Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Br
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Br)cc1

Procedure:
2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579–1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analog according to the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-methylphenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the title compound according to the method of Example 10 (yield: 210 mg, 98%). mp 154–156° C. 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 3.07 (s, 3H), 4.89 (q, J=9 Hz, 2H), 7.08 (s, 4H), 7.37 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.59; H, 4.11; N, 6.53.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3Cl)[CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:33])[CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:32][C:9]1([CH3:33])[CH2:10][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][NH:8]1
Reactant: CC1(C)CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)CC(Oc2cccc(NC(=O)c3ccc(F)cc3)n2)CCN1
Temperature: 80 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
Combine N-[6-(1-benzyl-2,2-dimethyl-piperidin-4-yloxy)-pyridin-2-yl]-2-chloro-4-fluoro-benzamide (preparation 93, 0.056 g, 0.12 mmol), ethanol (5 mL), 10% palladium/carbon (0.01 g) and ammonium formate (0.064 g, 1.2 mmol), stir and heat to 80° C. After 16 hr., cool to ambient temperature. Filter through celite, rinsing with ethanol. Concentrate filtrate. Dissolve the residue in methanol (10 mL) and load on an SCX column (10 g); wash with methanol (2×50 mL); elute product with 2M ammonia/methanol (2×50 mL). Concentrate the eluent to obtain the title compound (0.042 g, 100%): Mass spectrum (electrospray): m/z=344.2 (M+1); 1H NMR (CDCl3): 8.2 (bs, 1H), 7.9 (m, 3H), 7.7 (m, 1H), 7.2 (m, 2H), 6.5 (d, 1H), 5.2 (m, 1H), 3.1 (m, 1H), 3.0 (m, 1H), 2.1 (m, 1H), 2.0 (dd, 1H), 1.5 (m, 2H), 1.25 (s, 6H).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[O:10]([CH2:11][CH2:12][Br:13])[C@@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@H:16]([OH:22])[C@H:17]([OH:18])[C@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](OCCBr)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 4 h
Yield: 91.7 %

Procedure:
A solution of NaOMe (0.104 M, 0.8 mL) was added to a solution of 4j (See FIG. 7) (778 mg. 1.71 mmol) in MeOH (10 mL) under N2. After 4 hours, the reaction solution was passed through a Dowex 50W(H+) plug (3×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl β-D-galactopyranoside (4e) (See FIG. 7) (450 mg, 92%) (The synthesis of unstable 4e has been described previously. Dahmén et al., “2-Bromoethyl Glycosides 4.2-Bromoethyl Glycosides in Glycoside Synthesis—Preparation of Glycoproteins Containing Alpha-L-Fuc-(1->2)-D-Gal and Beta-D-Gal-(1->4)-D-Glcnac,” Carbohydr. Res., 125:237-245 (1984), which is hereby incorporated by reference) as a white solid which was used directly in the next step. NaSSO2CH3 (180 mg, 1.34 mmol) was added to a solution 4e (See FIG. 7) (290 mg, 1.01 mmol) in DMF (12 mL) under N2 and warmed to 50° C. After 15 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1e (See FIG. 7) (229 mg, 71%) as a white foam; [α]27D=+2.9 (c 0.58, H2O); IR (film) 3358 cm−1 (br, O—H), 1306, 1120 cm−1 (S—SO2); 1H NMR (500 MHz, D2O, COSY) δ 3.29-3.33 (m, 2H, —CH2S—), 3.30 (dd, J1,2 7.7 Hz, J2,3 10.0 Hz, 1H, H-2), 3.35 (s, 3H, CH3SO2—), 3.43 (dd, J2,3 10.0 Hz, J3,4 3.6 Hz, 1 H, H-3), 3.48 (ddd, J4,5 0.9 Hz, J5,6 4.3 Hz, J5,6′ 7.9 Hz, 1H, H-5), 3.52 (dd J5,6 4.3 Hz, J6,6′ 11.7 Hz, 1H, H-6),3.57 (dd, J5,6′ 7.9 Hz, J6,6′ 11.7 Hz, 1H, H-6′) 3.70 (dd, J3,4 3.6 Hz, J4,5 0.9 Hz, 1H, H-4), 3.80 (dt, Jd 11.2 Hz, Jt 6.1 Hz, 1H, —OCHH′—), 4.01 (dt, Jd 11.4 Hz, Jt 5.8 Hz, 1H, —OCHH′—), 4.24 (d, J1,2 7.7 Hz, 1H, H-1); 13C NMR (100 MHz, D2O) δ 36.7 (—CH2S—), 50.8 (CH3SO2—), 61.9 (—OCH2—), 69.2, 69.6, 71.7. 73.7, 76.2 (C-2, C-3, C-4, C-5, C-6), 104.0 (C-1); HRMS m/z (FAB+): Found 319.0523 (M+H+); C9H19O8S2 requires 319.0521.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:19]#[N:20])[CH:15]=[C:16]([CH2:18][Br:21])[CH:17]=2)[O:9][N:8]=1
Reactant: Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol), N-bromosuccinimide (0.339 g, 1.91 mmol), and benzoyl peroxide (0.0010 g, 0.04 mmol) in carbon tetrachloride (25 mL) was heated at 80° C. for 18 hours. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine to afford 0.595 g (91%) of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1)(=O)C.O.[OH-].[Li+]>O.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-n2nnnc2CO)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {1-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 47, 330 mg, 1.02 mmol) in water (2 mL) and tetrahydrofuran (4 mL), cooled in an ice bath, was added lithium hydroxide monohydrate (42.6 mg, 1.02 mmol). The reaction was stirred at room temperature for 1 hour and 30 min. The organic solvent was removed from the reaction under vacuum and the residual mixture diluted with water (30 mL) and extracted with DCM (2*50 ml). The organic extracts were combined, dried (hydrophobic frit) and the solvent removed to yield the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[O:18])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7].[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:19])[C:4]([OH:18])([C:21]([F:23])([F:22])[F:20])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)C(=O)CC(C)(C)c1ccc(I)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O)(CC(C)(C)c1ccc(I)cc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0° C. and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13].[I-].[K+].[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: Cc1cccc(NC(=O)NCC(=O)Nc2ccccc2I)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2I)c1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 91.7 %

Procedure:
To a solution of N-(2-iodophenyl)-2-(3-m-tolylureido)acetamide (1.02 g, 2.5 mmol) in DMSO (5 ml) are added at room temperature potassium iodide (83 mg, 0.2 mmol), tetra-n-butylammonium bromide (81 mg, 0.1 mmol), t-butylbromoacetate (0.55 ml, 3.75 mmol) and potassium carbonate (1.04 g, 7.5 mmol), and stirred at room temperature for 2.25 hours. To the reaction mixture are added water and ethyl acetate, and the pH is adjusted to 2 with 2N hydrochloric acid. The aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with 0.1N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated. To the residue is added isopropylether, and the precipitated solid is filtered off to obtain the objective compound (1.20 g). Yield 92%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1ncccn1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3ncccn3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and pyrimidine-2-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(pyrimidin-2-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.09 (br s, 3H), 3.04 (m, 4H), 3.28-3.29 (m, 2H), 3.33-3.40 (m, 4H), 3.68 (m, 4H), 3.86 (m, 2H), 6.50 (s, 1H), 7.14-7.20 (m, 1H), 7.29-7.30 (m, 1H), 7.52 (s, 1H), 7.63 (t, J=4.8 Hz, 1H), 7.78 (br s, 1H), 8.37 (s, 1H), 8.93 (d, J=5.2 Hz, 2H). Mass Spectrum (ESI) m/e=546.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[F-].[Cs+]>O1CCOCC1.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>[Cl:16][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2
Reactant: CCOC(=O)c1cc2c(Cl)ccc(Br)c2[nH]1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(Cl)ccc(-c3ccccc3C)c2[nH]1

Procedure:
To a solution of EXAMPLE 166B (610 mg), o-tolylboronic acid (330 mg), cesium fluoride (930 mg) in dioxane (5 mL) was added tetrakis(triphenylphosphine)palladium (240 mg). The resulting mixture was heated under reflux overnight and concentrated. The residue was diluted with ethyl acetate and saturated ammonium acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:17])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>O1CCCC1>[OH:17][C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
8-Pyridin-2-yl-1,4-dioxaspiro[4.5]decan-8-ol (1.44 g) was dissolved in tetrahydrofuran (25 ml). 2M hydrochloric acid (25 ml) was added and the solution stirred at room temperature overnight. The THF was removed in vacuo and remaining solution made basic with 2M aqueous sodium hydroxide and partitioned with dichloromethane (2×100 ml). Combined organics were dried (sodium sulphate) and concentrated in vacuo to give 4-hydroxy-4-pyridin-2-ylcyclohexanone as an off-white solid (1.07 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[Cl:25])[CH:3]=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:17]([Cl:25])[CH:18]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(N)cc1Cl
Reaction time: 5 h

Procedure:
A mixture of the product from step (ii) (0.2 g) and Pd(OH)2/C (0.04 g) in ethanol (4 ml) was hydrogenated at 1 Bar for 5 h then filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 20% ethylacetate/isohexane, yield 0.13 g.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1>CS(C)=O.O>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: BrC1CCN(Cc2ccccc2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN2CCC(Sc3ccccc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 727.5 %

Procedure:
A solution of 55 g (0.5 mole) of thiophenol in 50 ml of dimethylsulfoxide was added dropwise with stirring to 250 ml of dimethylsulfoxide containing 21.5 g (0.55 mole) of sodamide. After stirring the mixture at 40° C. for 1 hr, 120 g (0.05 mole) of 3-bromo-1-benzyl-pyrrolidine (slightly exothermic) was added dropwise. The solution was stirred at 60° C. for 1 hr, diluted with 500 ml of water and extracted with isopropyl ether. The ether phase was dried over sodium sulfate and concentrated, and the residue distilled, b.p. 170°-170° C./5 mm. to give 98 g (73%) of product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:15]2[CH2:16][CH2:17][CH2:18][N:12]([C:4]3[CH:3]=[C:2]([NH:28][CH2:27][CH2:26][NH2:29])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:13][C:14]=2[CH:22]=1)[CH3:25]
Reactant: NCCN
Reactant: CCOc1ccc2c(c1)CN(c1cc(Cl)c3ccccc3n1)CCC2
Product: CCOc1ccc2c(c1)CN(c1cc(NCCN)c3ccccc3n1)CCC2
Temperature: 160 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-8-ethoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (28 mg, 0.79 mmol) and ethane-1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave process vial for 2 hours at 160° C. under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 12 mg of product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 377. 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J=7.6 Hz, 1 H,), 7.62 (d, J=8.0 Hz, 1 H), 7.57 (m, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.38 (m, 1 H), 7.19 (m, 2 H), 6.00 (s, 1 H), 4.78 (s, 2 H), 4.12 (m, 2 H), 3.99 (q, J=6.8 Hz, 2 H), 3.48 (m, 2 H), 2.98 (m, 4 H), 1.94 (m, 2 H), 1.34 (t, J=6.8 Hz, 3 H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[S:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([C:28]2[S:27][C:26]([S:23]([NH:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:24])=[O:25])=[CH:30][CH:29]=2)=[N:3][CH:4]=1
Reactant: COCCNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 19.7 %

Procedure:
A mixture of 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (250 mg, 0.795 mmol), N-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (359 mg, 1.034 mmol, 1.3 eq), Pd(dppf)Cl2 (65 mg, 0.0795 mmol, 0.1 eq) and Na2CO3 (295 mg, 2.783 mmol, 3.5 eq) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 50:1 as eluent) to afford title compound 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-(2-methoxyethyl) thiophene-2-sulfonamide (Compound 88) (71.2 mg, 28.1%) as solid. LC-MS (m/z)=455.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.75 (d, J=3.6 Hz, 2H), 0.99 (d, J=6.4 Hz, 2H), 1.94 (s, 1H), 3.04 (t, J=5.2 Hz, 2H), 3.20 (s, 3H), 3.37 (t, J=5.0 Hz, 2H), 6.39 (s, 1H), 7.61 (d, J=3.2 Hz, 1H), 7.77 (d, J=3.6 Hz, 1H), 8.15 (s, 1H), 8.46 (s, 1H), 9.49 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=2)[O:2]1.[H-].[Na+].[CH3:23][O:24][C:25](=O)[O:26]C>>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]([C:10](=[O:12])[CH2:11][C:25]([O:24][CH3:23])=[O:26])[CH:7]=2)[O:2]1
Reactant: COC(=O)OC
Reactant: CC(=O)c1cc2c(cc1OCc1ccccc1)OCO2
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1cc2c(cc1OCc1ccccc1)OCO2
Yield: 91.2 %

Procedure:
A mixture of 1-[4,5-(methylenedioxy)-2-(phenylmethoxy)phenyl]ethanone (5.4 g, 0.02 mol), sodium hydride (1.6 g of 60% sodium hydride, 0.04 mol) and dimethylcarbonate (18 g, 0.2 mol) was heated to 70°-75° C. for 20 minutes. After evaporating the excess dimethylcarbonate under reduced pressure, the residue was acidified with 10% HCl solution and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was filtered through silica gel using chloroform as eluent to afford 5.99 g (91.3%) of methyl 4,5-(methylenedioxy)-β-oxo-2-(phenylmethoxy)benzenepropanoate mp (EtOH) 86°-86.5° C.; IR (KBr) 1750 (ester), 1652 (carbonyl) cm-1 ; NMR (CDCl3, 90 MHz) δ, 3.61 (S, 3H, CO2CH3), 3.92 (S, 2H, CH2CO2CH3), 5.11 (S, 2H, CH2Ph), 5.98 (S, 2H, OCH2O), 6.54 (S, 1H, ArH), 7.39 (S, 5H, CH2Ph), 7.41 (S, 1H, ArH). Anal. calcd. for C18H16O6 : C, 65.85; H, 4.91. Found: C, 65.92; H, 5.11.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[OH:23][C:24]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:49])([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=2)=[O:35])[CH2:27][CH2:26]1.O.OO>O1CCCC1>[OH:23][C:24]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=2)[OH:35])[CH2:27][CH2:26]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc([C@@H](O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve (-)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, ethyl ester (2 g, 3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stir at room temperature for 3 days and cool to 0° C. Add water (1 mL) and 30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylene chloride (30 mL) and wash with brine (30 mL), then aqueous sodium hydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].COC1C(OC)=NS(=O)(=O)N=1.OCC1NC=NC=1CSC[CH2:34][NH:35][C:36]1[C:40](OC)=[N:39][S:38](=[O:44])(=[O:43])[N:37]=1.CN>>[OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:40]1[C:36]([NH:35][CH3:34])=[N:37][S:38](=[O:44])(=[O:43])[N:39]=1
Reactant: NCCSCc1nc[nH]c1CO
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1CO
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1CO

Procedure:
2-[(5-Hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamine [prepared according to the procedure described in Belgian Pat. No. 843,840] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and the resultant 3-{2-[(5-hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy- 1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine according to the general procedure described in Example 2, and the title compound is thereby produced.