Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>>[OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2cccnc2c1O
Temperature: 170 °C
Yield: 79.8 %

Procedure:
8-Hydroxyquinoline (50.0 g) and potassium carbonate (142.8 g) are mixed together in a stainless steel bomb and heated at 170° C. under 1200 p.s.i. CO2 for 7 days. The reaction is then cooled and the resulting solid is partitioned between water (6 L) and EtOAc (1 L). The organic layer is extracted with water (2×300 mL). The combined aqueous layers are extracted with EtOAc (3×500 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and triturated with i-PrOH to yield 51.97 g of the title compound as a tan solid.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cnc(F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc(F)cc2)c(C)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol, Step-1 of Amine-36), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90° C. for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), and the organic layer is dried over sodium sulfate. After filtration, and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 3.46 g (93% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:23])[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:5][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:23])[CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(NC(=O)CN2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2-(4-methylthiazol-2-ylamino)-2-oxoethyl)piperazine-1-carboxylate (0.072 g, 0.21 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(4-methylthiazol-2-yl)-2-(piperazin-1-yl)acetamide (a semi-solid material) that was dried in vacuo. To a mixture of this material (supposedly 0.20 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.044 g, 54%). 1H-NMR (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.65 (br s, 4H, piperazine N(CH2)2), 3.10 (br s, 4H, piperazine N(CH2)2), 3.33 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 6.96 (br s, 2H, NH2), 8.07 (s, 1H, 6-H), 11.75 (s, 1H, CONH);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:19]=[CH:18][C:17]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:19]=[CH:18][C:17]=2[F:29])[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(-c3ccnc(Cl)n3)ccc2F)CC1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(-c3ccnc(Cl)n3)ccc2F)S(C)(=O)=O)CC1

Procedure:
Intermediate 90 was coupled with methanesulfonyl chloride following procedure D LC-MS showed the product was >95% pure and had the expected M+H+ of 499.
Reaction SMILES: [F:1][C:2]([F:22])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18](NC)=[O:19])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4]>ClC1C=CC=CC=1>[F:22][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:15])=[O:16])[C:3]([F:6])([F:5])[F:4]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Yield: 95.7 %

Procedure:
74.6 g of N-(2-pentafluoroethoxyphenylsulfonyl)-N'-methylurea are suspended in 1300 ml of chlorobenzene and made absolute by distilling off about 100 ml of solvent as an azeotrope. Then 48 g of phosgene are introduced at 120°-130° C. over 3 hours. The chlorobenzene is then completely distilled off, affording 65 g of 2-pentafluoroethoxyphenylsulfonyl isocyanate in the form of an almost colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5].C(N(CC)CC)C>C(#N)C>[CH:10]1[N:9]=[CH:8][N:7]2[CH2:2][CH2:3][C:4](=[O:5])[C:6]=12
Reactant: O=C(CCBr)c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCn2cncc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Bromo-1-(1H-imidazol-4-yl)-1-propanone (28.5 g) was suspended in acetonitrile (1100 ml) and the suspension was warmed to 70° C. A solution of triethylamine (15.3 ml) in acetonitrile (25 ml) was slowly added dropwise and the mixture was stirred at 70° C. for 2 h. Triethylamine (25 ml) was further added and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The solvent was evaporated and the residue was dissolved in ethyl acetate again. The insoluble material was filtered off and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane:methanol containing ammonia (5%)=10:1) for purification to give the title compound (6.67 g) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c(F)c1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3,4-trifluoroaniline to yield 2-[(2,3,4-trifluorophenyl)amino]phenylacetic acid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[CH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
To a solution of 1.68 g of t-butyl diethylphosphonoacetate in 5 mL of THF was added 400 mg of sodium hydride (60% dispersion in mineral oil) at 0° C. The reaction was warmed to rt and stirred at rt for 20 min. To the resulting solution was added a solution of 1.05 g of 1-benzyl-4-piperidone in 5 mL of THF. The solution was refluxed for 3 h and cooled to rt. After quenching with aqueous NH4Cl, the aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried over MgSO4 and concentrated to give 1.05 g of the title compound as a oil, which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:6][C:5]2=1.[H-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:11]1[C:10]2[CH2:9][CH2:8][CH:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
Add N-(6-bromo -2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (0.25 g, 0.75 mmol) to a suspension of sodium hydride (0.036 g, 0.90 mmol of a 60% dispersion in mineral oil) in DMF (3 mL) and stir for 15 min. Add 3-fluorobenzylbromide (0.10 mL, 0.90 mmol) and stir for 18-72 h. Dilute with water and collect the precipitate by filtration. Purify by silica gel chromatography eluting with 20-100% EtOAc/hexanes gradient to give 0.23 g of a white solid (71%). MS (ES): m/z 443 (M+1), 445 (M+H+2); HPLC: Rt=3.71 min (97.1%); m.p.=177-179° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]([C:5]1[N:6]=[CH:7][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing methyl 5-bromopicolinate 49-1 (1.48 g, 6.85 mmol), tert-butyl piperazine-1-carboxylate 49-2 (1.53 g, 8.22 mmol), Pd2(dba)3 (315 mg, 0.34 mmol), BINAP (462 mg, 0.69 mmol) and Cs2CO3 (5.50 g, 17.20 mmol) under argon was added anhydrous toluene (30 mL). The mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was redissolved in ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 49-3 as a yellow solid. MS m/z 322.1 (M+1)
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[C:2]([C:27]4[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Brc1c(-c2ccco2)nn2c(NC3CCCC3)cccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(-c2c(-c3ccco3)nn3c(NC4CCCC4)cccc23)ccn1
Temperature: 75 °C
Yield: 23 %

Procedure:
N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine (0.2 g, 0.6 mmol) was dissolved in N,N-dimethylformamide (8 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (0.09 g, 0.64 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.020 g, 0.03 mmol) and saturated aqueous sodium carbonate (580 μl). The resulting solution was heated in a 75° C. oil bath overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. The product was purified by silica gel chromatography (7:1 hexane:ethyl acetate) to give 50 mg (24%) of N-cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine as a solid. 1H NMR (CDCl3) δ 8.1 (d, 1H), 7.5 (s, 1H), 7.24 (1H), 7.03(s, 1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.5 (m, 1H), 6.01 (m, 2H), 4.0 (m, 1H), 2.19–2.09 (m, 2H); 1.88–1.77 (m, 4H), 1.77–1.64 (m, 2H);MS m/363 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[F:22])[CH3:2].COC(=O)COC1C=CC(N(C(OC(C)(C)C)=O)C)=CC=1F.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[F:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1F
Agent: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)cc1F

Procedure:
Analogously, to example 1.4, crude [4-(tert-butoxycarbonyl-methyl-amino)-2-fluoro-phenoxy]-acetic acid ethyl ester containing [4-(tert-butoxycarbonyl-methyl-amino)-2-fluoro-phenoxy]-acetic acid methyl ester was deprotected with TFA to give (2-fluoro-4-methylamino-phenoxy)-acetic acid ethyl ester containing (2-fluoro-4-methylamino-phenoxy)-acetic acid methyl ester as an orange oil, MS: 228 (MH+) and 214 (MH+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCBr
Reactant: Oc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution was prepared by combining 15 g of (4-hydroxyphenyl) phenyl sulfide which had been synthesized according to the well-known formulation, 11 g of 1-bromohexane, 9 g of potassium carbonate, and 30 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 30 g of water was added to quench the reaction. To the solution, 50 g of toluene was added for extraction. The organic layer was separated and washed with sodium hydroxide aqueous solution and water in sequence. On subsequent concentration in vacuum, 16 g of the target compound, (4-hexyloxyphenyl) phenyl sulfide was obtained as oily matter. Yield 90%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CS(C)=O.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:34][C@H:35]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc2cc(-c3cnc4ccc(Cl)nn34)sc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 33 mg of the yellow solid, 75%.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:15]2)[N:7]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:8]2[NH:7][C:6](=[O:5])[CH:11]=[N:10][CH:9]=2)[CH2:15]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCCC(COc3ccccc3F)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cncc(CCN2CCCC(COc3ccccc3F)C2)[nH]1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
After dissolving 160 mg of 2-tert-butoxy-6-[2-[3-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine in 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate was added, and the mixture was allowed to stand at room temperature for 30 minutes. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, active carbon was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (108 mg, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][OH:12])=[NH:9])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cnc(N)nc1
Yield: 72.1 %

Procedure:
A stirred mixture of commercially available 2-amino-5-cyano-pyrimidine [CAS-No. 1753-48-6] (1.39 g, 11.6 mmol), hydroxylamine hydrochloride (1.61 g, 23.2 mol) and potassium carbonate (4.8 g, 34.7 mol) in ethanol (57 ml) was heated under reflux conditions for 3 h. The reaction mixture was evaporated and purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound (1.28 g, 72%) as an off-white solid. MS (EI) 153.1 [(M)+]; mp 218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]OS(C)(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCCCCCCC=Cc1cccs1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(c1ccccc1)c1ccc(NCCCCCCCCC=Cc2cccs2)cc1
Temperature: 25 °C

Procedure:
p-Aminoacetophenone is heated with 5 g. 10-(2-thien-yl)-1-methanesulfonyloxy-9-decene (prepared by the method of Example 9) in 50 ml. hexamethylphosphoramide containing anhydrous potassium carbonate (1.9 g.) for 16 hours a 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (50 ml.). The amber solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:23])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:11][C:10]([Cl:24])=[C:9]([OH:25])[CH:8]=2)=[O:4].C([O-])(O)=O.[Na+]>CO>[Cl:24][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[OH:25])[O:6][C:5]([C:3]([OH:4])=[O:2])=[C:14]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:13]2=[O:23]
Reactant: COC(=O)c1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2c(C(=O)O)oc3cc(O)c(Cl)cc3c2=O)cc1
Temperature: 25 °C

Procedure:
6-Chloro-7-hydroxy-3-(4-methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid methyl ester was taken up in a 2:1 mixture of sat. NaHCO3 (aq): Methanol and all was heated at 65° C. for 5 hours. The solution was cooled to room temperature and concentrated in vacuo to remove the methanol. The residual aqueous solution was acidified with 1M HCl (aq) and a buff coloured precipitated dropped out of solution. This was collected by vacuum filtration, washed with water and with diethyl ether, to give 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid
Reaction SMILES: [Na:1].C(C1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.OCC[CH:50]1[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]1>>[Na:1].[CH3:55][C:52]1([CH3:56])[O:53][CH:54]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])[CH2:50][O:51]1
Reactant: CC1(C)OCC(CCO)O1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCCC2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.7 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan to obtain the title compound (412 mg, total yield: 8.7%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 67 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 67%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.40 (m, 6H), 3.14-3.22 (m, 4H), 3.69-3.76 (m, 3H), 4.06-4.18 (m, 4H), 6.97-7.04 (m, 3H), 7.20-7.85 (m, 4H).