Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2]/[CH:3]=[CH:4]/C.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.C(C1C=C(O)C(=CC=1)O)(C)(C)C.S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O>>[CH2:1]1[CH:7]2[C:6]([O:11][C:9](=[O:10])[CH:8]2[CH2:4][CH:3]=[CH:2]1)=[O:12]
Reactant: C=C/C=C/C
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12
Reaction time: 0.5 h

Procedure:
3Me--THPA was produced by the gas phase aeration method. Thus, the air in a 300-ml four-necked flask equipped with a stirrer, thermometer, condenser, a dropping funnel for feeding crude trans-1,3-pentadiene, and an unreactive fraction recovery vessel was replaced with nitrogen and, then, the flask was charged with 98 g of maleic anhydride, 500 ppm of p-tert-butylcatechol by way of radical polymerization inhibitor and 1000 ppm of dilauryl thiodipropionate as auxiliary polymerization inhibitor. The charge was melted at 50° to 55° C. and after the internal atmosphere was replaced with nitrogen gas, nitrogen gas containing 4% of oxygen was passed through the gas phase at a rate of 10 ml/min throughout the reaction period. Under this atmosphere, 374 g of crude trans-1,3-pentadiene of the same composition as that used in Example 1 was continuously added at 50° to 55° C. over a period of 4 hours. During the reaction, major portion of unreactive fractions was distilled off from the reaction system. After completion of addition, the reaction was conducted at 70° C. for 30 minutes. After completion of the reaction, the reaction mixture was distilled at 85° C. under atmospheric pressure and, then, under reduced pressure to remove the volatile fraction. In this manner, 164 g of 3Me--THPA was obtained. The investigation revealed no gels in the product.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]>O.C(O)C>[Br:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:15][CH3:16])[C:5]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1SC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(Br)ccc(C(=O)O)c1SC

Procedure:
A solution of potassium hydroxide (2.0 g) in water was added to a solution of ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)-benzoate (4.5 g) in ethanol. The resulting solution was stirred and heated at reflux for 3 hours. After cooling, the mixture was evaporated to dryness and the residue was dissolved in water and washed with ethyl acetate. The aqueous solution was acidified to pH 1 and extracted with ethyl acetate, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-bromo-3-methoxy-2-(methylsulphenyl)benzoic acid as a white solid, NMR (CDCl3) 2.5(s,3H), 3.9(s,3H), 7.4(s,2H), 10.9(bs, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:18]
Reactant: Cc1cccnc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1CCl

Procedure:
A solution of 24 g of 2-chloromethyl-3-methylpyridine in 200 ml of methylene chloride was treated while cooling with ice with a solution of 44 g of m-chloroperbenzoic acid in 200 ml of methylene chloride. The reaction mixture was heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue was chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2-chloromethyl-3-methyl-pyridine 1-oxide obtained was processed directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH:24][C:26]3[N:27]=[CH:28][C:29]4[CH:34]=[C:33]([C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[N:32]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:30]=4[N:31]=3)=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 95 %

Procedure:
Following general Scheme 5 on a 1.023 mmole scale, 3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide which yielded after SiO2 gel Chromatograped (5-8% CH3OH-ethyl acetate), 0.57 grams (95% yield) of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester, TLC RF 0.4 in 5% CH3OH-ethyl acetate, MS m/z 589 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH2:15])[C:13]([CH2:16][CH2:17][CH3:18])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.CO[C:21](OC)([CH3:23])[CH3:22]>C(#N)C.C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([N:15]=[C:21]([CH3:23])[CH3:22])[C:13]([CH2:16][CH2:17][CH3:18])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1N
Reactant: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1N=C(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A suspension of 7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-amine (17.6 g, 57.7 mmol) in 160 mL of acetonitrile and 40 mL of glacial acetic acid was treated with 2,2-dimethoxypropane (35.5 mL, 288 mmol). The reaction mixture was heated to 100° C. under an atmosphere of nitrogen. After 16 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown oil. The oil was dissolved in CHCl3 (200 mL). The CHCl3 solution was washed with saturated NaHCO3 solution (2×50 mL), water (50 mL) and brine (50 mL). The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to yield 18.4 g of N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine as a red/brown foam.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[O:29][CH3:30])CC2CCCC2)=[O:14])=[N:9][CH:8]=1)C.[CH:32]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:36][CH2:35][CH2:34][CH2:33]1.[CH:61]1(CNC2C=CC=C(Cl)C=2OC)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:28][C:24]1[C:23]([O:29][CH3:30])=[C:22]([N:15]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13](=[O:14])[N:12]([CH3:61])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:31])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2OC)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: COc1c(Cl)cccc1NCC1CCCC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1c(Cl)cccc1N(C(=O)N(C)c1ncc(SCC(=O)O)s1)C1CCCC1

Procedure:
The title compound was prepared via {2-[3-(3-chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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.C(O)C>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: Brc1ncccn1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ncccn2)cc1[N+](=O)[O-]
Yield: 55 %

Procedure:
To a toluene (40 ml)-ethanol (40 ml) mixed solvent were added 4-methyl-3-nitrophenylboronic acid (2.66 g, 14.7 mmol), 2-bromopyrimidine (3.15 g, 19.81 mmol), tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.874 mmol) and sodium carbonate (3.93 g, 37.08 mmol), and the mixture was heated under reflux for 24 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a solid. This was purified by silica gel column chromatography (ethyl acetate-dichloromethane) to give the title compound (1.74 g, yield 55%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11].[C:13]([O-:16])([O-])=O.[Na+].[Na+].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.[I-].[K+]>[CH2:8]1[C:25]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:16][C:13]=2[CH2:5][CH2:6][N:7]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)NCCCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NCCCCCN1CCc2oc3ccccc3c2C1

Procedure:
A mixture of intermediate (1) (0.03 mol), ethyl (5-chloropentyl)carbamate (0.04 mol), potassium iodide (0.1 g) and Na2CO3 (5.7 g) in toluene (250 ml) was stirred and refluxed overnight. The reaction mixture was cooled, stirred in water (200 ml), and the layers were separated. The organic phase was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 7 g of ethyl [5-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)pentyl]carbamate (interm. 15).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:10]=2.[H-].[Na+].S(OC)(O[CH3:32])(=O)=O.C(O)C>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([O:21][CH3:32])([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:18])[F:19])[CH:10]=2
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)SCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CCS2)(C(F)(F)F)C(F)(F)F

Procedure:
To a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one in dimethyl formamide can be added sodium hydride and dimethyl sulfate. The mixture can be stirred and heated in a nitrogen atmosphere until the reaction is complete, treated with ethanol and purified to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[F:54].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])=[CH:41][C:40]=1[F:54]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 3.09 g, 6 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 5.88 g, 21 mmol) and dichlorobis(triphenylphosphine)palladium (II) (420 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 7.5 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 83%) as a white solid: LC/MS m/e calcd for C26H22F2N2O4S [M+H]+ 497.54, observed 496.7.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.O=C1C2C(=CC=CC=2)C(=O)[N:9]1[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[CH:26][C:27]=2[O:29][CH3:30])[C:22]([NH:33][C:34]2[S:35][CH:36]=[C:37](C(O)=O)[N:38]=2)=[CH:21][N:20]=1.[CH3:42][N:43]([CH:45]=[O:46])C.CN>ClCCl>[CH3:42][NH:43][C:45]([C:37]1[N:38]=[C:34]([NH:33][C:22]2[C:23]3[C:28](=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[C:19]([CH2:18][NH2:9])=[N:20][CH:21]=2)[S:35][CH:36]=1)=[O:46]
Reactant: CN(C)C=O
Reactant: COc1cc(OC)c2c(CN3C(=O)c4ccccc4C3=O)ncc(Nc3nc(C(=O)O)cs3)c2c1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1csc(Nc2cnc(CN)c3c(OC)cc(OC)cc23)n1
Reaction time: 1 h
Yield: 60 %

Procedure:
Oxalyl chloride (8 μL, 0.092 mmol) was added to a solution of Example 49A (30 mg, 0.061 mmol) in dichloromethane (4 mL). Catalytic DMF was added, and the reaction stirred for 1 h. Methylamine (180 μL, 2M in THF, 0.366 mmol) was added, and the reaction stirred for 30 min. Organics were washed with brine, dried (MgSO4) and concentrated. Deprotection was carried out with hydrazine (0.2 mL) in methanol (3 mL), stirring for 1 h. Purification by Prep-HPLC gave 17.8 mg (60%) of the title compound (TFA salt) as a yellow solid. H1-NMR (MeOD-d4): δ 9.16 (s, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 4.83 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 2.91 (s, 3H). MS (ES) (M+H) calc'd for C17H19N5O3S, 374; found 374.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[N:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:23]3[N:22]=[N:21][S:20][CH:24]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1csnn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1csnn1
Yield: 52 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,2,3-thiadiazole-4-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 70°-72° C., in a 52% yield.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[CH:18].Br[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.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.O>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 18a (0.74 g, 2.4 mmol) and 2-bromoquinoline (2.0 g, 9.6 mmol) in a vial was evacuated and back-flushed with Argon. Dry DMF (10 mL) and DIEA (1.7 mL, 9.7 mmol) were added via syringe and the mixture was deoxygenated by bubbling Argon through the stirred solution for 5 min. To the mixture was added CuI (46 mg, 0.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.17 g, 0.24 mmol). The reaction mixture was stirred at rt overnight, and was poured into water (50 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain a residue which was purified by flash column chromatography on silica gel (30-70% EtOAc/heptane) to obtain compound 18b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H16BrN5O: 434.1 (M+H). found: 434.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH3:23])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate (21.3 g, 59.1 mmol) was dissolved in acetone (300 ml), and K2CO3 (16.3 g, 118.3 mmol, 2 eq.) was added thereto. Methyl iodide (7.4 ml, 118.3 mmol, 2 eq.) was then added, and the suspension was heated overnight at 40° C. The solid materials were filtered off and the filtrate was concentrated using a rotary evaporator. Purification was carried out by filtration over silica gel (DCM).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25]C)=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:27]([Mg]Br)[CH2:28][CH3:29].O1C[CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23]([OH:25])([CH2:33][CH2:34][CH3:35])[CH2:27][CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Reactant: CCC[Mg]Br
Product: CCCC(O)(CCC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 14 h
Yield: 26 %

Procedure:
To a solution of methyl 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200.0 mg, 0.487 mmol) in tetrahydrofuran (3.0 mL) was added n-propylmagnesium bromide (1.0 M solution in tetrahydrofuran, 2.44 mL, 2.435 mmol). The reaction mixture was stirred at 60° C. for 14 hrs. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (60.0 mg, 0.129 mmol, 26%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].O=C1NC2[C:11](=[N:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[N:10]1[CH2:24][C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26].CI>C(Cl)(Cl)Cl.O>[CH3:3][N:4]1[C:7]2[C:11](=[N:12][C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[N:10]([CH2:24][C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26])[C:5]1=[O:6]
Reactant: CCCN(CCC)C(=O)Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CI
Product: CCCN(CCC)C(=O)Cn1c(=O)n(C)c2cnc(-c3ccccc3)nc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of about 60% sodium hydride (oily) (0.8 g) and dimethylformamide (50 ml) is added 7,8-dihydro-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide (6 g) obtained in Example 79 in portions at 0-5° C., and the mixture is stirred at 0° C. for one hour. To the mixture is added dropwise methyl iodide (2.9 g) at the same temperature. After the addition, the mixture is stirred at room temperature for two hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (6 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C([Li])CCC.[CH:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].O>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH2:22][CH:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: COCOc1cc(C(F)(F)F)ccc1N(C(C)C)S(C)(=O)=O
Reactant: CCCCC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC(O)CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Reaction time: 1.5 h
Yield: 40.8 %

Procedure:
To a solution of 2-(N-isopropyl-methylsulfonylamino)-5-trifluoromethylphenyl methoxymethyl ether (135 mg; prepared in Reference Example 30.) in THF (3.0 ml), hexamethylphosphoramide (420 μl) was added in a stream of argon. At −78° C., n-butyl lithium (742 μl) was added dropwise thereto. The mixture was stirred for 1.5 hours. To the mixture, a solution of valeraldehyde (102 mg) in THF (1.0 ml) was added dropwise. The mixture was stirred for 30 minutes. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=4:1) to give the title compound (69 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[I:12]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:12])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1cn2nc(Cl)ccc2n1
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2ccc(Cl)nn2c1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Added to a solution of 7.00 g (41.8 mmol) of 6-chloro-2-methylimidazo[1,2-b]pyridazine (CAS 14793-00-1) in 300 ml of chloroform, cooled to 0° C., are 10.2 g (62.7 mmol) of iodine monochloride in solution in 20 ml of methanol. The reaction is then left at ambient temperature for 16 hours then poured over a mixture of a 5% sodium thiosulphate solution and of sodium hydrogen carbonate. The product is extracted with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure.