Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][C:5]2[O:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:27]=[N:26][C:5]2[O:6][C:7]([CH3:24])([CH3:25])[C:8](=[O:23])[N:9]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Cl)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2ncc(Cl)cc2N(C2CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under ice cooling, to a dichloromethane solution (145 ml) of tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (74.2 g) was added trifluoroacetic acid (145 ml), followed by stirring at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, ether was added to the residue, and the slurry was stirred overnight. The insolubles were collected by filtration to afford 7-chloro-3,3-dimethyl-1-piperidin-4-yl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one trifluoroacetate (76.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](Cl)=[O:29]>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:29]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccc(F)cc1Cl
Yield: 50.9 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.37 mL, 2.7 mmol) and 2-chloro-4-fluorobenzene-1-carbonyl chloride (Acros, 0.25 g, 1.3 mmol) in 15 mL THF were processed using the method described in Example 132 to afford the title compound (0.19 g, 0.56 mmol, 52% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.27 (s, 3H), 3.30 (s, 3H), 3.76 (t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 7.00 (ddd, J=8.5, 7.8, 2.4 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 8.04 (dd, J=8.8, 6.4 Hz, 1H); MS (DCI/NH3) m/z 343 (M+H)+; Anal. calculated for C15H16ClFN2O2S: C, 52.55; H, 4.70; N, 8.17. Found: C, 52.60; H, 4.38; N, 8.06.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25]>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25]
Reactant: O=C(O)Cc1c(Br)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c(CCO)c(Br)cnc12)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 54.3 %

Procedure:
To a solution of 3-bromo-4-carboxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (130 mg) in dry tetrahydrofuran was added 10M solution of borane-methyl sulfide complex in tetrahydrofuran (0.286 ml) at ambient temperature, and the mixture was stirred for 4 hours at the same temperature. The mixture was quenched by 1N hydrochloric acid and stirred for 1 hour at the same temperature. The mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane, 1:2, v/v) and crystallized from ethyl acetate-n-hexane to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(2-hydroxyethyl)quinoline (68.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of the product of Example 5A (544.5 mg, 2.59 mmol) in anhydrous DMF (26 mL) was added imidazole (264 mg, 3.89 mmol) and TBDMS-Cl (586 mg, 3.89 mmol). The reaction mixture stirred at room temperature overnight and was quenched with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product (677.5 mg, 2.19 mmol) in 84% yield. 1H (CDCl38.01, 600 MHz): δ (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.4 Hz), 4.63 (2H, s), 3.91 (2H, s), 3.82 (2H, t, J=5.0), 3.58 (2H, t, J=5.1 Hz), 0.91 (9H, s), 0.07 (6H, s); 13C(CDCl3166.5, 143.5, 129.2, 128.8, 126.5, 72.1, 71.6, 150 MHz): δ 62.3, 51.5, 25.4, 17.9, −5.8.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])O.[Na+].[C:19]1(=[O:47])[N:23]([CH2:24][C:25]([N:27]2[C@@H:33]3[CH2:34][CH2:35][CH2:36][C@@H:32]3[C:31](=[O:37])[NH:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]2=3)=[O:26])[C:22](=[O:42])[C:21]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:20]12.[H-].[Na+]>O.C(OCC)(=O)C.CN(C)C=O>[C:22]1(=[O:42])[N:23]([CH2:24][C:25]([N:27]2[C@@H:33]3[CH2:34][CH2:35][CH2:36][C@@H:32]3[C:31](=[O:37])[N:30]([CH2:3][C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]2=3)=[O:26])[C:19](=[O:47])[C:20]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:21]12
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc3ccccc3n2)C(=O)[C@H]2CCC[C@H]21
Yield: 45.8 %

Procedure:
2-(Chloromethyl)quinoline hydrochloride (321 mg, 1.5 mmol) was dissolved in water (0.5 mL) and ethyl acetate (1 mL), which was neutralized with sodium hydrogencarbonate. The organic layer was separated, and the aqueous layer was subjected to extraction twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, which was concentrated under reduced pressure. To the concentrate were added (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (390 mg, 1.0 mmol) and N,N-dimethylformamide (3 mL). To this suspension was added, at 0° C., sodium hydride (60% liquid paraffin dispersion, 48 mg, 1.2 mmol), and the mixture was stirred for 20 minutes at room temperature. To the reaction mixture was added water, which was subjected to extraction twice with chloroform. Organic layers were combined, washed with water, dried over magnesium sulfate, subjected to filtration and, then, concentrated under reduced pressure. The concentrate was crystallized from ethanol-hexane to give 243 mg (yield 46%) of the titled compound, m.p. 258°-260° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH2:30](O)[CH3:31]>>[CH2:30]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:8][CH:9]=1)=[O:3])[CH3:31]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(C(=O)O)cc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
A mixture of 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.2 g) and hydrogen chloride in ethanol (50 ml) was refluxed for 6 hours. The solvent was evaporated and the residue was recrystallized from ethanol to give crystals of 1-[4-(ethoxycarbonyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.3 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[BH4-].[Na+]>O1CCCC1.CO.[Ni+2]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Ni+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (15.94 g, 43.50 mmol) in tetrahydrofuran (200 mL) and methanol (300 mL) was cooled to 0° C. Nickel(II) chloridehexahydrate (5.18 g, 21.80 mmol) was added in one portion. The solution was stirred for 30 minutes followed by portion-wise addition of sodium borohydride (3.29 g, 87.00 mmol). Prior to warming the reaction to room temperature additional nickel (II) chloridehexahydrate (5.18 g, 21.80 mmol) and sodium borohydride (3.29 g, 87.00 mmol) were added to the reaction. The solvent was removed in vacuo and the residue was taken up in dichloromethane, filtered through celite, and washed with ethyl acetate. Purification by flash chromatography provided 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (13.46 g, 40.10 mmol, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (qd, J=11.9, 3.6 Hz, 2 H) 1.76 (d, J=12.1 Hz, 2 H) 2.12-2.20 (m, 1 H) 2.35-2.45 (m, 10 H) 2.53 (dt, JHF=28.6 Hz, J=4.9 Hz, 2 H) 3.37 (d, J=12.1 Hz, 2 H) 3.68 (s, 3 H) 4.14 (br. s., 2 H) 4.47 (dt, JHF=47.9 Hz, J=4.94 Hz, 2 H) 6.24 (dd, J=8.2, 2.4 Hz, 1 H) 6.43 (d, J=2.4 Hz, 1 H) 6.45 (d, J=8.4 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:6](C#N)=[C:5]([S:9][CH3:10])[N:4]([CH3:11])[N:3]=1.P([O-])([O-])(O)=O.[Na+].[Na+]>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([S:9][CH3:10])[N:4]([CH3:11])[N:3]=1
Reactant: CSc1c(C#N)c(N)nn1C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CSc1cc(N)nn1C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
5.55 g (33.0 mmol) 3-amino-4-cyano-1-methyl-5-methylmercaptopyrazole heated with 50 ml 32% caustic soda at boiling for 24 hours. The reaction mixture was cooled, made slightly acidic with aqueous sodium hydrogen phosphate, heated for 8 hours at 50° C. and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the residue purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][Cl:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:37][CH2:38][Cl:39])[N:9]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CCCl)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), 2-chloroethyl para-toluenesulfonate (745 μL, 4.11 mmol, 1.5 equiv), and cesium carbonate (2.16 g, 6.62 mmol, 2.4 equiv) in N,N-dimethylformamide (10 mL) was heated at 50° C. After 3 h, the reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate (30 mL) and half-saturated aqueous sodium chloride solution (30 mL). The aqueous was extracted with ethyl acetate (2×20 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (ethyl acetate) provided product (950 mg, 77% yield). LCMS (ESI): M+H=432.1.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([Cl:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([Cl:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(O)(C(F)(F)F)=O.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:18]\[N:19]([CH3:21])[CH3:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1cc(OCc2ccccc2)ccn1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)/C=N\c1cc(OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
A 250 mL, single-neck, round-bottomed flask was charged with 4-(benzyloxy)pyridin-2-amine (6.012 g, 30.02 mmol), dimethoxy-N,N-dimethylmethanamine (5.535 ml, 39.03 mmol) and ethanol (100.1 ml). A few drops of TFA were added and the reaction was heated to 50° C. for 4 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was used in the next step without purification.
Reaction SMILES: C(C1C=C2C(=C(C(C)C)C=1)N=CN(/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])C2=O)(C)C.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27]Cl)[CH3:24].C(O)(C)C.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CCOCC.C(Cl)Cl>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[C:19]([O:21][CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:29][CH3:30])(=[O:20])[CH:18]=[CH2:17]
Reactant: CCN(CC)CCCl
Reactant: CC(C)c1cc(C(C)C)c2ncn(/C=C/C(=O)O)c(=O)c2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CC(=O)OCCN(CC)CC

Procedure:
A suspension of 1.42 g. of trans-3-(6,8-diisopropyl-4-oxo-4H-quinazolin-3-yl)-2-propenoic acid and 1.36 g. of 2-(diethylamino)ethyl chloride in 150 ml. of isopropyl alcohol was stirred and heated at reflux for 16 hours. The reaction mixture was concentrated in vacuo and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The methylene chloride layer was dried (sodium sulfate) and concentrated in vacuo to yield 1.20 g. of an oil. The oil was dissolved in 5 ml. of methylene chloride and treated with a solution of 0.35 g. of maleic acid in 25 ml. of ether. After concentration in vacuo, the residue was crystallized from isopropyl alcohol-ether to give trans-3-(6,8-diisopropyl-4-oxo-4H-quinazolin)-3-yl)-2-propenoic acid, 2-(diethylamino)ethyl ester maleate, mp 81°-83°.
Reaction SMILES: Br[CH:2]([CH3:19])[C:3]([N:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>O>[CH3:19][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:3]1=[O:4]
Reactant: CC(Br)C(=O)N(c1ccccc1)C1CCN(C)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1C(=O)N(C2CCN(C)CC2)c2ccccc21
Temperature: 185 °C
Reaction time: 2.5 h
Yield: 81.6 %

Procedure:
2-Bromo-N-(1-methylpiperidin-4-yl)-N-phenylpropanamide (0.31 g, 0.953 mmol) was treated with anhydrous AlCl3 (0.5 g) and the resulting mixture was stirred at 185° C. for 2.5 h. The reaction was brought to room temperature, diluted with water (20 mL), then basified with 1 N NaOH solution (25 mL) and product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (MeOH:CH2Cl2, 5:95) to obtain 3-methyl-1-(1-methylpiperidin-4-yl)indolin-2-one (0.19 g, 82%) a solid. 1H NMR (DMSO-d6) δ: 1.31 (d, 3H, J=7.5 Hz), 1.50-1.58 (m, 2H), 1.99 (t, 2H, J=11.7 Hz), 2.20 (s, 3H), 2.32-2.42 (m, 2H), 2.84-2.90 (m, 2H), 3.44 (q, 1H), 3.99-4.10 (m, 1H), 7.00 (t, 1H, J=7.2 Hz), 7.12 (d, 1H, J=7.8 Hz), 7.23 (t, 1H, J=7.8 Hz), 7.30 (d, 1H, J=7.5 Hz); ESI-MS (m/z, %) 245 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2.Cl[C:33]1[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:33]2[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2
Reactant: N#Cc1cccc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
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: O
Solvent: COCCOC
Product: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A suspension of the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid produced in Example 1-1 (1.01 g, 2.37 mmol), 6-chloropyridine-2-carbonitrile (342 mg, 2.37 mmol), sodium carbonate (1.01 g, 9.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.12 mmol) in 1,2-dimethoxyethane (20.1 ml) and water (8.7 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 45 minutes. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=1:1, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (1.09 g, yield: 95%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-fluoropyridin-3-ylboronic acid (0.284 g, 2.016 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 47 h to give 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=309.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.Cl.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:22][C:21]([CH2:23][CH2:24][NH2:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:22][C:21]([CH2:23][CH2:24][NH:25][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C(O)c1c[nH]cn1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1c[nH]cn1

Procedure:
The title compound was prepared as in Example 12 starting from 4-imidazolecarboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using CH2Cl2/MeOH as a gradient eluent (100:0-99.6:0.4). The product was triturated in ethyl acetate. 1H NMR (400 MHz, DMSO-d6): 2.93 (21-1, t), 3.55 (2H, m), 6.33 (1H, d), 7.01 (1H, d), 7.59 (1H, s), 7.63 (2H, s), 7.71 (1H, s), 7.87 (1H, s), 8.05 (1H, broad s), 12.43 (1H, broad s).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11](Cl)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)c1ccc2snc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(Cl)c3c2)cc1
Reaction time: 6 h
Yield: 45.2 %

Procedure:
To a solution of 3-chlorobenzo[d]isothiazole-5-sulfonyl chloride (90 mg, 0.33 mmol) in methylene chloride (2 mL), diisopropylethylamine (142 μL, 0.82 mmol) and 4-methoxybenzylamine (85 μL, 0.65 mmol) were added at room temperature. After stirring for 6 h, the reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% HCl aqueous solution and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown residue. Purification by column chromatography, on silica gel, eluting with 2:8 ethyl acetate:hexanes provided 3-chloro-N-(4-methoxybenzyl)benzo-[d]isothiazole-5-sulfonamide (55 mg). 1H NMR (300 MHz, CDCl3): 8.22 (dd, 1H), 7.82 (dd, 1H), 7.75 (dd, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 5.06 (t, 1H), 4.18 (d, 2H), 3.73 ppm (s, 3H). MW=368 confirmed by LC-MS, tr=13.39 min (Method Y) MH+=369.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]([F:31])([F:30])[CH2:15]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:13][C:14]([F:31])([F:30])[CH:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Product: O=C(O)c1ccc(C=CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
4 Å molecular sieves (7 g; activated powder) were suspended in 8.8 ml of 1.0 m tbaf in thf and stirred overnight at room temperature under nitrogen. To the solution was added methyl 4-formylbenzoate (160 mg; 0.97 mmol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (415 mg; 1.46 mmol) in 10 ml of anhydrous thf. After stirring overnight, the solvents were evaporated to dryness. The residue was dissolved in EtOAc and washed with water and brine. The organic was dried over Na2SO4, filtered and evaporated. The residue was dissolved in 10 ml of thf and 10 ml of 1N NaOH and refluxed for 30 minutes. The mixture was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (125 mg; 60%). M/z=217 (m+1).