Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.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>[OH:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:15][CH:14]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:6]=2[CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
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: C1CCOC1
Product: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 25 °C

Procedure:
A 150-mL pressure vessel was charged with 2′-bromo-7′-hydroxyspiro[1,3-oxazole-4,9′-xanthen]-2-amine (845 mg, 2434 μmol) in THF (24 mL), pyrimidin-5-ylboronic acid (754 mg, 6085 μmol), tetrakis(triphenylphosphine)palladium(0) (281 mg, 243 μmol), and potassium carbonate (10.1 mL of a 1.2 M aqueous solution, 12.1 mmol). The vessel was sealed and placed in a 100° C. oil bath at for 4 h. The reaction mixture was cooled to RT and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude material was purified by chromatography on silica gel (eluting with 30-100% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as an off-white solid. MS m/z=347.2 [M+H]+. Calc'd for C19H15N4O3: 347.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])N(C)C.[CH3:9][C:10]([CH:12](OC)OC)=O.[OH-].[Na+].Cl.[NH2:20][C:21]([NH2:23])=[NH:22]>O>[CH3:8][O:7][CH:3]([O:2][CH3:1])[C:12]1[CH:10]=[CH:9][N:22]=[C:21]([NH2:23])[N:20]=1
Reactant: COC(OC)N(C)C
Reactant: COC(OC)C(C)=O
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(OC)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.6 %

Procedure:
A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvic aldehyde dimethyl acetal was heated at 100° C. for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 mmol, 36%) of 2-aminopyrimidine-4-carboxaldehyde dimethylacetal (I-8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][CH:15]2[CH:16]([CH3:19])[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:14]2)=[N:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)CCC4C)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1Nc1ncnc2[nH]ccc12
Temperature: 60 °C
Yield: 27.1 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(4-methyl-3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)ethanone (100 mg, 0.17 mmol) in MeOH:H2O (4:1 mL) was added K2CO3 (94 mg, 0.68 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted in EtOAc (50 mL). The EtOAc suspension was filtered through celite, the filtrate was dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (20 mg, 27%). 1H NMR (400 MHz, DMSO-d6): δ 11.61-11.45 (m, 1H), 8.19-8.06 (m, 1H), 7.08-6.43 (m, 5H), 6.22-6.15 (m, 1H), 4.59-4.21 (m, 2H), 4.15-3.75 (m, 3H), 3.25-2.98 (m, 2H), 2.78-2.45 (m, 1H), 2.15-1.99 (m, 1H), 1.86-1.7-62 (m, 2H), 0.98-0.77 (m, 3H). LC-MS: m/z [M+1]=433.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C@H:8]([C@H:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:12])[CH3:10])[C@@H:7]([C@H:19]([OH:21])[CH3:20])[C:6]1=[O:22])([OH:3])=[O:2].[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[I-].[Na+].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:13]1([C:11]([C@@H:9]([C@H:8]2[N:5]([CH2:4][C:1]([O:3][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:2])[C:6](=[O:22])[C@@H:7]2[C@H:19]([OH:21])[CH3:20])[CH3:10])=[S:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OCOC(=O)C(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Reaction time: 6 h

Procedure:
At room temperature (25° C.), 1.35 g (4.0 mmol) of (3S,4S)-1-carboxymethyl-4-[(1R)-1-(phenylthiocarbonyl)ethyl]-3-[(1R)-1-hydroxyethyl]-2-azetidinone was dissolved in 8 ml of dimethylformamide, and 1.20 (8.0 mmol) of-pivaloyloxymethyl chloride and 1.20 g (8.0 mmol) of sodium iodide were sequentially added thereto. Subsequently, 0.68 g (5.3 mmol) of diisopropylethylamine was added dropwise thereto, and stirring was performed at the same temperature for 6 hours. The reaction solution was diluted with 40 ml of ethyl acetate, and washing was performed several times using 5% aqueous sodium bicarbonate and water. The resulting ethyl acetate solution was dried over sodium sulfate, and then the solvent was removed by distillation. Thereby, 1.88 g of the target compound was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OCCCCCC=Cc1cccc(Br)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)CCc1ccc(NCCCCCC=Cc2cccc(Br)c2)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 7-(3-bromophenyl)-1-methanesulfonyloxy-6-heptene (prepared by the method of Example 9), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80° for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20].[CH3:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>C(#N)C>[CH:19]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:26]1[CH:27]=[C:23]([CH3:22])[N:24]=[CH:25]1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2OC(C)C)cn1
Yield: 11.2 %

Procedure:
A solution of 2.0 g (11.5 mmol) 2-chloro-5-nitrophenol in 15 ml of acetonitrile was treated with 11.26 g (34.6 mmol) cesium carbonate and 2.06 g (12.1 mmol) 2-iodopropane and heated overnight at reflux temperature. 993 mg (12.1 mmol) of 4-methylimidazole was added and the mixture refluxed again overnight. After evaporation of the solvent, water was added and the crude material extracted with ethyl acetate. The product was purified on silica gel with ethyl acetate to give 337 mg (11%) of 1-(2-isopropoxy-4-nitro-phenyl)-4-methyl-1H-imidazole as a slightly brownish solid. MS ISP (m/e): 262.0 (100) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.95-7.85 (m, 3H), 7.40 (d, 1H), 6.99 (s, 1H), 4.73 (sept, 1H), 2.31 (s, 3H), 1.40 (d, 6H).
Reaction SMILES: [F:1][C:2]1[C:13]([I:14])=[CH:12][C:5]([CH2:6]OS(C)(=O)=O)=[C:4]([CH2:15]OS(C)(=O)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30]1([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH:36]([N:43]1[CH2:15][C:4]2[C:5](=[CH:12][C:13]([I:14])=[C:2]([F:1])[CH:3]=2)[CH2:6]1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a mixture of 5.93 mmol methanesulfonic acid 4-fluoro-5-iodo-2-methanesulfonyloxymethyl-benzyl ester and 14.8 mmol N,N-diisopropylethylamine in 7 ml DMF at 0° C. was added dropwise a solution of 6.53 mmol diphenylmethylamine in 5 ml DMF. The mixture was heated at 60° C. for 16 h and was then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a light yellow solid (55% yield).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.BrBr.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CCCCC>[NH2:20][C:18]1[S:19][C:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=2[N:17]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a solution of compound tert-butyl 4-oxopiperidine-1-carboxylate (24.0 g, 120.6 mmol) in dry CHCl3 (500 mL) at 0-5° C., was slowly added a solution of Br2 in CHCl3 (100 mL) over 1.5 hours. The reaction mixture was warmed to RT and stirred for 3 hours. The reaction mixture was concentrated to obtain solid, which was thoroughly washed with Et2O. The resulting intermediate tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate was used immediately in the next reaction. Accordingly, this intermediate (20 g, 72 mmol) was suspended in pentane, filtered, washed with pentane, and the solid so obtained dried in vacuo and dissolved in EtOH (100 mL). Thiourea (5.46 g, 72.0 mmol) was added and the reaction mixture heated for 4 hours at 70-75° C. The reaction mixture was concentrated to yield a residue, which was treated with aq. Na2CO3 solution, adjusted to pH=10, extracted with EtOAc, washed with water, washed with brine solution, dried (Na2SO4), filtered, and concentrated. The residue was washed with pentane to obtain tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (8.7 g, 28% yield)
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([NH:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(O)(CN)c1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(O)(CNCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 1-amino-2-(4-benzyloxy-phenyl)-propan-2-ol (1.26 g; 4.9 mmol), benzaldehyde (0.55 mL; 5.4 mmol), and p-toluenesulfonic acid (0.04 g; 0.24 mmol) in toluene (30 mL) was heated under reflux in a Dean-Stark apparatus, overnight. Subsequently, the mixture was cooled to RT and the solvent was removed in vacuo. The residue was suspended in MeOH (30 mL), cooled to −15° C., and treated with NaBH4 (0.74 g; 19.6 mmol), portionwise. After the addition was complete the mixture was warmed to RT and stirred for one hour. Subsequently, the MeOH was removed in vacuo. The residue was partitioned between Et2O and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 2:1) to give 1-benzylamino-2-(4-benzyloxy-phenyl)-propan-2-ol (1.07 g).
Reaction SMILES: O.C([O:4]CC)C.[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C1COCC1>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:4])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Reactant: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)OCCC[Si](C)(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Deionized water (100 mL) and diethyl ether (200 mL) were added to a single-neck 500 mL round-bottom flask fitted with a magnetic stirrer. The flask was cooled in an ice bath to 0° C. The flask was fitted with a dropping funnel and a mixture of (10 g, 0.045 mol) of 3-methacryloxypropyl dimethylchlorosilane and 50 mL of anhydrous THF was added to the flask. The reaction was stirred for one hour at 0° C. The organic layer was separated and dried over anhydrous sodium sulfate and filtered. The solvent was evaporated on a rotovap to give 3-methacryloxypropyl dimethylhydroxysilane in 9.0 g quantity, 99% yield as a clear, colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:7][N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:34](F)=[CH:35][C:36]([F:55])=[C:37]([S:39]([N:42]([C:50]2[N:51]=[CH:52][S:53][CH:54]=2)[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:41])=[O:40])[CH:38]=1>CS(C)=O.C(OCC)(=O)C.ClC1C(F)=CC(F)=C(S(N(C2N=CSC=2)C(=O)OC(C)(C)C)(=O)=O)C=1>[Cl:32][C:33]1[C:34]([O:19][C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:7]=2)=[CH:35][C:36]([F:55])=[C:37]([S:39]([N:42]([C:50]2[N:51]=[CH:52][S:53][CH:54]=2)[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:41])=[O:40])[CH:38]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol (Preparation 868, 28.73 g, 80.41 mmol) in dimethyl sulfoxide (175 mL) was added potassium carbonate (22.3 g, 161 mmol). After stirring for 10 minutes, tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 453, 33.02 g, 80.37 mmol) was added. After stirring for 14 hours at room temperature, additional potassium carbonate (4.7 g, 34 mmol) and tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (1.25 g, 3.0 mmol) were added and the reaction mixture heated at 45° C. for 7 hours. The mixture was allowed to cool, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by manual flash column chromatography using 25% ethyl acetate/hexanes and an 8×46 cm column provided product as a yellow oil (40 g, 70%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:35]([O:36][CH2:37][CH3:38])=[O:39])[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)OCC)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of the compound obtained in Example 5A (1.12 g), ethyl chlorocarbonate (0.35 g), potassium carbonate (0.47 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate; the ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-ethoxycarbonyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.89 g, 56%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 119 to 120° C. ##STR54##
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.C(N)(C)C.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([O:35][C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=2)[CH:21]=[CH:20][N:19]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: O=C(Cl)c1cc(Cl)ccn1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method C1a to afford the urea.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine would be added. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH3:12])=[O:10].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>CO>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[N:24]1
Reactant: COC(=O)C(=O)CC(=O)c1ccco1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
A stirred solution compound 5 (10.0 g, 50 mmol) and (2-chlorophenyl)hydrazine hydrochloride (10.0 g, 56 mmol) in methanol 80 mL was heated to reflux for 6 h. On cooling to 0° C., solid crashed out, filtered and washed with cold methanol to afford the title compound 6 (12.0 g, 80.0%) which was used for further reaction.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[CH2:15](O)[CH3:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:15]([O:10][C:9](=[O:11])[CH2:8][N:7]([C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH3:13])[CH3:16]
Reactant: CCO
Reactant: CCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 3° C. solution of 86 g (423 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine, 21.4 g (465 mmole) of ethanol and 5.17 g (42.3 mmole) of 4-dimethylaminopyridine in 600 mL of dichloromethane is added 47 g (46.2 mmole) of triethylamine, followed by portionwise addition of 89.1 g (46.5 mmole) of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The stirred mixture is allowed to warm to ambient temperature and stir overnight. The reaction mixture is washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine ethyl ester (88 g) as an oil. MS (FAB) 232 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:16]>CO>[NH2:16][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CO
Product: Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 45 °C

Procedure:
2,4-dichloro-3-nitroquinoline (5.3 g, 0.218 mol) was combined with 75 mL of 15 percent ammonia in methanol and the mixture was heated at about 45° C. for about 4 hours. The reaction mixture was cooled to room temperature, and the precipitated product was removed by filtration. The volume of methanol was reduced to about 35 mL, and the precipitated product was removed by filtration. The volume of methanol was then reduced to about 10 mL and the precipitated product was again removed by filtration. The combined solids were stirred in aqueous sodium bicarbonate, filtered, and dried to afford a solid product 4-amino-2-chloro-3-nitroquinoline.