-methyl-hydroxylamine (LII) were reacted as described in Example 13 to yield O-benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII) (29% yield). 200 MHz 1H NMR (DMSO-d6, ppm) 7.52-7.28 (5H, m), 7.07-6.67 (2H, m), 4.93 (2H, s), 3.26-3.03 (7H, m), 1.58-1.39 (4H, m), 0.85 (6H, t, J=7.2 Hz). ESI-MS (m/z): 331 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCCCCC>[Br:13][CH2:14][CH2:15][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1
Reactant: OCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OCCBr)cc1
Reaction time: 12 h
Yield: 103.7 %

Procedure:
4-(Trifluoromethoxy)phenol (15 g), 2-bromoethanol (7.76 g) and triphenylphosphine (22.1 g) were dissolved in tetrahydrofuran (250 ml). Diethyl azodicarboxylate (13.3 ml) was added dropwise to the stirred mixture and stirring was continued for 12 hours. The mixture was concentrated in vacuo to give a yellow oil. The oil was diluted with hexane to precipitate the triphenylphosphine oxide by-product which was removed by filtration. The filtrate was concentrated and purified on silica using 10% ether in hexane as eluant to give the product (18.35 g). 1H NMR (250 MHz, CDCl3) δ 3.63 (2H, t, J 6.1 Hz), 4.30 (2H, t, J 6.2 Hz), 6.84-6.95 (2H, m), 7.12-7.17 (2H, m).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].CO>O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][C:18](=[O:21])[C:19](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:20]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(3-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (130 mg, 0.46 mmol) and dimethylformamide dimethylacetal (0.12 mL, 0.90 mmol) in 1,4-dioxane (2 ml) was heated under nitrogen at 100° C. for 4.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (25 g) eluted with dichlromethane:methanol 19:1 and gave the title compound (95 mg, 0.28 mmol, yield 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CO>[Br-:7].[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([CH2:8][N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: c1ccncc1
Solvent: CO
Product: O=Cc1ccc(C[n+]2ccccc2)cc1
Product: [Br-]

Procedure:
Reactants (1) and (2) were added together in MeOH to ultimately result in about 20-26 wt-% of (3) in MeOH in a flask as illustrated above in Table I. All reactant mixtures A through D were divided by MeOH (abs), to reduce viscosity. The mixtures were allowed to stir overnight at room temperature. It was observed that Trials C and D had formed a white rubber polymer. Addition of methanol and stirring for 1 hour did not dissolve the polymeric material.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][NH:17][CH3:18])=[CH:10][CH:9]=1>C(OCC)C>[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:18])=[CH:10][CH:9]=1
Reactant: C=CC(=O)OCC
Reactant: CNCCCc1ccncc1
Solvent: CCOCC
Product: CCOC(=O)CCN(C)CCCc1ccncc1
Reaction time: 8 h

Procedure:
15.1 g of ethyl acrylate are added portionwise to a solution of 22.5 g (0,15 Mol) of N-[3-(pyrid-4-yl)propyl]-N-methyl-amine in 50 ml of diethyl ether. The clear solution formed is allowed to stand overnight. The solvent is evaporated off. Ethyl 3-{N-[3-(pyrid-4-yl)propyl]-N-methyl-amino}-propionate is thus obtained as an oil.
Reaction SMILES: [P:1](Cl)([Cl:4])([Cl:3])=[O:2].[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][OH:15])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([Cl:4])([Cl:3])([O:15][CH2:14][CH:13]([CH:7]([CH3:6])[CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCC(COP(=O)(Cl)Cl)C(C)CC(C)(C)C)CC(C)(C)C
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of [2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octyl] dichlorophosphate (34.7% in concentration).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 3.14 (s, 4H), 3.70 (s, 4H), 4.15 (s, 3H), 6.95-7.01 (m, 3H), 7.26-7.46 (m, 3H), 7.61-7.81 (m, 2H).
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4]C.[O:8]=[C:9]1[CH2:13][CH2:12][CH:11](C(O)=O)[CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC=O.C[O-].[Na+]>CO>[CH3:7][O:6][C:3]([CH:11]1[CH2:12][CH2:13][C:9](=[O:8])[CH2:10]1)=[O:4]
Reactant: COC(OC)OC
Reactant: O=C1CCC(C(=O)O)C1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: COC(=O)C1CCC(=O)C1
Temperature: 10 °C

Procedure:
318.36 g (3 mol) of trimethylorthoformate are added gradually to a solution of 128.2 g (1 mol) of nonracemic 3-oxocyclopentanecarboxylic acid and 11.4 g (0.06 mol) of p-toluene sulfonic acid hydrate in 380 ml of methanol within 5-10 minutes while stirring, The mixture is heated and during 25 minutes a mixture of formic acid methyl ester and methanol is distilled off (about 185 g of distillate), Thereafter 29 g of 30% sodium methylate solution (0.16 mol) are added and the reaction mixture is kept boiling under reflux for 2 hours; methanol is distilled off, the residue cooled to 10° C. and dissolved by adding 230 ml of methylene chloride and 200 ml of water. By adding 5% sulfuric acid the mixture is adjusted to pH 1.4 and stirred at 10° C. for 30 minutes. The methylene chloride phase is separated and the aqueous phase extracted again with 100 ml of methylene chloride. The combined organic phases are stirred with 50 ml of water, separated and the solvent is distilled off in vacuo. The residue is fractionated in vacuo.
Reaction SMILES: CO[C:3](OC)([N:5](C)C)[CH3:4].Cl.[NH2:11]O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:29])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])[C:17]([OH:19])=O>>[CH3:29][C:21]1[CH:20]=[C:16]([C:17]2[O:19][N:5]=[C:3]([CH3:4])[N:11]=2)[CH:15]=[C:14]([CH3:13])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]
Reactant: NO
Reactant: COC(C)(OC)N(C)C
Reactant: C#CCCCOc1c(C)cc(C(=O)O)cc1C
Agent: Cl
Product: C#CCCCOc1c(C)cc(-c2nc(C)no2)cc1C

Procedure:
5-[3,5-Dimethyl-4-(3-ethynylpropoxy)phenyl]-3-methyl-1,2,4-oxadiazole [XIV; Y=(CH2)3, R1 and R2 =3,5-(CH3)2, R8 =CH3 ] was prepared from 4.7 g 3,5-dimethyl-4-(3-ethylnylpropoxy)benzamide, 31 ml dimethylacetamide dimethyl acetal and 1.7 g hydroxylamine hydrochlorde according to the procedure of Example 1, part (b), and was obtained (4.4 g) in the form of a viscous oil used directly in the next reaction. A sample when crystallized from isopropyl acetate/hexane had the m.p. 38°-40° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN(C(C)C)C(C)C.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]cnc3c2)CC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
In a 250 mL round bottom flask with a stirbar was added Benzimidazole-5-carboxylic acid (2.00 g, 12.3 mmol), Boc-piperazine (2.41 g, 13.0 mmol, 1.05 eq), and Hunig's Base (3.78 mL, 27.1 mmol, 2.2 eq) in DMF (35 mL). After 5 minutes 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.60 g, 13.6 mmol, 1.1 eq) was added portion wise and the dark solution stirred for 2 hr at 23° C. The reaction was diluted with Ethyl Acetate (250 mL) and partitioned between water (50 mL). The layers were separated and the organic washed with water (2×50 mL), brine (30 mL), dried (Na2SO4), and concentrated to a dark oil. The reaction was purified using Biotage MPLC system (40M column size, 0-20% Methanol/CH2Cl2 over 35 Column Volumes) giving the desired product as a beige solid (1.45 g, 4.39 mmol, 35.6%). 1H NMR (DMSO-d6, 400 MHz) δ 12.6 (s, 1H), δ 8.31 (s, 1H), δ 7.66-7.60 (m, 2H), δ 7.25 (bs, 1H), δ 3.60-3.25 (m, 8H), δ 1.40 (s, 9H); LRMS (m/z): 353 (M+Na), 331 (M+H), 275.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]C)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.O.[OH-].[Li+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.7 %

Procedure:
A mixture of methyl (±)-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.071 g, 0:18 mmol) and lithium hydroxide monohydrate (0.009 g, 2 mmol) in THF (5 mL) and H2O (2 mL) was stirred at room temperature for 18 hr, then was concentrated. The residue was dissolved in H2O and the pH was adjusted to 4 with 3 N HCl. The resulting solid was collected by filtration and dried to give the title compound (0.05 g, 73%) as a white solid: MS m/e 371.4 (M+H)+. Anal. Calcd for C19H22N4O4.0.5 H2O: C, 60.15; H, 6.11; N, 14.77. Found: C, 60.14; H, 6.06; N, 14.71.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14](=S)[C:13]=2[CH:12]=1.[C:26]1([C@@H:32]([OH:40])[CH2:33][CH:34]2[CH2:39][NH:38][CH2:37][CH2:36][NH:35]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>ClCCl.CO.ClCCl>[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:38]3[CH2:37][CH2:36][NH:35][C@H:34]([CH2:33][C@@H:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:40])[CH2:39]3)[C:13]=2[CH:12]=1.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][C@@H:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[OH:40])[CH2:39]3)[C:13]=2[CH:12]=1
Reactant: O[C@@H](CC1CNCCN1)c1ccccc1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](C[C@H](O)c2ccccc2)C1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@H](C[C@H](O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add methyl trifluoromethanesulfonate (174 μL, 1.53 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (315 mg, 1.28 mmol) in dichloromethane (4 mL). Stir 1 h at 0° C. then warm to ambient temperature and stir 18 h. Concentrate the reaction to an orange powder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol (264 mg, 1.28 mmol) and pyridine (5 mL). Heat to 110° C. for 5.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-dichloromethane (10%). Concentrate and purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2.5%–3%) as the eluent to give 39 mg of (S,R)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol and 130 mg of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1.[CH:26]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=1)[CH:33]=O)([CH3:28])[CH3:27].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:33][C:32]3[CH:35]=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=[C:30]([O:29][CH:26]([CH3:28])[CH3:27])[CH:31]=3)[CH2:20][CH2:21]2)[CH:13]=1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 4-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-butyric acid methyl ester (example 168b) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless oil. MS: 557.3 (MH+).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>C(#N)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1ccccc1F
Reactant: O=C(O)c1ccncc1F
Solvent: CC#N
Product: O=C(O)c1ccncc1NCc1ccccc1F
Temperature: 158 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 2-fluorobenzylamine (308 μL, 2.84 mmol) were combined in ACN (3 mL) and the solution was stirred at 158° C. in a microwave for 1 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% to 20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 18 mg (10%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247; found 247.