Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].O1CCC[CH2:19]1.O1CCCC1.C[Mg]Cl>CCOCC>[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)(=[O:5])[CH3:19]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: CCOCC
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100 ml round bottom flask was added tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate (2.6 g, 10.6 mmol) and 20 ml tetrahydrofuran. The resulting solution was cooled to 0° C. and methylmagnesium chloride tetrahydrofuran solution (4.3 ml, 3M, 12.8 mmol) was added by a syringe. The reaction mixture was stirred at 0° C. for 1 hour. It was diluted with 100 ml ether, and the resulting mixture was washed twice with 100 ml saturated ammonium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH:7](Cl)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C(O)C>O>[C:1]1([CH:7]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(Cl)c1ccccc1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCC(Sc1cccc[n+]1[O-])c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 16.9 gms (0.1 mol) of 1-phenylbutylchloride, 36 gms of a 40% aqueous solution of the sodium salt of 2-mercaptopyridine N-oxide (0.1 mol) and 50 ml of ethanol was warmed and stirred at 50° to 60° C. for 2.5 hours. The cooled reaction mixture was poured into 500 ml of water with agitation. The precipitated product was filtered, washed with water and dried. After recrystallization from ethanol a yield of 10 gms (45% theory) of white crystals was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[C:4]([F:13])[C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cc(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(F)cc(F)cc2N1CCCCl
Yield: 39.1 %

Procedure:
6,8-Difluoro-4H-benzo[1,4]oxazin-3-one (0.80 g, 4.3 mmol), Cs2CO3 (2.12 g, 6.5 mmol), and 1-chloro-3-iodopropane (0.98 g, 4.8 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 39%). Rf=0.65 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.66-6.59 (m, 2H), 4.64 (s, 2H), 4.09-4.03 (m, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.23-2.10 (m, 2H); 13C NMR (CDCl3) δ 164.2, 157.5 (dd, J=242.5 Hz, J=12.7 Hz), 151.7 (dd, J=248.5 Hz, J=14.4 Hz), 131.0 (dd, J=12.1 Hz, J=4.8 Hz), 130.4 (dd, J=15.0 Hz, J=3.2 Hz), 99.7 (dd, J=26.9 Hz, J=22.4 Hz), 98.2 (dd, J=28.4 Hz, J=3.4 Hz), 67.8, 42.2, 39.7, 30.0.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCCCCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 310 mg of 16i in 9 ml of dioxane was mixed with a solution of 200 mg of KOH in 3 ml of water and was stirred at 50° C. for 1 hr. The mixture was diluted with water and acidified to pH3 with 0.5N HCl and the product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to give 290 mg of 16j.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[Cl:20]C1C=C(CC(=O)C)C=CN=1>>[Cl:20][C:11]1[CH:12]=[C:7]([C:6]2[S:5][C:4]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=[CH:9][N:10]=1
Reactant: CC(=O)Cc1ccnc(Cl)c1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccncc1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1

Procedure:
The titled compound is prepared by an analogous procedure to (4-Methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) in this procedure with 1-(2-chloro-pyridin-4-yl)-propan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:26]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Temperature: 130 °C
Yield: 132.3 %

Procedure:
7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (708 mg), DABCO (112 mg), and N,N-Dimethylformamide (4 mL) were added to dimethyl carbonate (10 mL) at room temperature under stirring. The reaction mixture was heated to 130° C. for 36 h. After cooling the reaction, the organic solvent was evaporated off. The residue was purified by column chromatography (25% EtOAc in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (486 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.46 (6H, d), 3.78 (3H, s), 4.71-4.76 (1H, m), 6.60 (1H, d), 7.08 (1H, dd), 7.21 (1H, t), 7.56 (1H, dd), 7.80 (1H, dd), 7.96 (1H, dd), 8.27 (1H, d). MS (ES): C20H15ClN3O2 requires 367; found 368.1 (M+H+).
Reaction SMILES: [N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:13]3[N:1]=[C:2]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:3][N:4]3[C:5](=[O:14])[N:6]=2)[CH:11]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)c1nc2c3ccccc3nc(=O)n2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc2c3cc([N+](=O)[O-])ccc3nc(=O)n2[nH]1
Temperature: 0 °C

Procedure:
2.0 g (0.008 mole) of ethyl 1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate were introduced into 20 ml of concentrated H2SO4 at 20° C., whilst stirring, and 0.3 ml of 100% strength HNO3 was added dropwise. The mixture was stirred for a further 3 hours at 20° C. and then introduced onto 100 ml of ice water. The precipitate was filtered off and dissolved in methylene chloride/methanol, the solution was treated with active charcoal and filtered, and the solvent was stripped off. Yield: 1.4 g (60%), mp. 280° C.
Reaction SMILES: [C:1]([C:3]1([CH2:14]O)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1([CH2:14][F:22])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(CO)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C#N)(CF)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.0 g) was dissolved in DCM (100 mL). At 0° C., DAST (3.74 mL) was added thereto, followed by stirring at 0° C. for 3 hours. Three hours later, to the reaction liquid was added an aqueous NaHCO3 solution (100 mL), followed by extraction with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylate (1.24 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]([C:13]#[C:14][CH2:15][CH3:16])=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Fe+2].CN(C=O)C>[CH2:15]([C:14]1[C:2]2[C:3](=[CH:5][CH:6]=[C:7]([CH3:9])[CH:8]=2)[NH:4][C:13]=1[C:11]([CH3:12])=[CH2:10])[CH3:16]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: C=C(C)C#CCC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C=C(C)c1[nH]c2ccc(C)cc2c1CC
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 100 ml reaction flask equipped with a stirring bar and thermocouple are charged with Pd(OAc)2 (56 mg, 0.25 mmol), DtBPF (142 mg, 0.3 mmol), 2-chloro-4-methylaniline (0.71 g, 5 mmol), 2-methyl-1-hexen-3-yne (0.94 g, 10 mmol), K2CO3 (1.73 g, 12.5 mmol) and DMF (50 mL). The flask was purged with argon. The reaction was heated to 110° C. and stirred overnight. The reaction was complete after 20 h at 110° C. The mixture was filtered through a layer of diatomaceous earth and washed with EtOAc (10 mL). The filtrate was diluted with water (50 mL), extracted with EtOAc (100 mL×3). The combined organic phase was washed with water (50 mL×4) and brine, dried over MgSO4, filtered and concentrated to give a dark brown residue. The product was purified via chromatography on silica gel (hexane/EtOAc 50/1). The desired product was obtained as an off-white solid (0.6 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 2-tributylstannanylpyridine (226 g, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.05 mmol) and copper iodide (29 mg, 0.15 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 100° C. for 1 h using microwave irradiation. The reaction mixture was diluted with MeOH (20 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in DCM followed by Si-PCC, gradient 0-7% MeOH in EtOAc) affording the title compound as a cream solid (140 mg, 80%). LCMS: RT 2.52 min [M+H]+ 341.8/343.8.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15](O)=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1.[Cl-].[NH4+:31]>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15]([NH2:31])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1
Reactant: O=C(O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Yield: 45 %

Procedure:
10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 57 mg (45% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][C@H:20]1[CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:20]1[CH2:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)nc1
Temperature: 70 °C
Reaction time: 13 h
Yield: 32.4 %

Procedure:
To a stirred solution of methyl 2-hydroxypyridine-5-carboxylate (1.00 g, 6.529 mmol), N-tert-butoxycarbonylprolinol (1.31 g, 6.529 mmol), and Ph3P (2.06 g, 7.836 mmol) in THF (10 mL) was added DIAD (1.54 mL, 7.836 mmol) at room temp, and the resulting mixture was stirred for 13 hr at 70° C. The mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane:EtOAc (3:1, v/v) as eluent to give 712.3 mg (32%) methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ1.47 (s, 9H), 1.85-1.98 (m, 4H), 3.37 (br s, 2H), 3.92 (s, 3H), 4.12-4.33 (br m, 2H), 4.48 (brs, 1H), 6.75 (m, 1H), 8.15 (m, 1H), 8.79 (m, 1H); MS (FAB) m/z 337 (M++1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:26])=[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[CH:13]=2)[N:8]([C@H:27]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:28]([CH3:30])[CH3:29])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)(C)C>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:26])[N:8]([C@H:27]([CH2:31][OH:32])[CH:28]([CH3:30])[CH3:29])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(Cc3cccc(Cl)c3F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)[C@@H](CO)n1cc(C(=O)O)c(=O)c2cc(Cc3cccc(Cl)c3F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-6-(3-chloro-2-fluorobenzyl)-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (19 g, 33 mmol) obtained in Example 1, Step 5 was dissolved in isopropanol (100 ml), 1N aqueous sodium hydroxide solution (200 ml, 200 mmol) was added, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was filtered through Celite. The filtrate was acidified by adding concentrated hydrochloric acid, and stirred at room temperature for 2 hr. The precipitated solid was collected by filtration and vacuum dried to give 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12 g, yield 82%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[NH:7]2.[C:17]1([S:23]([N:26]=C=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-acetyl-1,4-dihydroquinol-4-one (0.28 g, 1.1 mmol) and benzenesulfonyl isocyanate (0.16 mL, 1.2 mmol) in acetonitrile (5 mL). Heat at reflux for 3 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 163°-164° C. Rf =0.32 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C17H12Cl2 N2O3S: C, 51.65; H, 3.04; N, 7.09.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>ClC(Cl)C.C(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[CH:10][N:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][C:5]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:6][CH:7]=2)[N:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccnc(Oc2ccccc2)n1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Oc2nccc(C(F)(F)F)n2)cc1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a solution of 2-phenoxy-4-trifluoromethylpyrimidine (3.0 g, 12.5 mmol, prepared under a) in dichloroethane (30 ml) was added a solution chlorosulfonic acid (10.2 g, 88 mmol) in DCM (20 ml). The reaction mixture was stirred 7 h at 50° C. Subsequently the reaction mixture was slowly quenched with water and extracted with MTBE. The organic layer was washed with water and dried and the solvent was removed in vacuo. The residue was suspended in n-pentane and stirred for 10 minutes. Filtration yielded 4-(4-trifluoromethylpyrimidin-2-oxy)benzenesulfonyl chloride as a brownish solid (1.5 g). 1H-NMR (CDCl3): δ=7.5 (m, 3H), 8.17 (m, 2H), 8.9 ppm (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[O:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]([C:14]2[S:13][C:12]([CH2:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:24][CH2:25]1
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC2CCOCC2)s1
Yield: 60 %

Procedure:
As described for example 48e, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.23 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (55 mg, 60%) which was obtained as a light brown oil. MS: m/e=392.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:21]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:16][C:14]2[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[C:12]([C:17]([F:20])([F:18])[F:19])[N:13]=2)=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(C(F)(F)F)c(C(=O)NCc2ccccc2)s1
Product: CCCCCc1ccc(C(=O)Nc2nc(C(F)(F)F)c(C(=O)NCc3ccccc3)s2)cc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-amino-4-trifluoromethylthiazole-5-carboxylic acid benzylamide in place of 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide to react with 4-pentylbenzoyl chloride, the title compound was obtained as a white solid in 89% yield; 1H NMR (CDCl3, 300 MHz) δ 13.18 (s, 1H), 9.28 (t, J=5.8 Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.36-7.23 (m, 7H), 4.41 (d, J=5.8 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 1.58-1.51 (m, 2H), 1.26-1.20 (m, 4H), 0.81 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.2, 148.9, 139.1, 159.5, 158.7, 129.1, 128.9, 128.8, 127.9, 127.8, 127.7, 127.5, 43.4, 35.5, 31.3, 30.7, 22.4, 14.3; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[O:29][CH3:30])[C:14]=2[CH:31]=1>>[CH2:5]([O:4][C:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[O:29][CH3:30])[C:14]=2[CH:31]=1)=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)Nc1ccc2ncn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 34 %

Procedure:
Using a similar procedure to that described in Example 35, but using butyl chloroformate and (J) , the title compound was obtained as a solid in 34% yield; partial NMR: 0.9(t,3H, CH3CH2), 1.4(m,2H, CH3CH2) , 1.6 (m, 2H, CH2CH2O), 4.1 (t, 2H, CH2O).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:13][O:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: O=Cc1ccc2c(c1O)CCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)ccc2c1CCC2
Temperature: 26.5 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a stirred suspension of 4-Hydroxy-indan-5-carbaldehyde (52.0 gm, 0.320 mole) and Potassium carbonate (57.2 gm, 0.414 mole) in Dimethylformamide (200 ml) solution of Methyl iodide (22 ml, 0.351 mole) in 60 ml Dimethylformamide was added at 0-5° C. The reaction mixture was stirred at 25-28° C. for 4 hours and then poured into water (200 ml), further it was extracted with Ethyl acetate (2×500 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give crude product which was purified through column chromatography using Ethyl acetate:Hexane (3:97) as mobile phase. The collected fractions were distilled under vacuum to give 30 gm of desired product as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH3:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][N:33]([CH3:40])[CH3:32])[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Reactant: CN(C)CC(C)(C)CO
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(OCC(C)(C)CN(C)C)n1

Procedure:
Using an analogous procedure to that described in Example 8, 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine was reacted with 3-dimethylamino-2,2-dimethylpropanol. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.85 (s, 6H), 2.14 (s, 6H), 2.18 (s, 2H), 3.94 (s, 2H), 6.22 (d, 1H), 7.23 (d, 1H), 7.4-7.58 (m, 4H), 7.78 (d, 1H), 7.84 (d, 1H), 7.96 (m, 2H), 8.2 (d, 1H), 8.31 (d, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[K+].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1>C1OCCOCCOCCOCCOCCOC1>[CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2ccccc2n1Cc1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2-methylindole (7.60 mmol, 1.00 g) was added 18-crown-6 (60 mg, 0.06 mmol) and subsequently powdered KOH (416 mg, 7.60 mmol) and methyl 4-(bromomethyl)benzoate (1 eq). The reaction was heated to 100° C. for 2 hr, and was added additional KOH (416 mg, 7.60 mmol). The reaction was stirred for another 1 hr. The reaction was cooled and then quenched with HCl and extracted with EtOAc (2×100 mL). The organic layers were collected, dried and concentrated in vacuo. The crude was flashed to yield the desired acid (798 mg, 40%). MS found: (M+H)+=274.