Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])=[CH:19][C:18]=1[C:30]([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:23](=[O:24])[CH:22]([O:21][C:20]2[CH:28]=[CH:29][C:17]([Cl:16])=[C:18]([C:30]([F:32])([F:33])[F:31])[CH:19]=2)[CH2:26][CH3:27])=[CH:4][CH:5]=1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Reactant: NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccncc1
Yield: 42.9 %

Procedure:
In 50 ml of toluene were dissolved 1.3 g (0.012 mole) of 4-(aminomethyl)pyridine and 1.0 g (0.010 mole) of triethylamine. Thereto was added dropwise a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring, and the mixture was treated according to the same procedure as in Synthesis Example 10. The resultant oily substance was subjected to silica gel column chromatography by eluting with toluene to obtain 1.6 g of N-(4-pyridylmethyl)-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide showing nD19 1.5228 as pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([Cl:15])=[O:11])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 300 mg (1.99 mmol) 3-pyridine propionic acid in 10 mL CH2Cl2 was added one drop DMF and 2.3 mL (4.56 mmol) oxalyl chloride, and the mixture stirred at rt for 4 h. The volatiles were evaporated under reduced pressure and the material used crude in the following procedure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38].C(N(C(C)C)CC)(C)C>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4]([NH:46][CH:43]2[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]2)[N:3]=1
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Yield: 59.8 %

Procedure:
To a solution of (4-amino-2-chloro-pyrimidin-5-yl)-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone (860 mg, 2.0 mmol, Example 269) in ethanol (12 mL) was added 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetate salt (613.8 mg, 2.1 mmol, Example 162) and diisopropylethylamine (1.2 mL, 6.889 mmol). The mixture was heated at reflux for 4 hours and then concentrated to dryness. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with brine (1×10 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 45-60% ethyl acetate in hexanes) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone as white glass (684 mg, 60%). LR-MS (M+) 572.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH2:22]([Sn](CC)(CC)CC)[CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([CH2:22][CH3:23])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: CC[Sn](CC)(CC)CC
Product: CCc1nc(C(=O)OC)c(O)c2oc(-c3ccccc3)nc12

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tetraethyltin under conditions analogous to example 3b. MS: (+) m/z 299.1 (M+1).
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:18][C:19]([NH2:21])=[O:20])=[C:15]([CH:17]=1)[NH2:16])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][C:27](=[N:30][C:31]([O:33][CH3:34])=[O:32])SC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:34][O:33][C:31]([NH:30][C:27]([NH:26][C:24]([O:23][CH3:22])=[O:25])=[N:16][C:15]1[CH:17]=[C:11]([S:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:9])=[O:10])[CH:12]=[CH:13][C:14]=1[NH:18][C:19]([NH2:21])=[O:20])=[O:32]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)NC(=Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(N)=O)NC(=O)OC

Procedure:
15.3 g of 5-phenoxysulfonyl-2-ureidoaniline, 12 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 80 ml of methanol and 80 ml of ethyl acetate are stirred under reflux for four hours. After cooling down, the solid is filtered off with suction and washed with ethyl acetate and diisopropyl ether. For recrystallization, the solid is dissolved in dimethylformamide at about 50° C., treated with active charcoal, filtered, ethyl acetate and diisopropyl ether are added and crystallization is allowed to occur, melting point 193° C., decomposition.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+]>ClCCCl>[CH:9]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:10]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A mixture of N-methylformanilide (2.25 ml) and phosphoryl chloride (1.70 ml) was stirred at ambient temperature for 15 minutes. 1,2-dichloroethane (30 ml) was then added, followed by ethyl indole-2-carboxylate (3 g) and the reaction was heated at reflux for 90 minutes. The reaction mixture was then poured into a mixture of ice/water (200 ml) and sodium acetate (10 g) and extracted with ethyl acetate (2×200 ml). Combined organic phases were evaporated and the crude residue purified by column chromatography using dichloromethane as eluent to give the product as a white solid (2.27 g, 66%); NMR d (CD3SOCD3) 1.40 (t, 3H), 4.42 (q, 2H), 7.25 (m, 1H), 7.40 (m, 1H), 7.55 (m, 1H), 8.20 (m, 1H), 12.77 (s, 1H); M/z (+) 218.3 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH2:15](Cl)[C:16]#[CH:17].O>CN(C)C=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:17][C:16]#[CH:15])[C:8]=2[CH:14]=1
Reactant: C#CCCl
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2ccc(N)cc21
Temperature: 0 °C
Yield: 58.5 %

Procedure:
Sodium hydride (0.08 g) was suspended in dry N,N-dimethylformamide (3 ml), and the suspension was cooled to 0° C. While stirring, 6-amino-2H-1,4-benzoxazin-3(4H)-one (0.5 g) was portionwise added to the suspension at 0° C., and the resultant mixture was stirred at the same temperature for 30 minutes. To the mixture, propargyl chloride (0.25 g) was dropwise added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.36 g). m.p., 260.1° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: COC(=O)c1cc(N)c2nc(-c3ccccn3)nn2c1

Procedure:
The title compound, MS m/e (%): 270.3 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-Diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and pyridine-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([F:27])[CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)O)cc2)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3cc(F)ccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol) was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 2 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 16.0 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (6.20 mg, 45% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.50 (d, J=2.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.54 (dd, J=9.9, 2.5 Hz, 1H), 7.45-7.41 (m, 2H), 7.38 (dd, J=9.1, 6.0 Hz, 1H), 7.14 (td, J=8.7, 2.7 Hz, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 4.40 (s, 1H), 4.23 (dd, J=9.4, 4.1 Hz, 1H), 4.20-4.08 (m, 2H), 3.70 (q, J=6.2 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.52 (sxt, J=8.8 Hz, 1H), 2.09-1.97 (m, 1H), 1.71 (dd, J=19.7, 0.4 Hz, 2H), 1.63 (dd, J=8.0, 4.1 Hz, 1H), 1.31-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:28]([F:38])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)=[CH:27][C:28]=1[F:38]
Reactant: CC(C)(C)COc1ccc(-c2csc(NC(=O)CBr)n2)cc1F
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(OCC(C)(C)C)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl}acetamide (124 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 55 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 1.06 (s, 9H), 2.26 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 3.75 (s, 2H), 5.32 (s, 2H), 6.07 (s, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.65-7.75 (m, 2H), 12.77 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 514.16 (M+H)+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([C:7]1[N:8]=[N:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:13])[N:12]=1)[NH2:6]>C(Cl)Cl.C(OC(C)C)(C)C>[CH3:13][C:11]1[N:12]=[C:7]([NH:5][NH:6][C:3]([NH:2][CH3:1])=[O:4])[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CN=C=O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CNC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 98.7 %

Procedure:
A solution of methyl isocyanate (0.92 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3 g) in methylene chloride (20 ml) at room temperature. The reaction mixture was diluted with diisopropyl ether (30 ml). The resultant precipitates were collected by filtration to give a solid of 5-methyl-3-(4-methylsemicarbazido)-6-phenyl-1,2,4-triazine (3.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.OC[CH2:39][N:40]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]1=[O:50].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][CH2:39][N:40]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:50])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN4C(=O)c5ccccc5C4=O)c(C)c3C)c2cc1OC
Yield: 25.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(2-hydroxyethyl)-1,3-isoindolinedione (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (21 mg, yield 24%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][NH:14][CH3:15].O>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)nc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 6-bromomethylnicotinate (350 mg) in tetrahydrofuran (5 ml) was added a 50% aqueous dimethylamine solution (3 ml), and the mixture was vigorously stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=100:1) to obtain methyl 6-(dimethylamino)methylnicotinate (276 mg) as brownish powder.
Reaction SMILES: [O:1]=[C:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=O.C(N=C=NCCCN(C)C)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:24]([N:26]([CH2:27][CH3:28])[C:3](=[O:5])[C:2](=[O:1])[CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH3:25]
Reactant: CCNCC
Reactant: O=C1CCC(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Compound 13 was synthesized starting from treating oxo-(4-oxo-cyclohexyl)-acetic acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 eq.) and 4-dimethylaminopyridine (catalytic amount) in DMF. After stirring at room temperature for approximately 10 min., the reaction mixture was cooled in an ice-bath and diethylamine (1.5 eq.) was added. The resulting mixture was stirred at room temperature for 5 hours with TLC monitoring. The solvent was removed by evaporation. The residue was diluted with EtOAc and washed with H2O twice. The aqueous then was extracted with EtOAc and the organic layer was dried over Na2SO4. The desired intermediate N,N-diethyl-2-oxo-2-(4-oxo-cyclohexyl)-acetamide was obtained after purification through a combiflash chromatography system using a silica gel cartridge and CH2Cl2/MeOH gradient eluent, which further condensed with 3-hydroxybenzaldehyde (2.5 eq.) by following the same procedure described above to get the desired product as a yellow solid ESI MS m/z: 406.51 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ: 7.54 (s. 2H, benzylidene CH═), 7.25 (t, 2H, J=7.8 Hz, aromatic ring H), 6.93-6.89 (m, 4H, aromatic ring H), 6.81-6.78 (m, 2H, aromatic ring H), 3.23 (q, 4H, J=7.2 Hz, —NCH2CH3), 2.95 (m, 4H, 4-oxo-cyclohexyl-H-2,6), 2.54 (m, 1H, cyclohexyl-H-1), 0.94 (m, 6H, —NCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:7]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:29])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (0.31 g, 0.80 mmol [peak 1 from Examples 192, step 3]; 0.31 g, 0.80 mmol [peak 2 from Examples 192, step 3]) in DMF (4 mL) at 0° C. were each treated individually with sodium hydride dispersed in mineral oil (80 mg, 2.0 mmol). The ice bath was removed and the reaction mixtures were stirred for 30 min and heated at 60° C. for 30 minutes. The reaction mixtures were cooled down to 0° C., treated with methyl iodide (0.060 mL, 0.96 mmol) in DMF (2 mL, 26 mmol), and stirred at room temperature for 16 hours. The reaction mixtures were cooled to 0° C., quenched with saturated ammonium chloride, and extracted with EtOAc. The organic extract was concentrated to give a crude oil which was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give diastereoisomer from peak 1 (28 mg, 9%, retention time: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retention time: 2.51 min). Peak 1: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1. Peak 2: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1.
Reaction SMILES: [CH2:1]([N:8]([C:10]([NH:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]2[C:20]([CH3:25])=[N:21][O:22][C:23]=2[CH3:24])[CH:17]=1)=[O:11])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27](OCC)=[O:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[CH2:1]([N:8]1[C:10](=[O:11])[N:12]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[C:20]([CH3:25])=[N:21][O:22][C:23]=3[CH3:24])[CH:17]=2)[C:27](=[O:28])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)N(N)Cc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
1-benzyl-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)hydrazinecarboxamide (2.00 g, 5.88 mmol), ethyl chloroformate (6.38 g, 58.77 mmol), and triethylamine (1.78 g, 17.63 mmol) in acetonitrile (50 mL) were heated at 100° C. for 48 hours. The mixture was cooled to 80° C., 1 M NaOH(aq) (5 mL) was added and the reaction mixture was stirred for 1 hour. The reaction was cooled to room temperature and concentrated on the rotpvap. The residue was dissolved in dichloromethane and filtered to remove salts and the solution was concentrated to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (1.28 g, 60%) as a yellow oil. MS M+H calculated 367.14; found 367.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([O-:13])([O-])=O.[K+].[K+].[C:16](#[N:18])[CH3:17]>>[CH3:10][O:13]/[N:18]=[C:16](/[C:2]1[CH:9]=[CH:8][CH:5]=[CH:4][CH:3]=1)\[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Product: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of acetonitrile. To the stirred solvent was added 4-Hydroxy-benzylalcohol (0.27 g, 2.175 mmol) and K2CO3 (0.4 g, 2.89 mmol). Then it was stirred for 5 min. 2-Bromo-1-phenyl-ethanone o-methyl-oxime (0.5 g, 2 mmol) was added. Then RM heated 80° C. for 5 h. After completion of the reaction (reaction monitored by TLC), the RM was concentrated in vacuum to remove the acetonitrile. To the residue was then added 10 mL of water and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL), dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (0.5 g, yield: 92.2%); 1H NMR (300 MHz, DMSO-d6): δ 7.61-7.64 (m, 2H), 7.38-7.40 (t, 3H), 7.18-7.21 (d, 2H), 6.83-6.86 (d, 2H), 5.20 (s, 2H), 5.02-5.06 (t, 1H), 4.38-4.39 (d, 2H), 3.99 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:11]=2)[CH2:26][CH2:25]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 96 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (167 mg, 96%) which was obtained as a white solid. MS: m/e=350.3 [M+H]+.