Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1,1-dimethylurea (607 mg) was dissolved in tetrahydrofuran (20 ml)-methanol (20 ml), and then 10% palladium carbon (236 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (529.5 mg, 96.7%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH3:3].O=S(Cl)Cl.[NH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]([CH:11]=1)[C:5]([NH:21][CH2:22][CH2:23][CH3:24])=[N:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCN=C(NCCC)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
In a sulfonation flask 32.8 g (0.125 mol) 5-chloro-2-nitrobenzoic acid propylamide are dissolved in 74.4 g (0.625 mol) SOCl2 and heated at reflux temperature for 4 hours. Then the excess SOCl2 is removed in a water jet vacuum and the crude imidoylchloride is dissolved in 30 ml of absolute THF. The resulting solution was added dropwise to a stirred solution of 15.4 g (0.26 mol) 1-aminopropane in 30 ml THF. The mixture is stirred for 5 hours at reflux temperature and then the solvent is removed in a water jet vacuum. The residue is taken up in ethylacetate and the organic phase is washed twice with water and saturated sodiumcarbonate solution. After drying of the organic phase, the solvent is removed in a water jet vacuum and the raw material purified by column chromatography over silica gel (eluant: hexane/THF=3:1). Yield: 27.8 g 5-chloro-2-nitro-N,N′-dipropylbenzamidine in the form of brown crystals; m.p. 63-64° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Se](=O)=[O:14].O1CCOCC1>O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:14])[CH:8]=[CH:7]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2cccc(O)c2n1

Procedure:
8-hydroxy-2-methylquinoline (2 g, 12.4 mmol.), selenium dioxide (1.74 g, 15.8 mmol), 300 ml of pre-dried 1,4-dioxane, and 1.5 ml of water were mixed and stirred in a 1-L round bottom flask. The resulting solution was then refluxed for 24 h. The reaction was monitored until completion using TLC method. The reaction mixture was then filtered off, and the selenium metal was then washed with dichloromethane, and the combined filtrates were then evaporated off under reduced pressure. The crude product was then purified by sublimation under reduced pressure or by silica gel column chromatography to yield pure yellow needle crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:15]([CH2:14][CH2:13][CH2:12][CH2:11][Cl:10])(=[O:17])=[O:16]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: O=S(=O)(Cl)CCCCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)CCCCCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine, combined with 2.67 g (10.5 mmol) 75% m 4-chlorobutyl-sulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with 6-molar hydrochloric acid, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=9:1->7:3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].O>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)ccc1=O
Reactant: CCS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2ccc(=O)n(C)c2)c1
Temperature: 30 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
To a solution of 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO2Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30° C. for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL×3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26%) as light yellow gum. 1H NMR (CDCl3, 400 MHz) δ7.68-7.66 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.13-7.10 (m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 421.
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:29].O>C1COCC1>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2([O:21][CH3:29])[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH3:25]
Reactant: CI
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OC)CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (1.19 g, 3.66 mmol, prepared as described in Example 3) in THF (18 mL) at rt was added sodium hydride (60% dispersion in oil, 161 mg, 4.03 mmol). The mixture was stirred for 1 h and iodomethane (0.25 mL, 4.03 mmol) was added. The mixture was heated to 50° C. for 3 h and then was left to stand at rt overnight. More sodium hydride (60% dispersion in oil, 80 mg) and iodomethane (0.13 mL) were added. The mixture was heated for 2 h, then water was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated to an oil. The crude product was purified by flash chromatography (silica gel, eluted with ethyl acetate) to yield 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinoline as a yellow oil (0.30 g, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7][NH2:8])=[O:6].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([C:20](=O)[CH3:21])[CH:19]=1>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:7]/[N:8]=[C:20](/[C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[OH:23])\[CH3:21])=[O:6]
Reactant: NNC(=O)c1ccc(Cl)c(Br)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccc(Cl)c(Br)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.1 %

Procedure:
3-Bromo-4-chlorobenzohydrazide (30 mg, 0.120 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (20.51 mg, 0.120 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (15 mg). 1H NMR (400 MHz, acetone-d5): δ 8.30 (s, 1H), 7.98 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.61 (d, 1H, J=2.4 Hz), 7.29 (dd, 1H, J=2.4 & 8.4 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.55 (s, 3H). ESI-MS: 402.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](I)=[N:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:24]([C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]=1)#[N:25]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(F)cc3)noc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)noc2c1O
Temperature: 110 °C
Yield: 45.5 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (290 mg, 0.678 mmol) and CuCN (182 mg, 2.03 mmol) were added to 4.5 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (4 mL, 15% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 101 mg of the title compound. MS: (+) m/z 328.32 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:30]2=[O:31])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 6-(pyridin-3-yl)hexanoate (2.0 eq., prepared in Synthetic Example 12) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-3-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 184.4 to 185.2° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: O[C:2]1[C:3]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[O:22][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=C(Nc1c(O)cccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Yield: 83.3 %

Procedure:
3-Hydroxy-2-(4-nitrobenzamido)benzoic acid (1.8 g, 6.0 mmol) and 4-methylbenzenesulfonic acid (2 g, 12.0 mmol) were added to toluene (36 mL) and the mixture was stirred at reflux for 17 hr. The solvent was evaporated under reduced pressure and the residue was washed with water (100 mL×3), filtered and dried under reduced pressure at 50° C. to obtain a yellow solid of 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxylic acid (1.42 g, yield 83%). LC-MS (ESI) m/z 285 [M+1]+.
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:12])([CH3:11])[C:8]#[C:9][CH3:10].Cl[CH2:14][C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=1>C1COCC1>[CH3:20][N:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=[C:15]1[CH2:14][CH2:10][C:9]#[C:8][Si:7]([CH3:12])([CH3:11])[CH3:6]
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution of trimethyl-prop-1-ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at −78° C. After 2 hours, a solution of 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (5 mL) was added to the reaction mixture at −78° C. then the reaction mixture was stirred for 30 min at −78° C. and 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to yield 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol, 23%).
Reaction SMILES: OC1C(C2(CO)C3C(=CC=CC=3)N([CH2:20][CH2:21][CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])C2=O)=CC2OCOC=2C=1.O[C:38]1[C:39]([C:47]2([CH2:57][OH:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49][C:48]2=[O:56])=[CH:40][C:41]2[O:45][CH2:44][O:43][C:42]=2[CH:46]=1>>[O:56]=[C:48]1[C:47]2([C:39]3=[CH:40][C:41]4[O:45][CH2:44][O:43][C:42]=4[CH:46]=[C:38]3[O:58][CH2:57]2)[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]1[CH2:20][CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]
Reactant: O=C1Nc2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 45 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione to replace 142-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 45% yield: 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H), 7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68- (m, 4H), 2.15-2.10- (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 168.2, 155.9, 148.8, 142.4, 141.9, 134.0, 132.5, 132.0, 128.9, 124.1, 123.4, 123.3, 119.4, 108.4, 103.2, 101.5, 93.6, 80.4, 58.2, 38.0, 35.6, 26.8; MS (ES+) m/z 469.3 (M+1), 491.3 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:11][O-:12].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[N:7]=1
Reactant: O=Cc1ncc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc(C=O)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 3,5-dichloro-pyrazine-2-carbaldehyde (150 mg, 0.85 mmol) in methanol (5 mL) is added sodium methoxide (25% w/w in MeOH, 183 mg, 0.85 mmol) at 0° C. After the mixture is stirred at 0° C. for 2 hours and then at room temperature overnight, the reaction is quenched with saturated NH4Cl (1 mL) and solvent removed in vacuo until dryness. DCM (20 mL) is added, and the solution is dried and solvent removed to give 140 mg of 3-chloro-5-methoxy-pyrazine-2-carbaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine yields 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2c(F)cccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution (14 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetate was added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→8:2) to give the title compound as yellow crystals (yield 10.0 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13](OCC)=O)[CH:9]([CH3:18])[CH2:8]1)=[O:5].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][N:37]=[C:36]([NH2:39])[CH:35]=2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:39][C:36]2[CH:35]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[NH:38][N:37]=2)[CH:9]([CH3:18])[CH2:8]1)=[O:5]
Reactant: Nc1cc(-c2ccc(F)cc2)[nH]n1
Reactant: CCOC(=O)C1CCC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1C
Product: CC1CC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CCC1CNc1cc(-c2ccc(F)cc2)[nH]n1

Procedure:
The title compound is prepared analogously to Example 1 by replacing trans-4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexane carboxylic acid methyl ester (Ex. 1 Step 2) with ethyl 4-(2-chloro-5-(trifluoromethyl)benzamido)-2-methyl cyclohexane carboxylate (Ex. 1.35 step 2) and by replacing 2-amino-3-picoline (Ex. 1 step 4) with 5-(4-fluorophenyl)-1H-pyrazol-3-amine. [MH]+ 509.40.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Na+].F[C:20]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:27][C:20]=1[O:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:23]
Reactant: Cc1ccccc1C(O)CCCC(=O)[O-]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C#N
Temperature: 57.5 °C

Procedure:
To a stirred suspension of sodium hydride (0.69 g, 60% dispersion in mineral oil) in dry tetrahydrofuran (50 mL) is added a solution of sodium (RS)-5-hydroxy-5-(2-methylphenyl)pentanoate (1.23 g) in dry tetrahydrofuran (100 mL). The mixture is stirred at room temperature for 1.5 hours when 2-fluoro-4-(3-thienylmethoxy)benzonitrile (1.57 g) is added in one portion. The reaction mixture is heated at 55-60° C. for 18 hours and evaporated. The residue is dissolved in water (100 mL), the solution acidified to pH 1 with 1 N hydrochloric acid and the mixture extracted three times with ethyl acetate (100 mL). The combined extracts are washed with brine (100 mL), dried over magnesium sulphate and evaporated to give (RS)-5-[2-cyano-5-(3-thienylmethoxy)phenoxy]-5-(2-methylphenyl)pentanoic acid as a white waxy solid (0.4 g), mp.p.106-108° C. [Elemental analysis:- C,67.15; H,5.84; N,2.75; S,6.99%. Calculated for C24H23NO4S.0.5EtOAc:- C,66.66; H,4.66; N,6.48%].
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCCC>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[O:1]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(O)C(N)=O
Reactant: COc1cccc(OCc2ccccc2)c1C=O
Solvent: CCCCCCC
Solvent: O
Product: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Temperature: 240 °C
Yield: 60.7 %

Procedure:
A mixture of commercially available 2-hydroxyisobutyramide (638.5 mg, 3 eq), 2-benzyloxy-6-methoxy-benzaldehyde (500 mg) (Katritzky A. R. et al ARKIVOC 2001, 2, 3, 3-12) is heated at 240° C. for 5 min using microwave irradiation (Lecolier S. et al Chimica Therapeutica 1969, 4,6, 437-445). The crude oil is poured into water and extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 1/1 to 1/0) gives the title compound as a yellow solid (0.41 g, 61%); LC-MS: tR=0.65 min; [M+H]+=328.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH:23][S:34]([CH:33]=[CH2:32])(=[O:36])=[O:35])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A solution of 3-[6-(3-chloro-4-fluorophenylamino)-pyrimidin-4-ylamino]phenylamine (IR-4) (300 mg, 0.9 mmol) and triethylamine (500 mg, 5 mmol) in 10 mL of THF was stirred at RT. 2-Chloroethanesulfonyl chloride (360 mg, 2.25 mmol) was added into the reaction mixture and stirring was continued at RT for 1 hr. The crude product was purified by flash chromatography on silica gel with EtOAc/heptane solvent system to afford 35 mg (9%) of the title compound, a brown colored solid. MS (m/z): MH+=420, 422. 1H NMR (DMSO): 9.92 (s, 1H), 9.29 (s, 1H), 9.21 (s, 1H), 8.26 (s, 1H), 7.92 (m, 1H), 7.40-7.22 (m, 4H), 7.14 (m, 1H), 6.20 (m, 2H), 6.05 (m, 3H) ppm.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C1COCC1>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
NaH (60% w/w in mineral oil; 0.532 g, 13.30 mmol) was added (portionwise, over 2 min) to a solution of methyl 3-iodo-1H-indole-5-carboxylate (3.64 g, 12.09 mmol) in THF (30 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 5 min. p-Toluenesulfonyl chloride (2.54 g, 13.30 mmol) was then added (portionwise, over 2 min), and the resulting mixture was stirred at 0° C. for 1 h. H2O (50 mL) was carefully added to the mixture at 0° C. and the reaction was warmed to 25° C. THF was removed in vacuo, and the resulting tan mixture was vacuum filtered. The collected solid was washed with H2O (150 mL) and dried in vacuo to provide crude methyl 3-iodo-1-tosyl-1H-indole-5-carboxylate (5.94 g) as a tan solid: MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.03-8.11 (2H, m), 7.97-8.02 (1H, m), 7.79 (2H, d, J=8.2 Hz), 7.75 (1H, s), 7.26 (2H, d, J=8.2 Hz), 3.94 (3H, s), 2.36 (3H, s).