Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8].[NH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([S:27][CH3:28])[C:17]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:30][C:29]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:15]=[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([S:27][CH3:28])[C:17]=12
Reactant: COC(=O)C#CC(=O)OC
Reactant: CSc1nn(-c2ccccc2)c(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc2c(c(SC)nn2-c2ccccc2)c(N)c1C(=O)OC
Yield: 25.6 %

Procedure:
A dimethylsulfoxide (20 ml) solution of 9.0 g (63 mmol) of dimethyl acetylenedicarboxylate was dropwise added to a mixture comprised of 11.5 g (50 mmol) of 5-amino-3-methylthio-1-phenylpyrazole-4-carbonitrile, 20.8 g (145 mmol) of anhydrous potassium carbonate and 300 ml of dimethylsulfoxide, while stirring and cooling with ice, and then stirred for further 60 hours at room temperature. During the stirring, the reaction liquid was changed from brown to greenish brown. After the reaction, the liquid reaction mixture was poured into 500 ml of water with ice and stirred for 30 minutes at room temperature. The blackish brown solid thus precipitated was taken out, and 20 ml of methanol was added thereto and heated. The white crystals thus formed were taken out by means of filtration under suction and recrystallized from methanol to obtain 4.80 g (12.8 mmol) of the entitled product as colorless, needle-like crystals having a melting point of 120° to 122° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:47])[NH:31][C:32]3[S:33][C:34]4[C:39]([N:40]=3)=[CH:38][CH:37]=[C:36]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:35]=4)[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:25]1([CH2:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)[C:30]([NH:31][C:32]2[S:33][C:34]3[C:39]([N:40]=2)=[CH:38][CH:37]=[C:36]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[N:35]=3)=[O:47])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(N5CCOCC5)nc4s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccc(N3CCOCC3)nc2s1)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCNCC2)cc1
Reaction time: 1 h

Procedure:
Title compound G, 4-{4-[2-Cyclopentyl-1-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.378 mmol) was dissolved in 5 mL DCM and 2 mL of TFA was added. The solution was stirred for 1 h and then evaporated to afford a crude oil. The residue was partitioned between 2N NaOH and ethyl acetate and extracted numerous times with ethyl acetate, dried over MgSO4, filtered and concentrated to afford a green solid. This material was taken on crude to the next reaction. 1H NMR (400 MHz, DMSO) δ 1.07-1.16 (M, 2H) 1.39-1.50 (m, 2H) 1.52-1.63 (m, 3H) 1.68-1.79 (m, 3H) 2.16 (m, 1H) 2.71 (d, J=4.80 Hz, 4H) 2.76 (d, J=5.05 Hz, 4H) 3.43-3.51 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (d, J=8.84 Hz, 1H) 6.97 (d, J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.73 (m, 2H) 7.88 (d, J=9.09 Hz, 1H) MS 585.31 [M+1]+.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:36]([O:42][C:43]1[CH:44]=[C:45]2[C:49](=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=1)[NH:48][C:47]([C:55]([NH:57][CH2:58][CH:59]([S:65]CC1C=CC=CC=1)[CH:60]([O:63][CH3:64])[O:61][CH3:62])=O)=[CH:46]2)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:36]([O:42][C:43]1[CH:44]=[C:45]2[C:49](=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=1)[NH:48][C:47]([C:55]1[S:65][CH:59]([CH:60]([O:61][CH3:62])[O:63][CH3:64])[CH2:58][N:57]=1)=[CH:46]2)(=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40]
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OC(=O)C(C)(C)C)cc([N+](=O)[O-])c2[nH]1)SCc1ccccc1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc([N+](=O)[O-])c3[nH]2)S1
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of triphenylphosphine oxide (14.8 g) in dichloromethane (50 mL) was added dropwise trifluoromethanesulfonic anhydride (3.0 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of 2-({[2-(benzylthio)-3,3-dimethoxypropyl]amino}carbonyl)-7-nitro-1H-indol-5-yl pivalate (9.38 g) and thioanisole (10.4 mL) in dichloromethane (100 mL) was added dropwise to this solution at −78° C., and the reaction mixture was stirred at −78° C. for 1 hr, and then at 0° C. for 1 hr. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0-4:6) to give the title compound (4.32 g, yield 58%) as a pale-yellow amorphous powder. MS: 422 (MH+).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].O>CO.CN(C)C=O>[C:1]([O:6][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCCCCCCl
Reactant: C=C(C)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCO
Reaction time: 0.5 h

Procedure:
Methacrylate acid (43.0 g=0.5 mole) was dissolved in 50 mL methanol. Tetrabutylammonium hydroxide (25% in methanol, 519 gm=0.5 mole) was added to the latter solution. The solution was stirred for 30 minutes, and then freed of solvent on a rotary evaporator. The residue was dissolved in 100 mL of N,N-dimethylformamide (DMF) and a solution of 6-chloro-1-hexanol (68.3 gm+0.5 mole) in 200 mL DMF was added. This was stirred at 50° C. for 4 hours, the heat was discontinued, and the solution was stirred at room temperature overnight. An equal volume of H2O was combined and the solution was extracted with three portions of ethyl acetate. The combined ethyl acetate layers were back-extracted with three portions of H2O, dried over MgSO4, and the mixture evaporated to an amber oil. 1H NMR (CDCl3): δ (ppm) 4.1 (2H, t). Elemental Analysis: C10H18O3, mol. wt. 186. Calcd.: C, 61.5; H, 9.7; O, 25.8. Found: C, 61.7; H, 9.7.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C:15]3([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:23][C:24]([NH2:26])=[NH:25])=[N:4][CH:3]=1.Cl.NC(N)=N.[CH2:32](OC(=O)C1(CCCC1)NC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)[CH3:33]>CC(O)(C)C>[CH2:32]([O:21][C:20](=[O:22])[C:15]1([CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:10][CH:9]=1)=[O:13])[CH3:33]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC3(C(=O)O)CCCC3)cc12
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Agent: Cl
Agent: N=C(N)N
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(NC(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 15.2 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine ##STR62## NaH (45 mg, 60% dispersion in mineral oil, 1.13 mmol) was added to t-BuOH and the mixture heated at 50° C. for 15 min. Guanidine hydrochloride (105 mg, 1.10 mmol) was added and the mixture heated at 50° C. for an additional 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]cycloleucine ethyl ester (350 mg, 0.92 mmol) was added and the mixture heated at reflux for 17 h. The solvents were evaporated in vacuo and the residue purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (90:10:1) as eluant, followed by trituration with CH2Cl2 -i-Pr2O, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine ethyl ester (55 mg, 0.14 mmol) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:4]=[C:3]1[CH2:21][O:22]C(C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:4]=[C:3]1[CH2:21][OH:22]
Reactant: CCOC(=O)c1c(COc2cccc(C)c2)cc(COC(C)(C)C)n1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(COc2cccc(C)c2)cc(CO)n1C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 1-methyl-2-(t-butoxymethyl)-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate (3.82 g, 0.01 mol) is allowed to stand in trifluoroacetic acid (50 ml) at room temperature until all starting material is gone by TLC. The TFA is then removed in vacuo and the residue is stirred for 30 minutes with a saturated solution of sodium carbonate in 50% aqueous ethanol (200 ml). Saturated brine (250 ml) is then added, along with ethyl acetate (250 ml) and the layers are separated. The organic layer is washed twice with H2O (100 ml) then brine (50 ml) and dried over anhydrous sodium sulfate. The solvent is then removed and the residue subjected to preparative HPLC to obtain pure ethyl 1-methyl-2-hydroxymethyl-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][OH:15]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][OH:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: NCCO
Product: O=[N+]([O-])c1cc(F)ccc1NCCO

Procedure:
This compound was prepared from 1,4-difluoro-2-nitrobenzene (21.8 ml, 100 mmol) and 2-amino ethanol (10 ml, 300 mmol) using analogous procedure described in Step A of Example 3. Yield (19.2 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:11][OH:12]
Reactant: O=Cc1cnccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cnccc1Cl
Temperature: 0 °C
Yield: 85.3 %

Procedure:
Combine 4-chloropyridine-3-carboxaldehyde (2.75 g, 0.020 mol) with hydroxylamine hydrochloride (1.38 g, 0.021 mol) and ice (50 g) in an ethanol/water (25 mL/25 mL) mixture. Add aqueous sodium hydroxide (2.00 g, 0.049 mol, in 25 mL of water) dropwise and stir for 3 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry the combined extracts over sodium sulfate and concentrate in vacuo which leaves the desired crude oxime (2.67 g, 88%). MS(ES): (M+1)+ 156.0, 158.0 m/z.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][C:5]2[C:7]([C:13]3[C@H:22]4[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]4)[C:16](=[O:23])[NH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.[CH:25]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1([CH3:24])[CH2:6][C:5]2[C:7]([C:13]3[C@H:22]4[C@H:17]([CH2:18][CH:19]=[CH:20][CH2:21]4)[C:16](=[O:23])[N:15]([CH:25]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:14]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1
Reactant: BrC1CCCCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2
Product: COc1ccc(C2=NN(C3CCCCCC3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from compound 4 and cycloheptyl bromide as described for compound 11. M. p. 114-115° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])(C)(C)C.[B:21](OC)([O:24]C)[O:22]C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[C:11]([O:10][C:9]([NH:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[B:21]([OH:24])[OH:22])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1B(O)O
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 2-fluorophenylcarbamate (from step 1) (1.0 eq.) in tetrahydrofuran (0.25 M) at −78° C. under N2 atmosphere was added dropwise 1.7 M tert-butyllithium (2.4 eq.). The reaction was warmed to −40° C. slowly over 2 hours, and neat trimethyl borate (3.8 eq.) was added. The reaction was warmed to room temperature over 30 minutes. An aqueous solution of 1N NaOH was slowly added to the reaction and stirred for 15 minutes. The mixture was poured into ethyl acetate and acidified with 3N HCl to dissolve the solids. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The resulting solids were stirred in 1:1 ether/hexane, filtered, and dried. The solids were carried onto the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH3:5].BrBr.[NH2:9][C:10]([NH2:12])=[S:11]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:10]([NH2:12])[S:11][CH:5]=1
Reactant: NC(N)=S
Reactant: COCC(C)=O
Agent: BrBr
Solvent: CO
Product: COCc1csc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
A solution of 1-methoxypropan-2-one (20.3 g, 231 mmol) in 200 mL of MeOH was added to a 250 mL round-bottom flask. The flask was then immersed in an ice-water bath. Br2 was added dropwise to the reaction mixture through an addition funnel. After the addition, the addition funnel was rinsed with 50 mL MeOH, and the reaction mixture was stirred for 20 minutes at 0° C. The ice-water bath was then removed, and the reaction mixture was stirred for two more hours. Thiourea (18 g, 231 mmol) was then added to the reaction mixture, and the reaction was heated at reflux overnight. The reaction was concentrated, and saturated sodium bicarbonate and solid sodium carbonate were used to adjust the pH to 8-9. The resulting mixture was then extracted three times with 200 mL portions of EtOAc. The organic layers were concentrated and then purified by recrystallization to give 4-(methoxymethyl)thiazol-2-amine (11 g, 33% yield over two steps). MS m/z: 145 (M+1).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([NH:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]2[N:32]=[CH:31][NH:30][CH:29]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 190 mg of (±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoic acid and 400 mg of bis(P-toluenesulfonic acid) salt of L-histidyl-L-leucinal semicarbazone in 7 ml of N,N-dimethylformamide were successively added 0.16 ml of diphenylphosphoryl azide and 0.28 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted withh ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1 by volume) to obtain 151 mg of N-[(±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoyl]-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(OCc3ccccc3)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-(benzyloxy)acetophenone (T. Fujii, M. Ohba, M. Tsuchida, K. Saito, Y. Hirano, and J. Sakaguchi, Chem.Pharm.Bull., 1986, 34, 496-507).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[NH:5][C:6](=[O:8])[CH:7]=1.[CH3:15][C:16]1[CH:17]=[C:18]([SH:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(O)C.C(N(CC)CC)C>[CH3:15][C:16]1[CH:17]=[C:18]([S:23][C:2]2[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[NH:5][C:6](=[O:8])[CH:7]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: CCOC(=O)c1c(Cl)cc(=O)[nH]c1C
Reactant: Cc1cc(C)cc(S)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(Sc2cc(C)cc(C)c2)cc(=O)[nH]c1C

Procedure:
A mixture of the intermediate 13 (1.2 g; 5.6 mmol) in ethanol (15 ml), triethylamine (1.5 ml) and 3,5-dimethylthiophenol (1.45 ml; 11 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, diethylether (50 ml) was added and the precipitate was filtered off. The intermediate 14 was obtained (1.42 g; 80%) as a colorless solid m.p.=233–235° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[C:13]([C:8]1[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][CH:9]=1)=[CH:14]2
Reactant: O=[N+]([O-])c1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Yield: 98.5 %

Procedure:
Compound 109 (0.4 g, 1.485 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) and hydrazine hydrate (0.46 mL, 1.029 mmol). The resulting mixture was placed in a pre-heated oil bath and refluxed for 2 min (until yellow colour disappears). The reaction was brought to room temperature, filtered through celite bed and washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 110 (0.35 g, quantitative) as a foam. mp 65-67° C.; 1H NMR (DMSO-d6) δ 1.42-1.54 (m, 2H), 1.62-1.74 (m, 2H), 2.52-2.56 (m, 2H), 2.86-2.94 (m, 2H), 2.98-3.02 (m, 1H), 4.75 (s, 2H), 6.41 (dd, 1H, J=2.1, 8.4 Hz), 6.53 (d, 1H, J=1.8 Hz), 6.69 (s, 1H), 7.16 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=8.4 Hz), 10.57 (s, 1H); ESI-MS (m/z, %): 240 (MH+, 100).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29](SC)[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([CH3:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:51][NH2:52]>C1COCC1>[C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29]([NH:52][CH3:51])[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([CH3:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3C)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3C)c(=O)n(C)c2n1
Yield: 71 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (148 mg, 0.263 mmol), MCPBA (81 mg, 0.328 mmol) and 2.0N methylamine in THF (1.3 mL) were combined to afford 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (103 mg, 71% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 9H), 2.08 (s, 3H), 2.92 (s, 3H), 3.55-3.62 (m, 3H), 7.25-7.30 (m, 1H), 7.69 (s, 1H), 7.70-7.80 (m, 1H), 7.93 (s, 1H), 7.95-8.05 (m, 1H), 8.51 (s, 1H), 8.20-8.25 (m, 1H), 9.04 (s, 1H); MS (ESI) m/z: 547.2 (M+H+).
Reaction SMILES: C([CH:5]1[C:9](C)(C)[C:8](=[O:12])[C:7](O[SiH3])([CH:13]([OH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]1[CH:26]=[CH:27][CH:28]([O:34][Si](C(C)(C)C)(C)C)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C)(C)C.C(O)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC.O>[OH:34][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:6]1[CH:7]([CH:13]([OH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:8](=[O:12])[CH:9]=[CH:5]1
Reactant: CCCCCC(C=CC1C(C(C)(C)C)C(C)(C)C(=O)C1(O[SiH3])C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)C=CC1C=CC(=O)C1C(O)CCCCCC(=O)OC
Temperature: 80 °C
Reaction time: 7 h
Yield: 1 %

Procedure:
370 mg (60 mmoles) of 4-t-butyldimethyl silyloxy-3-(3-t-butyldimethylsilyloxy-1-octenyl)-2-(1-hydroxy-6-methoxycarbonylhexyl)cyclopentanone obtained in Example 22, (1) was dissolved in 10 ml of a mixed solvent consisting of acetic acid, tetrahydrofuran and water in a ratio of 2:1:1, and the solution was stirred at 80° C. for 7 hours. An aqueous solution of sodium bicarbonate and ethyl acetate were added to perform extraction. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dried product was filtered, concentratd, and subjected to silica gel column chromatography (silica gel), 10 g; eluent, hexane:ethyl acetate=5:1→1:2) to give 218 mg (yield 62%) of 4-(3-hydroxy-1-octenyl)-5-(1-hydroxy-6-methoxycarbonylhexyl)cyclopentenone
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2c(F)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-fluoroisatin (0.082 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.