Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][C@H:27]([CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[N:26]([CH2:35][C:36]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=4)[CH:39]=[N:38][CH:37]=3)[CH2:25][C:24]2=[O:51])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[H][H]>CO.CCOC(C)=O.[Pd]>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][C@H:27]([CH2:29][CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[N:26]([CH2:35][C:36]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=4)[CH:39]=[N:38][CH:37]=3)[CH2:25][C:24]2=[O:51])[CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)CC[C@H]1CN(c2cc(Cl)ccc2-c2cccc(OCc3ccccc3)c2)C(=O)CN1Cc1cncn1Cc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC[C@H]1CN(c2cc(Cl)ccc2-c2cccc(O)c2)C(=O)CN1Cc1cncn1Cc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
To a solution of the product from Step D (383 mg, 0.527 mmol) in 10 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (300 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 1.5 hours, the solution was filtered through celite, the filter pad was rinsed with 1:1 MeOH/THF, and the filtrate was concentrated in vacuo. The crude material containing the titled product was used in the next reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[CH:39][C:38](I)=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[CH:39][C:38]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1cc(I)ccc1F)C(=O)OC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)ccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of 0.016 g (0.093 mmol) of palladium chloride and 0.0486 g (0.185 mmol) of triphenylphosphine in 5 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 10 mL of acetonitrile and 0.80 g (1.89 mmol) of dimethyl N-(2-fluoro-5-iodobenzoyl)L-glutamate, 0.50 g (1.85 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0088 g (0.046 mmol) of copper iodide, and 0.54 mL (3.89 mmol) of triethylamine. The mixture is then heated to reflux for 3 hours. After cooled to room temperature, the solvent is removed in vacuo and the residue is flash chromatographed on silica gel using 1:19 methanol:chloroform as the eluent to yield 0.92 g (88%) of dimethyl N-(2-fluoro-5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)-ethynyl]-benzoyl)-L-glutamate as a dark yellow solid m.p. 189°-191° C. (dec); Rf =0.48 (1:19 methanol:chloroform), Mass (FD)=565; IR (KBr, cm-1)=1146, 1228, 1263, 1440, 1488, 1549, 1596, 1607, 1622, 1673, 1742; UV (EtOH) λmax =319 (epsilon=30600), 259 (epsilon=11200), 212 (epsilon=42100); 1NMR (300 MHz, CDCl3) delta 1.38 (s, 9H), 2.19 (m, 1H), 2.3-2.6 (m, 3H), 3.72 (s, 3H), 3.85 (s, 3H), 4.95 (m, 1H), 7.21 (dd, 1H, J=8.5, 11.2 Hz), 7.45 (m, 1H), 7.68 (m, 1H), 8.26 (dd, 1H, J=2.0, 7.2 Hz), 8.37 (s, 1H), 8.63 (d, 1H, J=2.2 Hz), 9.0 (d, 1H, J=2.0 Hz).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F.[F-].[K+]>>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[Br:14]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: [F-]
Agent: [K+]
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1

Procedure:
In other embodiments, the present invention provides methods of preparing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamide-dibenzo[b,d]furan-1-carboxamide, as shown in FIG. 1. For example, 4-difluoromethoxy-3-hydroxybenzaldehyde may be reacted with 2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising potassium fluoride to produce 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde (scheme I). In a second step, the 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde may be cyclized in a second solvent comprising a catalyst to produce 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran (scheme II). In a third step, the 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran may be oxidized in a third solvent comprising an oxidizing agent to produce 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid (scheme III). In a fourth step, 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid may be reacted in a fourth solvent comprising an inorganic acid halide, 4-amino-3,5-dichloropyridine and a first base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (scheme IV). In a fifth step, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide may be reduced in the presence of a reducing agent to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide. Suitable reducing agents include, but are not limited to, zinc, indium, iron, tin, Raney-nickel and sodium borohydride. In a sixth step, the N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide may be reacted in a fifth solvent comprising methanesulfonyl chloride and a second base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenzo[b,d]furan-1-carboxamide.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:30])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.[ClH:32].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.[ClH:32]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(N)O
Reaction time: 3 h

Procedure:
In 2 ml of dichloromethane, 1019 mg (2.25 mmol) of the Boc-aminopropanol-diclofenac obtained above was dissolved, and 8 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 3 hours. 150 ml of diethyl ether was added thereto for precipitation, and the precipitate was dried under reduced pressure to give 791 mg (90%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 55.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577 intermediate 4 D, 1 g, 1.877 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 1, 1.279 g, 5.63 mmol), Pd(PPh3)2Cl2 (0.066 g, 0.094 mmol), copper(I) iodide (0.018 g, 0.094 mmol), triphenylphosphine (0.049 g, 0.188 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 mins. The solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column 40+M and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent to afford the title compound (750 mg, 1.036 mmol, 55.2% yield) as a white solid. UPLC: Rt 1.02 min, m/z 724 [M+H]+.
Reaction SMILES: [K].[N+:2]([C:5]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:4])=[O:3].OS(O)(=O)=O.[CH3:21]O>>[N+:2]([C:5]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:6]=1[C:7]([O:9][CH3:21])=[O:8])([O-:4])=[O:3]
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [K]
Product: COC(=O)c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The potassium salt of 5-nitroorotic acid (25.0 g, 0.1 mol) was dissolved in MeOH (75 ml). Concentrated H2SO4 (21 mL) was added drop wise. The reaction was refluxed for 12 hrs. After cooling to room temperature, the white precipitate was collected by filtration, washed with water (50 mL×4), and dried under vacuum for 48 hrs. to afford compound 2 as a white power (26.0 g, 75%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][CH:12]=1>C(#N)C>[BrH:1].[NH:16]=[C:14]1[N:13]([CH2:2][C:3]([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[O:4])[CH:12]=[C:11]([CH3:10])[S:15]1
Reactant: Cc1cnc(N)s1
Reactant: O=C(CBr)c1cccs1
Solvent: CC#N
Product: Br
Product: Cc1cn(CC(=O)c2cccs2)c(=N)s1
Reaction time: 1 h

Procedure:
A mixture of 51 parts of 2-bromo-1-(2-thienyl)ethanone, 28.5 parts of 5-methyl-2-thiazolamine and 240 parts of acetonitrile was stirred for 1 hour while heating on a waterbath. After cooling, the precipitate was filtered off, washed with ethanol and dried in vacuo, yielding 54 parts of 2-(2,3-dihydro-2-imino-5-methyl-3-thiazolyl)-1-(2-thienyl)ethanone hydrobromide; mp. 207.5°-208° C. (interm. 56).
Reaction SMILES: C(#N)C.Cl[C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:12][C:13]2[S:14][C:15]([C:18]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[O:19])=[CH:16][N:17]=2)[CH:6]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[CH3:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:18]([C:15]1[S:14][C:13]([NH:12][C:7]2[CH:6]=[C:5]([N:35]3[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]3)[N:10]=[C:9]([CH3:11])[N:8]=2)=[N:17][CH:16]=1)=[O:19].[OH2:19]
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 32.5 °C
Reaction time: 0.21 h
Yield: 179.2 %

Procedure:
Take 12 ml of acetonitrile in RB flask and charge 1 g of 2-((6-chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula I), 1.98 g of 1-(2-Hydroxyethyl)piperazine (Formula II), 1.28 g of triethyl amine and 1.02 g of TBAB. Stir the reaction mass for 10-15 min at 30-35° C. Heat the reaction mixture to 75-80° C. and stir for 20-24 h. Check for the completion of reaction with Thin Layer Chromatography (TLC). Charge 4 mL of water slowly and stir the reaction mass for 30-45 mins at 75° C. Cool the reaction mass to 30-35° C. and stir for 2-3 hrs. Filter the reaction mass and wash with acetonitrile and water mixture (1:1). Dry the material to get 1.15 g of crystalline Dasatinib monohydrate.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]2)([CH3:13])[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]1([S:7]([C:10]([CH:14]2[CH2:19][CH2:18][C:17]3[C:27]4[C:26](=[CH:25][CH:24]=[C:23]([CH3:22])[CH:28]=4)[NH:29][C:16]=3[CH2:15]2)([CH3:13])[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C#N)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c3c(c2c1)CCC(C(C)(C#N)S(=O)(=O)c1ccccc1)C3
Yield: 29.5 %

Procedure:
To 322 mg (1.10 mmol) of 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile in 10 mL of glacial acetic acid, 193 mg (1.21 mmol, 1.1 eq) of (4-methyl-phenyl)-hydrazine hydrochloride were added and stirring was continued at RT over night. An aqueous solution of NaHCO3 was added until pH=7, and the product was extracted with EtOAc, the organic phase was dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with AcOEt/heptane 1:4, and triturated with Et2O. 158 mg (38%) of (RR,SS)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile and 123 mg (29%) of (RS,SR)-2-benzenesulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionitrile were isolated as light yellow solids, MS: 379 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][C:14]([OH:18])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(CCO)on1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 13.5 g of 2-[3-(4-fluorobenzoyl)-isoxazol-5-yl]ethanol and a few crystals of tetrabutylammonium hydrogen sulfate in 1 liter of CH2Cl2 was added 150 ml of 9M H2SO4. To this was added 16.9 g of pulverized K2Cr2O7 and the mixture was stirred at room temperature for 1 hour. The organic phase was separated from the aqueous phase and washed with water. The acid product was extracted from the organic phase using 100 ml of 5% NaHCO3. The alkaline solution was washed with CH2Cl2 several times, until all of the neutral impurities were removed, and then acidified slowly with 5% HCl. The precipitated solid was collected, washed with water and dried to yield 6.7 g of a powder. Recrystallization from 180 ml of 50% toluene/hexane gave 5.9 g (41%) of crystals, m.p. 113°-115°.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.C(Cl)(Cl)Cl>[CH3:21][O:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc(C#N)c(-c2cnc3c(O)cccn23)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: ClC(Cl)Cl
Product: COc1cccn2c(-c3nc(SC)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
150 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 3 mL of dimethylsulfoxide, then 293 mg of potassium carbonate and 40 μL of methyl iodide were added thereto, and stirred at room temperature for 30 minutes. The reaction solution was diluted in 200 mL of chloroform, and washed with water. Then, the organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of a mixed solvent of chloroform and methanol (chloroform:methanol=9:1), and solidified by hexane, to obtain 58 mg of 4-(8-methoxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-2] as a brown solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][CH2:33][Br:34]>CC#N>[Br-:34].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:33][CH2:32][CH2:31][O:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Cc1ccccc1OCCCBr
Solvent: CC#N
Product: Cc1ccccc1OCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 73.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0447 g, 0.152 mmol) and 3-bromopropyl 2-methylphenyl ether (0.0934 g, 0.407 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0586 g, 76.5%). EI-MS m/z 442 (M+) Rt (2.17 min).
Reaction SMILES: [C:1]([CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8])#[N:2].C(O)(C)(C)C.[NH2:24][OH:25]>CO>[NH2:2]/[C:1](=[N:24]\[OH:25])/[CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: NO
Reactant: CC(O)CCCC(C#N)N(C)C(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: CO
Product: CC(O)CCCC(/C(N)=N/O)N(C)C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
The tert-butyl (1-cyano-5-hydroxyhexyl)methylcarbamate (129 g) which contained an undetermined amount of t-butanol was dissolved in methanol (250 mL) and treated with 50% aqueous hydroxylamine (33 mL). The mixture was then heated to 60° C. for 3 hours. The reaction mixture was then cooled and the solvents removed in vacuo. The residue was azeotropically dried twice with toluene (200 mL each time) and dried in vacuo at 50° C. to give the product as a very thick clear oil which was contaminated by t-butanol: ES MS M+1=290.0.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[C:1]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:16][CH3:17])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)COCCCCC1=CCCC1=O

Procedure:
In the manner described in Example 23, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3)c2n1
Reactant: O=S1CCNCC1
Product: O=S1CCN(c2nc(N3CCOCC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine melting point: 159°-161° C.) and thiomorpholine-1-oxide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1>>[CH3:30][C:25]1[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:23]=2)=[C:28]([CH3:29])[O:27][N:26]=1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1noc(C)c1-c1nc(Cn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.44 (s, 2H), 2.71 (s, 3H), 2.66 (s, 3H), 2.49 (s, 3H); MS (ES) m/z 402 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C@@H:20]([OH:32])[CH2:19]1)=[O:17].C(N(CC)CC)C>CS(C)=O.C(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=[O:32])[CH2:19]1)=[O:17]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (318 mg; example 1C) in DMSO/CH2Cl2 1:1 (6 ml) were added triethylamine (0.73 ml) and SO3-pyridine complex (638 mg). The mixture was stirred overnight at r.t. The clear brown solution was diluted with dichloromethane, washed with 0.5 N HCl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 95:5) to give 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide (225 mg) as light yellow amorphous solid. MS 474.1 ([M+H]+).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4]1=[O:17].[C:18](Cl)([Cl:20])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[Cl:20][C:18]([NH:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4]1=[O:17])=[O:19]
Reactant: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: O=C(Cl)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: -33 °C
Reaction time: 12 h

Procedure:
After dilution with 200 ml of tetrahydrofurane, 34 g of 3-amino-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione hydrobromide (obtained in Example 2b) are added at -20° C. to 104 ml of a 20% solution of phosgene in toluene. Then 27.9 g of triethylamine in 100 ml of tetrahydrofurane are added dropwise at -37° to -28° C. and the reaction mixture is thereafter stirred for a further 12 hours at -33° C. to bring the reaction to completion. The precipitate is collected by filtration at -20° C. and the solution is concentrated. The 3-(N-chlorocarbonylamino)-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione obtained is used direct for the consequent reaction.