Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9](=[O:10])[N:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(=O)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
[(1S)-Benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (320 mg, 1 mmol) was added in one portion to a mixture of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DEC, 575 mg, 3 mmol) and dichloroacetic acid (192 mg, 1.5 mmol) in anhydrous toluene (2 mL) and anhydrous dimethylsulfoxide (2 mL). The mixture was stirred at 0-20° C. for 1 h, diluted with ethyl acetate, the resulting solution washed twice with 1N HCl, twice with saturated aqueous NaHCO3, dried and concentrated giving a colorless solid (304 mg, 96%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([CH:29]([OH:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[K+].[Br-]>C(Cl)Cl>[C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([C:29](=[O:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])[CH2:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)OC(C)(C)C)C(O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O

Procedure:
was synthesized from 215c by the same method as compound 216e as a glassy white solid (300 mg, 83%): mp 80-125° C.; [α]D23 −89.1 (c 1.08, CH2Cl2); IR (KBr) 3356, 2979, 2935, 1740, 1659, 1532, 1434, 1369, 1276, 1260, 1151; 1H NMR (CDCl3) δ7.39-7.32 (3H, m), 7.13 (1H, d), 6.34 (1H, d), 5.22-5.17 (1H, m), 5.11 (1H, d), 5.04 (1H, d), 4.99-4.88 (2H, m), 4.64-4.52 (1H, m), 3.29-3.11 (1H, m), 3.05-2.67 (4H, m), 2.39-2.29 (1H, m), 2.02 (3H, s), 1.98-1.75 (4H, m), 1.46 (9H, s); Anal. Calcd for C28H34N4Cl2O9: C, 52.42; H, 5.34; N, 8.73. Found: C, 52.53; H, 5.70; N, 7.85. MS (ES−) 643/41/39 (M−1, 100%). Accurate mass calculated for C28H35N4Cl2O9 (MH+): 641.1781. Found: 641.1735. Accurate mass calculated for C28H34N4Cl2O9Na (Mna+): 663.1601. Found: 663.1542.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH2:20][CH3:21])[N:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:5]1[C:4]([CH2:20][CH3:21])=[N:3][C:2]([C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[CH3:22])=[C:7]([CH2:8][CH3:9])[N:6]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1-c1cc(C)ccc1C
Temperature: 80 °C

Procedure:
The product from step 3 (90 mg, 0.3 mmol), 2,5-dimethylphenylboronic acid (105 g, 1 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg), toluene (4 mL) and potassium carbonate (2M, 2 mL) were combined in a pressure tube and heated at 80° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the upper layer is loaded onto a preparative thin layer chromatography plate and the desired product is obtained after elution with 20% ethyl acetate in hexanes. MS: 377. H-1 NMR (400 MHz, CDCl3): 1.13 (t, 3H), 1.14 (t, 3H), 2.06 (s, 3H), 2.34 (s, 3H), 2.65 (m, 4H), 3.78 (s, 3H), 3.86 (s, 3H), 6.56 (d, 1H), 6.62 (dd, 1H), 7.1-7.2 (m, 3H), 7.31 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CC(C)c1nc2c(Cl)cccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Yield: 51 %

Procedure:
[step 2] Using 8-chloro-3-iodo-2-isopropylimidazo[1,2-a]pyridine (393 mg, 1.23 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{8-[(8-chloro2-isopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (254 mg, 51%) was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[C:8]1([CH3:22])[CH:13]=[CH:12][C:11]([S:14]([NH:17][NH:18][C:19]([NH2:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH-].[K+]>O>[C:8]1([CH3:22])[CH:9]=[CH:10][C:11]([S:14]([N:17]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[NH:18][C:19](=[O:20])[NH2:21])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)NNC(N)=O)cc1
Reactant: CC(C)OC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(NC(N)=O)C(=O)OC(C)C)cc1
Temperature: 10 °C

Procedure:
The reaction is conducted in a 2 liter reaction flask equipped with thermometer, mechanical stirrer, dropping funnel, and an ice-water bath. 400 ml. water is placed in the flask and cooled to 10° C. Then 73.4 g. (0.6 mole) of isopropyl chloroformate is added. The mixture is stirred at 10° C. as a filtered solution of 114.5 g. (0.5 moles) of p-toluenesulfonyl semicarbazide in a mixture of 36.5 g. (0.55 mole) of KOH in 400 ml. of water is dropped in over the period of an hour, keeping the temperature near 10° C. (A small amount (7.5 g.) of caustic insoluble solid is filtered from the p-toluenesultonyl semicarbazide salt solution). The reaction mixture in the flask is stirred for an additional hour as the temperature is allowed to rise to 25° C. (the cooling bath is removed). A heating mantle is applied and the stirred mixture is warmed to 45° C. The warm mixture is then filtered and the white crystalline product washed with water and dried overnight at 60° C. in a circulating hot air oven. Yield 145 g. (98.4%). m.p. 210°-212° C. A sample is treated with concentrated ammonium hydroxide, washed with water and dried. m.p.=211°-213° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C(O)(C)(C)C.O1CCCC1>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C#N)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(C#N)nc2)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.9 %

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (62 mg) was dissolved in a mixture of tert-butanol (3 ml)-tetrahydrofuran (3 ml) and added thereto was sodium tert-butoxide (48 mg). The mixture was stirred at room temperature for 3.5 hours. Sodium tert-butoxide (19 mg) was further added thereto, and the mixture was stirred at room temperature for 1 hour. To the mixture was added a saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (23 mg) as colorless powder. APCI-Mass m/Z 470 (M+NH4).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:15][C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:11]([CH:14]=1)[C:12]#[N:13].O=C1CCCC(NC2C=CC=CC=2C#N)=C1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[NH2:13][C:12]1[C:11]2[C:10]([N:15]=[C:16]3[C:17]=1[C:18](=[O:22])[CH2:19][CH2:20][CH2:21]3)=[CH:9][CH:8]=[C:7]([Cl:6])[CH:14]=2
Reactant: N#Cc1cc(Cl)ccc1NC1=CC(=O)CCC1
Agent: N#Cc1ccccc1NC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccc(Cl)cc13)CCCC2=O
Yield: 3.8 %

Procedure:
In 5 liters of toluene were combined 200ml of dimethyl-formamide, 180.71 g of 5-chloro-2-(3-oxocyclohexen-1-yl)amino-benzonitrile hydrochloroide prepared in the same manner as the compounds of EXAMPLES 1 and 2, 176 g (2 eq) of milled K2CO3 and 3 g of cuprous chloride (CuCl). After 6 hours of reflux 3 g more of CuCl was added. After 12 hours of reflux 3 g more of CuCl was added. After overnight reflux the reaction mixture was evaporated and the residue extracted with dichloromethane via a Soxhlet extraction apparatus for 12 hours. The dichloromethane solution was evaporated to a solid. The solid was suspended in water and H2SO4 was added. The resultant salt which precipitated out was filtered and made basic with 10% NaOH. The solid was filtered and recrystallized twice from isopropanol/toluene to yield 6.84 g (4%) of a solid, melting point over 260° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.COC(C1OC2C=CC(S[CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[N:33][C:32]=3[CH3:46])=CC=2C=1)=O>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([O:14][CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=4)=[N:33][C:32]=3[CH3:46])=[CH:10][C:7]=2[S:8][CH:9]=1
Reactant: COC(=O)c1cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2o1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Product: COC(=O)Cc1csc2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
The title compound was prepared from compound 23C in a manner analogous to compound 6E. MS m/z 478 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=S)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1.C[OH:34].Cl.O>O1CCOCC1.[Hg]=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:34])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1
Reactant: CO
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=S)NC3CCCCC3)cc2)C(=O)C1
Agent: Cl
Agent: O=[Hg]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2)C(=O)C1

Procedure:
0.5 g N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamide)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-isourea methyl ether (m.p. 138°-140° C., prepared by desulfurization of N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-thiourea with mercury oxide in the presence of methanol) is dissolved in 5 ml of dioxan, and heated for a short time on a steam bath with 2 ml of concentrated hydrochloric acid. Subsequently, the water is added to the reaction mixture, the product is suction-filtered, reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea obtained has a melting point of 176°-178° C. and, with the substance obtained according to Example 8, shows no depression.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1)[CH3:25]
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: CCNCC
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and diethylamine are converted to the named compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(Oc3cccc(C#N)c3)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3′-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(18.5 g, 50 mmol) dissolved in ethanol/ethyl acetate (500 mL, 2/3) was added 10% palladium on carbon (1.8 g). After subjecting the mixture to hydrogen at 15 psi for 2 hours, the reaction was suction filtered through celite. The solvent was removed in vacuo to give 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.5 (m,7), 7.2 (m,2), 6.6 (d,1), 3.8 (br,2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[C:22]([NH:24][C:25]3([C:28]([O:30]CC)=[O:29])[CH2:27][CH2:26]3)=[O:23])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].[OH-].[Na+].Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=3)[C:22]([NH:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)=[O:23])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC(C(=O)NC1(C(=O)O)CC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg (0.106 mmol) of the compound of Example 5 were dissolved in 3 ml of methanol, and 422 μl of a 1M aqueous lithium hydroxide solution (0.42 mmol) were added. The mixture was stirred at RT overnight. Since the reaction was very slow, another 210 μl (0.21 mmol) of a 1M sodium hydroxide solution were added and the mixture was stirred at RT for another 5 days. By addition of 1N hydrochloric acid, the mixture was adjusted to pH 2, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 37 mg (61% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>O>[Br:22][CH2:23][CH2:24][C:25]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:26]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C(Cl)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a stirred solution of 22.5 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 21.2 g of sodium carbonate in 200 ml of water, cooled by an ice-water bath, 18.8 g of 3-bromopropanoyl chloride is added dropwise. The resulting mixture is continuously stirred for 2 hr at room temperature, acidified with 2 N aqueous hydrochloric acid solution, and extracted with 300 ml of ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. After removal of ethyl acetate in vacuo, 100 ml of chloroform is added to the residue and the separated crystals are filtered to give 24.3 g (70%) of the product. The product is recrystallized from methanol to yield the titled compound: mp 109°-115° C.; IR (nujol) 3330, 1709, 1629, 1594, 1229, 1198, 1029 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:13](Cl)(=[O:15])[CH3:14].C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:13]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:15])[CH3:14]
Reactant: O=C1CCc2cccc(F)c2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc(F)c2c(c1)CCC(=O)N2
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a stirring solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (1.6 g, 9.69 mmol) and acetyl chloride (1.722 mL, 24.22 mmol) in carbon disulfide (20 mL, 9.69 mmol) at 0° C. was added in portions aluminum chloride (6.59 g, 49.4 mmol). The reaction mixture was stirred at 100° C. without a condensor until the solvent evaporated, then a condensor was fitted in place and stirring continued at 100° C. for 4 h. After cooling, the reaction contents were carefully poured into ice water and partitioned between DCM and water. The aqueous layer was extracted with DCM (3×150 mL). The combined organic washes were dried over MgSO4 and concentrated under vacuum to a tan solid. This was purified by flash chromatography on silica gel using 1% MeOH in DCM to give 6-acetyl-8-fluoro-3,4-dihydroquinolin-2(1H)-one as a yellow solid (1.6 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (br. s., 1H), 7.68-7.60 (m, 1H), 2.76-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.58 (s, 13H). LCMS: R.T.=1.335 min; [M+H]+=208.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[NH:18][C:17](=[O:19])[C:16]3([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:26]([O:33][C:34]([CH2:36][CH2:37][N:38]=[C:39]=[O:40])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[N:18]([C:39]([NH:38][CH2:37][CH2:36][C:34]([O:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:35])=[O:40])[C:17](=[O:19])[C:16]3([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C=NCCC(=O)OCc1ccccc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)N2CCN(C)CC2)cc1
Product: CCC1(CC)C(=O)N(C(=O)NCCC(=O)OCc2ccccc2)C1Oc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
According to the method of Shrenik et al (J. Med. Chem., 35, 3745-3754 (1992)), 4-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-2-azetidinone, prepared as in Example 5, step F, (0.68 g, 1.97 mmol) and 2-(benzyloxycarbonyl)ethylisocyanate (0.705 g, 3.94 mmol) gave, following purification by flash column chromatography (gradient from petrol/EtOAc, 1:1 to MeOH/EtOAc, 1:9 to MeOH/EtOAc, 1:1), the title compound (840 mg, 78%) as an oil.
Reaction SMILES: [C:1]1([C:7](=[O:14])[CH2:8][C:9]2[N:10]=[N:11][NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]I>CC(C)=O>[CH3:15][N:10]1[C:9]([CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:14])=[N:13][N:12]=[N:11]1
Reactant: CI
Reactant: O=C(Cc1nn[nH]n1)c1ccccc1
Solvent: CC(C)=O
Product: Cn1nnnc1CC(=O)c1ccccc1
Yield: 34 %

Procedure:
1-Phenyl-2-(2H-tetrazol-5-yl)-ethanone (13.24 g, 70.4 mmol) was dissolved in acetone (300 mL). MeI (4.6 mL, 73.9 mmol) and KCO3 (10.68 g, 77.4 mmol) were added and the reaction mixture was heated to reflux for 30 min. The reaction mixture was filtered and the solvent was removed in vacuo. The crude product contains a mixture of 2-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-ethanone and 2-(2-methyl-2H-tetrazol-5-yl)-1-phenyl-ethanone. The two compounds were separated by flash column chromatography using ethyl acetate/hexane (6/4) as eluent. 2-(1-Methyl-1H-tetrazol-5-yl)-1-phenyl-ethanone was obtained as a white solid. Yield: 34%.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(OCC)C>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH3:19])[C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 23.7 %

Procedure:
8-Cyclopentyl-6-methyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 3.43 mmol) was added to 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.91 g, 6.86 mmol) in toluene (5 ml). The mixture was heated to 100° C. over 18 hours then treated with diethyl ether to produce a precipitate. This precipitate was collected by filtration then dried in vacuo to provide 4-[6-(8-cyclopentyl-6-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.411 g). MS (APCI) M++1: Calc'd, 506.28. Found 506.2.