Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][N:21]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccc(C(=O)O)cn1)n2Cc1ccc(F)cc1
Yield: 97.7 %

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methoxycarbonylpyridin-2-yl)indole (0.37 g), potassium hydroxide (0.12 g) and methanol (40 ml) was heated under reflux for 3 hours under nitrogen atmosphere. To the reaction solution was added water and the mixture was neutralized with hydrochloric acid. The precipitated crystal was filtered off. The resulting crude crystal was recrystallized (ethanol) to obtain 0.35 g of the desired product.
Reaction SMILES: Cl.[Cl-].[CH:3]([NH2+:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:24]([NH2:26])=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:5])[CH3:4]>C(OCC)C>[CH:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:24]([NH2:26])=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:5])[CH3:4]
Reactant: CC(C)[NH2+]CCCCC(C(N)=O)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)NCCCCC(C(N)=O)c1ccccc1-c1ccccc1

Procedure:
A solution of 4.9 g. of N-isopropyl-5-cyano-5-(1,1'-biphenyl-2-yl)pentylaminium chloride in 18.0 g. of conc. sulfuric acid containing 2.0 g. of water was heated at 100° C. for three hours. After cooling the reaction mixture to 5° C., the mixture was made alkaline by the addition of 10% sodium hydroxide. The alkaline solution was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with water, dried, and the solvent was removed by evaporation to provide the product as a solid. The solid was dissolved in fresh diethyl ether and converted to thehydrochloride salt by the addition of hydrogen chloride. Crystallization ofthe salt from ethanol and diethyl ether afforded 3.7 g. of N-isopropyl-5-aminocarbonyl-5-(1,1'-biphenyl-2-yl)pentylaminium chloride. M.P. 2.5°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(Cl)nc3ccccc23)cc1

Procedure:
A mixture of 12 g of 4-(4-fluorophenyl)carbostyril and 50 ml of phosphorus oxychloride is heated under reflux for 1.5 hours and then concentrated under reduced pressure. Ice-water is added to the residue and the resulting mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from diethyl ether - ethanol to give 11.1 g of the title compound, m.p. 118° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](N)[CH:10](C)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH3:17].Cl>[Pd].O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:9][N:8]([CH2:16][CH3:17])[CH2:1][CH3:2])[CH2:10][C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: CC1C(=O)N(Cc2ccccc2)CC1N
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
A mixture of 11.5 g (0.056 mol) of (-)-1-benzyl-4-amino-methyl-pyrrolidin-2-one, 130 ml of water, 13 g of acetaldehyde, 5.8 ml of concentrated hydrochloric acid and 6.5 g of 20% palladium-on-charcoal was hydrogenated for 51/4 hours at 5 bar and at 25° C. The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in 30 ml of water, and the solution was extracted with methylene chloride. The aqueous hydrochloric acid solution was made alkaline and then extracted with methylene chloride. By distillation of the combined extracts in a bulbed tube, 11.2 g (76.4% of theory) of the title compound were obtained, αD =-9.4 (c =1.0; :ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH3:18])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: CCBr
Product: CCCc1cc(C)cc(-n2c(C)ccc2C)n1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with bromoethane to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-propylpyridine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11]CCCCC.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: CCCCCC
Reactant: NC1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-amino-1-cyclohexanecarboxylic acid (500 mg) in dichloromethane (20 mL) and methanol (10 mL) was added 10% hexane solution of trimethylsilyldiazomethane (638 mg), and the mixture was stirred for 21 hours at ambient temperature. The mixture was evaporated in vacuo to give methyl 4-amino-1-cyclohexanecarboxylate as a colorless oil (544 mg).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:16]([C:15]2[CH:14]=[N:13][C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[CH:20][CH:19]=2)=[O:18])[CH2:25][CH2:24][CH2:23]1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: C1CNC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N2CCC2)cn1
Yield: 39 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using azetidine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (45 mg, 39%) which was obtained as a light yellow oil after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=330.3 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([F:14])[F:15])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 97.5 %

Procedure:
A mixture of 4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.018 ml), water (0.018 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 57) (0.4 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)=[N:6][C:5]=2[CH:7]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3cc(Cl)ccc3o2)CC1)c1ccccn1

Procedure:
Compound 24 is prepared using synthesis method 3 using intermediates 2h and 6a (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccncc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCc1ccncc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.40 (1H, br), 11.31 (1H, br), 10.15 (1H, br), 8.48 (2H, br m), 8.20 (1H, br s), 7.29 (5H, m), 7.14 (2H, t, J=8.7 Hz), 4.52 (2H, br m), 4.01 (2H, s); ES+ MS: 405 (M+H+, 100).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:15]([CH2:16]C)=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@@H:21]([CH3:23])[OH:22].O>CS(C)=O>[Cl:7][C:8]1[C:15]([CH3:16])=[C:14]([NH:19][C@H:20]([C@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
K2CO3 (3.15 g, 22.8 mmol) was added to a solution of 2-chloro-3-ethyl-4-fluorobenzonitrile (2.1 g, 11.4 mmol) and D-allo-threonine (2.04 g, 17.1 mmol) in DMSO (25 mL) at room temperature The reaction mixture was heated to 80° C. and stirred for 72 h then allowed to cool to room temperature. H2O (200 mL) was added and the brown solution was extracted with MTBE (200 mL). The aqueous layer was cooled to 0° C. and solid citric acid monohydrate was added in 200 mg portions until the evolution of gas ceased. The aqueous layer was then extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×300 mL), dried with Na2SO4, filtered and concentrated to provide the title compound (1.44 g, 32%): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.47 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 5.46 (d, J=8.7 Hz, 1H), 4.55-4.43 (m, 1H), 4.27 (dd, J=5.9 Hz, 8.7 Hz, 1H), 2.90-2.81 (m, 2H), 1.33 (d, J=6.3 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:14]([CH2:24][O:25][CH3:26])[O:13][C@H:12]1[N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([CH2:51][OH:52])=[N:31][C:32]=2[NH:36][CH2:37][CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[CH2:53]([O:52][CH2:51][C:30]1[N:29]=[C:28]2[C:33]([N:34]=[CH:35][N:27]2[C@H:12]2[C@H:11]([O:10][Si:3]([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:4])[CH3:5])[C@H:15]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[C@@H:14]([CH2:24][O:25][CH3:26])[O:13]2)=[C:32]([NH:36][CH2:37][CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:31]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCc4ccccc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.6 %

Procedure:
Sodium hydride (23 mg of an 80% dispersion in mineral oil, 0.76 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methanol (550 mg, 0.76 mmol) (preparation 15) in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 10 min and then benzyl bromide (0.117 ml, 1 mmol) added. The reaction mixture was stirred for a further 24 hr and then the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (3:1) rising in polarity to (2:1) to give the title compound (65 mg) as a gum. MS: 832 (MNa+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:29]=1.CC([O-])=O.[K+]>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[CH:29]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: CC(=O)[O-]
Agent: [K+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A glass microwave reaction vessel was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 272, Step 2) (0.530 g, 1.443 mmol), 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.554 g, 1.443 mmol), PdCl2 (AmPhos)2 (0.102 g, 0.144 mmol) and KOAc (0.425 g, 4.33 mmol). The tube was sealed and evacuated under vacuum and back-filled with nitrogen. Dioxane (3.75 mL) and water (0.375 mL) was added and Ar (g) was bubbled through the mixture for 5 minutes. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol, 24.79% yield) as a yellow oil. m/z (ESI, +ve) 671.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=9.39, 2.54 Hz, 1H); 8.13 (d, J=1.37 Hz, 1H); 7.18 (d, J=8.02Hz, 4H); 6.80-6.90 (m, 5H); 4.50-5.03 (m, 4H); 4.03 (d, J=5.28 Hz, 1H); 3.73-3.84 (m, 6H); 3.24-3.57 (m, 3H); 3.08-3.22 (m, 1H); 2.69-2.81 (m, 1H); 2.61 (s, 3H); 2.29-2.51 (m, 2H); 1.37-1.48 (m, 12H); 1.02 (d, J=6.26 Hz, 3H).
Reaction SMILES: C([O:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[O:15][C:16]([CH3:17])=[C:12]([CH2:11][CH2:10][OH:9])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(F)cc2)nc1CCO

Procedure:
The intermediate, 2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethyl benzoate (19.5 g, 60 mmol) was dissolved in 70 ml ethanol and stirred. 10% sodium hydroxide solution (NaOH: 4.8 g, 120 mmol) was slowly added dropwise, and the mixture was stirred overnight at room temperature. After the reaction was completed, the ethanol was concentrated, and the product was extracted with toluene, and then was washed with water and brine sequently, dried with anhydrous magnesium sulfate, and concentrated to obtain the intermediate, i.e. 2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethanol, which was directly applied in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][CH:12]=[CH:13][C:14](Cl)=[O:15])[CH3:10]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14](=[O:15])[CH:13]=[CH:12][O:11][CH2:9][CH3:10]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1ccccc1F
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccccc1F
Yield: 17.7 %

Procedure:
A solution of 2-fluoroaniline (ex. Aldrich) (3 g) in pyridine (20 ml) was treated at 0° with 3-ethoxyacryloyl chloride (3.64 g) (Prepared according to Paul et al, U..S. Pat. No. 2,768,174, (1956)). After 30 minutes at 0°-10° the reaction mixture was partitioned between ether and water and worked-up in conventional fashion. Chromatography on silica (ether : hexane, 1:1) gave N-(2-fluorophenyl)-3-ethoxyacrylamide (1 g). The latter was added in portions to conc. sulphuric acid (15 ml) at room temperature. After stirring overnight the mixture was poured onto ice-water. The resultant cream precipitate was collected and dried in vacuo to give 2-hydroxy-8-fluoroquinoline. This was converted to 2-chloro-8-fluoroquinoline by anlogy with Example IV.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[N:14]O.S(Cl)(Cl)=[O:17]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]3[CH2:13][CH:6]([NH:14][C:5]2=[O:17])[CH2:7]3)=[CH:10][C:11]=1[F:12]
Reactant: ON=C1c2cc(Br)c(F)cc2C2CC1C2
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Yield: 88.6 %

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime (3.5 g, 12.96 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) and thionyl chloride (24.7 g, 207.56 mmol, 16.00 equiv). The resulting solution was heated to reflux for 6 h, cooled, concentrated under vacuum, and quenched by the addition of 50 mL of water/ice. The solids were collected by filtration, washed with 2×50 mL of saturated aqueous NaHCO3 and 2×50 mL of water to afford 3.1 g (89%) of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:28])[C:16](=[O:27])[NH:17][C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:21]([NH2:22])=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>>[CH2:6]([O:5][P:4]([CH:9]1[N:14]2[C:15](=[O:28])[C:16](=[O:27])[NH:17][C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:21]([N:22]4[CH:31]=[CH:35][CH:34]=[CH:33]4)=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C1CCc2c(N)c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC1CCC(OC)O1
Product: CCOP(=O)(OCC)C1CCc2c(-n3cccc3)c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23

Procedure:
211 mg of 8-amino-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester and 66 mg of 2,5-dimethoxytetrahydrofuran are reacted for one hour at 140° C. bath temperature. After recrystallization from ethanol, 123 mg of 8-(1-pyrrolyl)-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester of melting point 268° C. is obtained.
Reaction SMILES: [C:1]([N:4]([CH2:9][C:10]([OH:12])=O)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH2:13]>C(O)(=O)C>[C:6]([CH2:5][N:4]1[CH2:2][C:1](=[O:3])[N:4]([CH2:5][C:6]([OH:8])=[O:7])[CH2:9][C:10]1=[O:12])([OH:7])=[O:13]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: O
Solvent: CC(=O)O
Product: O=C(O)CN1CC(=O)N(CC(=O)O)CC1=O
Temperature: 195 °C

Procedure:
N-acetyliminodiacetic acid (XVI) monohydrate (45 g) and varying amounts of water and acetic acid were heated at 175° C. or 195° C. for various periods of time. After cooling to room temperature, the mixture was filtered. The solid was washed with water (10 mL) and dried to give 1,4-di(carboxymethyl)-2,5-diketopiperazine. The table below shows the yields of solid under various conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:18]1[C:22]([CH:23]2[CH2:25][CH2:24]2)=[C:21]([CH:26]2[CH2:29][CH:28]([CH2:30][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:27]2)[O:20][N:19]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11].[OH-].[Na+:37]>C(O)C>[Na+:37].[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:18]1[C:22]([CH:23]2[CH2:24][CH2:25]2)=[C:21]([CH:26]2[CH2:27][CH:28]([CH2:30][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:29]2)[O:20][N:19]=1)[CH2:14][C:15]([O-:17])=[O:16])=[O:11]
Reactant: CCC(CC)CC1CC(c2onc(C(CC(=O)O)CC(=O)Nc3ccc(C)cc3Cl)c2C2CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)Nc3ccc(C)cc3Cl)c2C2CC2)C1
Reaction time: 0.33 h

Procedure:
4-(2-Chloro-4-methylphenylcarbamoyl)-3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}butanoic acid (28.9 mg) and ethanol (1 mL) were mixed. To the mixture was added aqueous 1 N sodium hydroxide (0.0577 mL) at ice temperature. The mixture was stirred at ice temperature 20 min., and then the solvent was evaporated to give the title compound (30.4 mg) as a crude product.