Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>C(Cl)Cl>[CH3:31][C@H:11]1[C:12]2[C:17]([C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]=3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (193 ΞL, 2.5 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (33 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour, and concentrated to give (5R,7R)-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol as an oil, which was used further without purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>C(O)CO>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(C)c(-c2cccc3c(Br)cc(C)nc23)c(C)c1
Reactant: NCCN
Solvent: OCCO
Product: Cc1cc(C)c(-c2cccc3c(NCCN)cc(C)nc23)c(C)c1
Reaction time: 4 h

Procedure:
In a sealed tube, heat 4-bromo-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (100 mg, 0.29 mmol) at 140° C. in a mixture of ethylene glycol (1 mL) and ethylene diamine (0.3 mL). After 4 h, cool the reaction mixture and partition between saturated aqueous NaHCO3 and chloroform. Dry the combined organic extracts on Na2SO4 and concentrate under reduced pressure to obtain the title compound as a yellow glass: +APcI MS (M+1)+ 320; 1H NMR (methanol-d4) δ: 7.78 (dd, 1H), 7.39 (t, 1H), 7.34 (dd, 1H), 6.95 (s, 2H), 6.31 (s, 1H), 3.34 (t, 2H), 3.11 (t, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 1.89 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:19][CH:16]([CH3:18])[CH3:17])=[C:3]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:12]
Reactant: Cc1c(Cl)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CCO
Product: Cc1c(Cl)cc([N+](=O)[O-])c(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a stirred mixture of 10.0 grams (0.04 mole) of 3,6-dichloro-2,4-dinitrotoluene in 50 ml. of ethanol is added 9.0 grams (0.15 mole) of isopropylamine. The mixture is stirred at room temperature for 2 hours and then at reflux for one hour. The solution is allowed to cool to room temperature and the crystalline precipitate is filtered and washed with a little hexane to give 10.2 grams of golden crystals, melting point 69° C. to 73° C. Two recrystallizations from methanol give the analytically pure compound, melting point 69° C. to 70° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2O)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 12.8 %

Procedure:
To a solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.050 g, 0.19 mmol) which similarly prepared according to the procedure described in the Example 4 and 7-azaindole-3-carboxaldehyde (0.023 g, 0.16 mmol) in ethanol (1.0 mL), piperidine (0.0010 mL, 0.010 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed hexane then dried to afford the titled compound (0.008 g, y. 11%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27]2)#[N:23]>>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:22]#[N:23])[CH:25]=4)[CH2:30]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)CCNC2
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CCN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.20 g) and 6-cyano-1,2,3,4-tetrahydroisoquinoline hydrochloride (WO98/50363) (0.15 g) using the procedure described for Example 1 and isolated as a white solid (0.13 g). MS electrospray (+ion) 404 (MH+). 1H NMR δ (DMSO-d6): 10.20 (1H, s), 7.69 (1H, s), 7.65 (1H, d, J=7.5 Hz), 7.45 (3H, m), 7.02 (2H, d, J=8.6 Hz), 4.76 (1H, s), 4.11 (1H, t, J=5.9), 3.68 (2H, m), 3.44 (2H, m), 3.17 (2H, m), 2.90 (4H, m), 2.19 (2H, m), 1.78-1.37 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4].N1C=CC=CC=1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4]
Reactant: COC(=O)C(C)Nc1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C
Reactant: COCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCC(=O)N(c1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C)C(C)C(=O)OC
Temperature: 25 °C

Procedure:
16.2 g of N-(1'-methoxycarbonyl-ethyl)-2,6-dimethyl-3-(3',5'-dichlorophenylcarbamoylmethyl)-aniline and 3.2 g of pyridine were placed into 120 ml of toluene; and within 15 minutes were added 4.7 g of methoxyacetic acid chloride, dissolved in 30 ml of toluene. After the exothermic reaction had subsided, stirring was maintained for 4 hours at room temperature, and the reaction suspension was then filtered with suction. The yellow filtrate was washed with water, dried over sodium sulfate, and concentrated in a rotary evaporator. The solid residue was digested with ether, and the white crystals were filtered off with suction; m.p. 126°-128° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccccc1
Product: O=C(O)c1cccnc1NCc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of 2-chloronicotinic acid (10.0 g) and benzylamine (13.34 ml) was heated at 130° C. for 2 hours. The mixture was cooled and the resulting solid was broken up, triturated with water, acidified to pH 6 and filtered. The solid obtained was boiled up in IMS (200 ml), cooled and filtered to give 2-benzylaminonicotinic acid, m.p. 223°-225° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=3[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.60) (1.50 g, 4.35 mmol) and commercially available 3-bromo-benzene-boronic acid (0.96 g, 4.78 mmol) according to the general procedure IVb. Obtained as a white solid (1.23 g, 61%). MS (EI) 466.0 [(M)+]; mp 109° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>N1CCCC1>[C:11]([N:18]1[CH2:19][CH2:20][C:21]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The examples listed in Table 1 were prepared according to Schemes 1-37. The synthesis of compounds 1A-1U is outlined in Scheme 1. The 2′-hydroxyacetophenone derivatives 1.1a-1.1m were condensed with 1-Boc-4-piperidone 1.2 in neat pyrrolidine (method 1A) at room temperature or in refluxing methanol in the presence of pyrrolidine (method 1B) to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 1.3. Conversion of the ketones 1.3 to the enol triflate derivatives 1.5 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Suzuki type coupling of the enol triflate derivatives 1.5 with either 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 (commercially available from Combi-Blocks Inc.) or 2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0) (method 1C) or palladium, 10 wt. % (dry basis) on activated carbon (method 1D), lithium chloride, and an aqueous solution of sodium carbonate afforded compounds 1.8 which were converted to the final products (compounds 1A-1T) under acidic conditions (method 1E: anhydrous HCl, diethyl ether, room temperature or method 1F: neat trifluoroacetic acid, room temperature). Demethylation of compound 1G using boron tribromide provided the corresponding phenolic derivative (compound 1U). The boronate derivative 1.7 was prepared in 4 steps from 2,5-dibromopyridine 1.9. Treatment of 2,5-dibromopyridine with n-butyllithium provided the corresponding lithiated derivative, which reacted with carbon dioxide to provide 5-bromopyridine-2-carboxylic acid 1.10. Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride furnished the acyl chloride 1.11, which reacted with diethylamine 1.12 to provide 5-bromo-2-(N,N-diethylaminocarbonyl)-pyridine 1.13. Conversion of the aryl bromide 1.13 to the corresponding boron derivative 1.7 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2].
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.Cl.[NH2:28][OH:29].[OH-].[Na+].O>CO>[N:28](=[C:20]1[CH2:22][CH2:23][C@:9]2([OH:24])[C@:10]34[CH2:11][CH2:12][N:13]([CH2:14][CH:15]5[CH2:17][CH2:16]5)[C@@H:8]2[CH2:7][C:6]2[CH:1]=[CH:2][C:3]([OH:25])=[C:4]([O:19][C@@H:18]13)[C:5]4=2)[OH:29]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 15 h

Procedure:
A mixture of naltrexone hydrochloride (1.34 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was dissolved in 20 mL of MeOH and 2.8 mL of aqueous NaOH added. The mixture was stirred for 15 h. Water was added (100 mL) and the mixture extracted with 150 mL CHCl3 (3×50 mL). The combined extracts were dried (MgSO4) and evaporated. The residue obtained was chromatographed on a column of silica gel (approx. size 40 microns) using ethyl acetate-ethanol-NH4OH (300:1.5:2) as eluent. The combined fractions were evaporated and the residue recrystallized from CH2Cl2 -petroleum ether. Yield: 0.54 g (50.5%) mp 235-236° C. IR (KBr): No C=O absorption at 1720 cm-1. 1H NMR (CDCl3) δ6.7 (2d, 2H, J=10 Hz) 5 (s,C5H); Rf: silica gel 60 in ethylacetate-EtOH-NH4OH (100:1:1) 0.22. Anal. Calcd for C20H24N2O4 : C, 67.40; H, 6.79; N, 7.86. Found: C, 67.12; H, 6.88; N, 7.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([C:23](=[O:33])[C:24]#[C:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([C:23](=[O:33])[C:24]#[C:25][C:26]([OH:28])=[O:27])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8]
Reactant: COc1cc(C(=O)C#CC(=O)OC(C)(C)C)ccc1OCC(=O)Nc1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)C#CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of 2-[2-methoxy-4-(3-t-butoxycarbonylpropioloyl)phenoxymethylcarbonylamino]benzothiazole (0.5 g) in methylene chloride (30 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at room temperature for 4 hours. The mixture is concentrated, and to the residue is added methylene chloride. The mixture is stirred, and the precipitated crystals are collected by filtration, and recrystallized from dichloromethane-trifluoroacetic acid to give 2-[2-methoxy-4-(3-carboxypropioloyl)phenoxymethylcarbonylamino]-benzothiazole (0.26 g) as brown powder.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20]C(O)=O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH:20]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cccc(CC(=O)O)c1
Product: COc1cccc(C=C2OC(=O)c3ccccc32)c1
Temperature: 255 °C
Yield: 73.1 %

Procedure:
A mixture of phthalic anhydride (89.6 g, 0.605 mol), m-methoxyphenylacetic acid, (100.5 g, 0.605 mol), and freshly fused sodium acetate (3.0 g) is heated to 255° C. for 1 hour under a Dean-Stark receiver. The orange melt is poured onto aluminum foil and allowed to cool. The solid residue is recrystallized from absolute ethanol (2500 ml) to give 111.5 g (73%) of (3-methoxybenzal)phthalide as a yellow solid: m.p. 119°-123° C. Without further purification it (111.5 g, 0.441 mol) is hydrogenated with Raney nickel (6 tablespoons) at 25° C. and 40 psi in absolute ethanol (3000 ml). The catalyst is removed by filtration through super cel and the filtrate is evaporated to dryness under reduced pressure. The oily residue is slurried with methylene chloride (1000 ml) and extracted with aqueous saturated NaHCO3 (3×500 ml). The basic aqueous extracts are combined, warmed on a steam bath to remove excess methylene chloride, filtered, and the filtrate acidified with 6 N hydrochloric acid to give 70.9 g (63%) of 2-[2-(3-methoxyphenyl)-ethyl]benzoic acid as a white solid: m.p. 119°-122° C. Without further purification it (70.9 g, 0.276 mol) is treated with polyphosphoric acid (437 g) and heated to 100° C. After 2 hours, the reaction mixture is hydrolyzed in ice water and the aqueous phase is extracted with ether (3×300 ml). The combined etheral extracts are washed with aqueous saturated NaHCO3 (1×150 ml), H2O (2×150 ml), dried over MgSO4 and filtered, and the filtrate evaporated to dryness under reduced pressure. Treatment of the residue with ether gives 60.6 g (92%) of title compound as a light yellow solid: m.p. 74°-76° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:35](=[O:36])[N:34]([CH3:37])[C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[CH:12]=1>C(O)(=O)C>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:35](=[O:36])[N:34]([CH3:37])[C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[CH:12]=1
Reactant: CCOC(=O)CCCc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(CCCC(=O)O)cc3)nc21
Yield: 34.5 %

Procedure:
A volume of 5 mL of 2N sodium hydroxide was added to a hot stirred solution of 0.170 g (0.33 mmol) of 4-[4-{6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-butyric acid, ethyl ester of Example 91. The solution was maintained at reflux for 1 hour. Glacial acetic acid (1 mL) was added, and the reaction solution was evaporated to ca. 25 mL volume. Water (50 mL) was added to precipitate a solid. The mixture was filtered, and the cake was washed well with water and dried; wt 0.130 g. Hydrolysis did not go to completion under these conditions. The product was purified to remove starting ester by silica gel chromatography eluting with 1:20 methanol:chloroform to obtain 55 mg of pure acid; mp 169°-171° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH:9][C@H:10]([C:12]([N:14]2[C:20](=[O:21])[CH:19]([CH3:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[C:16]3[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]2=3)=[O:13])[CH3:11])=[O:8])[CH2:2]1
Reactant: O=C(O)C1CCOC1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCOC2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-3-furoic acid and. 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 408 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[ClH:15]>O>[Cl:15][C:10]1[C:9]2[O:12][CH2:13][C:7]3[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=3[C:8]=2[CH:7]=[C:6]2[CH:5]=[CH:4][C:3]([OH:14])=[CH:2][C:11]=12
Reactant: COc1ccc2ccc(O)c(Cl)c2c1
Reactant: Cl
Solvent: O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Cl

Procedure:
A mixture of Example 9 (2.25 g, 6.92 mmol) and pyridiumium hydrochloride (21.9 g, 162 mmol) was heated to 184° C. for 2 hrs. The reaction mixture was allowed to cool and poured into water (300 mL) and extracted with ethyl acetate (2×200 mL), washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the product was chromatographed (40% ethyl acetate-hexanes) to afford a white solid which was triturated with methylene chloride (25 mL) to afford 1.2 g (58%); mp 230–231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)(C)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1]/[C:11](=[CH:10]\[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)/C=C(\Nc1ccccc1C#N)C(=O)OC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A solution of 2-aminobenzonitrile (5.00 g, 42.3 mM) and dimethyl acetylenedicarboxylate (6.42 g, 45.2 mM) in t-butanol (70.5 mL) was refluxed under a nitrogen atmosphere for 12 hr. After cooling the reaction mixture to room temperature, a precipitate formed and was collected by filtration. The material was washed with cold methanol and air dried to give a yellow solid (4.88 g). Recrystallization of this solid from methanol provided the title compound (4.39 g, 39.9%) as yellow crystals, mp 116.5°-117.5° C.; MS(CI): 261 (M+H). Analysis for C13H12N2O4 : Calculated: C, 60.00; H, 4.65; N, 10.76 Found: C, 60.03; H, 4.67; N, 10.84
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](Cl)[N:31]=1>C1COCC1>[Cl:25][C:26]1[N:31]=[C:30]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]2[CH3:1])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]
Reactant: C[C@H]1NCCC[C@H]1NC(=O)OC(C)(C)C
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
tert-Butyl (2R,3R)-2-methylpiperidin-3-ylcarbamate (310) (1.1 g, 5.1 mmol) was dissolved in THF (20 mL). To the stirred solution was added DIEA (1.34 mL, 7.7 mmol), followed by 3,5-dichloropyrazine-2-carbonitrile (1.07 g, 6.2 mmol). The reaction was stirred at room temperature for 1 hour. An additional amount of 3,5-dichloropyrazine-2-carbonitrile (200 mg, 1.2 mmol) was added, and the reaction was stirred for another hour. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc. The organic mixture was washed with 1N HCl (aq), saturated NaHCO3(aq) and brine, dried, and concentrated in vacuo. The residue was then purified by silica flash column chromatography (EtOAc/hexanes) to give tert-butyl (2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (311), (1.54 g, 4.38 mmol, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>CN(C=O)C.O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][N:7]1[C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]1[Cl:1]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c(Cl)nc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(Cl)nc(Cl)c(Cl)c1=O
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of 2,5,6-trichloro-3H-pyrimidin-4-one (20.0 g, 0.1 mol) in DMF (150 mL) was added NaH (60% in mineral oil, 6.0 g, 0.12 mol) in portions at 0° C. and the mixture was stirred for 30 min. Bromoacetic acid methyl ester (18.3 g, 0.12 mol) was then added, and the reaction mixture was stirred at RT overnight. The solution was diluted with water (800 mL) and extracted with EA (200 mL, 3×). The combined organics were washed with water (800 mL, 3×), washed with brine (500 mL), dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:50, EA:PE) to give 6.0 g of the title product (22%). 1H NMR (400 MHz, CDCl3): δ 3.80 (s, 3H), 5.04 (s, 2H). [M+H] Calc'd for C7H5Cl3N2O3, 271. Found, 271.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]([NH:10][C:11](=[N:14][CH3:15])SC)#[N:9]>N1C=CC=CC=1>[C:8]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])=[N:14][CH3:15])#[N:9]
Reactant: NCCCCCO
Reactant: CN=C(NC#N)SC
Solvent: c1ccncc1
Product: CN=C(NC#N)NCCCCCO

Procedure:
A mixture of 5-aminopentan-1-ol (20 g.) and N-cyano-N',S-dimethylisothiourea (L25 g.) in pyridine (130 ml) was heated on a steam-bath for 14 hours, evaporated to dryness, and the residue recrystallised from chloroform/methanol to give N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (15.7 g). A recrystallised sample had m.p. 116°-119°.