Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:53][CH2:54][CH2:55]O>C(Cl)Cl>[F:32][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][O:30][CH2:55][CH2:54][F:53])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO)cn12
Reactant: OCCF
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(COCCF)cn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F159) (95 mg, 0.216 mmol) was dissolved in DCM (1 mL) and DIEA (0.65 mmol). MsCl (0.65 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes at room temperature. The reaction mixture was subjected to aqueous workup, extracted with DCM (2 mL), dried over Na2SO4 and concentrated to give a crude which was dissolved in 0.8 mL of 2-fluoroethanol followed by addition of K2CO3(90 mg, 0.65 mmol). The resulting mixture was heated at 120° C. for 20 minutes. The reaction mixture was subjected to standard aqueous workup and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-((2-fluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (F176). 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.60 (d, J=1.6, 1H), 8.21 (s, 1H), 7.89 (dd, J=1.7, 7.9, 1H), 7.77 (d, J=9.2, 1H), 7.62 (s, 1H), 7.53 (dd, J=1.7, 9.2, 1H), 7.42 (d, J=8.1, 1H), 4.72-4.64 (m, 3H), 4.59-4.52 (m, 1H), 3.86-3.79 (m, 1H), 3.79-3.73 (m, 1H), 3.68 (m, 1H), 3.16 (m, 4H), 2.47 (s, 3H). MS m/z 486.1 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1>CN(C=O)C>[ClH:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:23]([F:28])[CH:22]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 150 °C
Yield: 50.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (3 g, 9.8 mmol), (prepared as described for the starting material in Example 5), and 4-chloro-2-fluoroaniline (2.2 ml, 19.6 mmol) in DMF (50 ml) was heated at 150° C. for 30 minutes. After dilution with isopropanol (50 ml), the precipitate was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (2.05 g, 50%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)[O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)=[CH:35][CH:34]=1>O1CCCC1>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]([C:50]2[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=2)[O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][C:46](=[CH:2][O:3][CH3:4])[CH2:45][CH2:44]2)=[CH:37][CH:38]=1
Reactant: O=C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Meanwhile, 1.066 g of methoxymethyltriphenylphosphonium chloride was added to 7 ml of tetrahydrofuran, and the mixture was cooled at -10° C. The lithium diisopropylamide solution previously prepared was then added to this mixture, which was then stirred for 30 minutes at -10° C. At the end of this time, 5 ml of a tetrahydrofuran solution containing 1.01 g of 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidone (prepared as described in preparation 6) were dropped into the reaction mixture, at -10° C. The mixture was stirred for 30 minutes, allowed to stand overnight at room temperature, and then condensed by evaporation under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The oily substance obtained was purified by silica gel column chromatography. Elution with a 2:1 by volume mixture of ethyl acetate and hexane afforded 718 mg (yield 66%) of a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (10.0114 g; 56.5520 mmoles) and 3,3,3-trifluoro-propionic acid (7.5 mL; 84.9 mmoles) were combined with 6N HCl (20 mL; 120 mmoles) and heated to 108° C. for 18 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (200 mL), then then sodium bicarbonate (15.15 g; 180.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×60 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:40])[CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH3:39]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCN
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.5 %

Procedure:
2-((tert-Butoxycarbonyl)(methyl)amino)acetic acid (240 mg, 1.27 mmol) was taken up in 5 mL of CH2Cl2 along with (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)docosa-4,7,10,13,16,19-hexaenamide (470 mg, 1.27 mmol), HATU (724 mg, 1.27 mmol). The resulting reaction mixture was stirred at room temperature for 20 h. The organic layer was washed with saturated NH4Cl, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 650 mg of tert-butyl (2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-2-oxoethyl)(methyl)carbamate (56% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:36]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C>[CH3:1][C:2]1([CH3:35])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(c1ccccc1)c1ccccc1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
53 mg of the compound of example 1 were dissolved in 1.1 ml of acetonitrile. 10.4 mg of sodium cyanoborohydride were added to this solution. Subsequently, 0.18 ml of a 37% formalin solution and 0.05 ml of glacial acetic acid were added dropwise. The mixture was stirred at room temperature for 2 h; thereafter and another 2 h later, the same amounts of sodium cyanoborohydride and formalin solution were once again added dropwise. For workup, the mixture was filtered through a silica gel cartridge and the filtrate was concentrated under reduced pressure and purified by chromatography (method [RP1]). 4-{4,4-Dimethyl-3-[2-(methylphenylamino)benzyl]-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile 59 was obtained in a yield of 60%. Molecular weight 492.17 (C27H23F3N4O2); retention time Rt=2.33 min. [B]; MS (ESI): 493.05 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.O>ClCCl.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1Cl
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a solution of (E)-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (1880 g, 7.82 mol) in dichloromethane (18.6 L) was added N-bromosuccinimide (1490 g, 8.29 mol) and 2,2′-azobis(2,4-dimethylvaleronitrile) (47 g, 0.188 mol) and the resulting solution heated to reflux for 23 h. The light yellow solution was cooled to room temperature and transferred to an extractor before water (19 L) was added. The biphasic mixture was stirred at room temperature for 1 h. The mixture was separated and the organic phase washed with a 20% sodium chloride solution (19 L). The solution was evaporated to give (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (87.8% pure by HPLC, 2824 g, 99%) as a red oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26].O>CN(C)C=O>[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:18]=2[S:17]1(=[O:26])=[O:27]
Reactant: SCc1ccccc1
Reactant: CN1Cc2cccc(Cl)c2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cccc(SCc3ccccc3)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 12 g of potassium-t-butoxide in 100 ml of dry dimethylformamide was added 12.9 mls of benzyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 12.2 g of 2-methyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours and poured into water to give a gummy solid. The water was decanted and extracted with ethyl acetate. The gummy solid was slurried in ethyl acetate and filtered to give 5.9 g of the title compound as a light orange solid, m.p. 119°-122° C. The combined ethyl acetate extract and filtrate were washed with water and brine, dried over MgSO4 and concentrated to a solid which was slurried in ether and filtered to give an additional 7.6 g of product, m.p. 121°-124° C. Total yield was 13.5 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCn1c(=O)nnc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 6-chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (see Example 60(c) for a preparation) (420 mg, 1.77 mmol) in MeOH (10 ml) was added sodium methoxide solution (25% w/v, 8.84 mmol, 1.9 ml) and then the reaction was stirred at rt for 2 h. The reaction was then treated with water (100 ml) and extracted with DCM (2×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient, followed by trituration with diethyl ether (50 ml) to provide the desired compound as a yellow foam (205 mg, 53%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:81])[CH2:77][CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][CH2:77][N:76]([CH3:81])[CH3:75])=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(F)c1
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a mixture of 0.070 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) and 4 mL of dimethylformamide was added 0.0346 g (0.256 mmole) of 1-hydroxybenzotriazole, 0.0950 g (0.250 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1253 g (0.936 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0246 g (0.242 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.052 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-fluoro-benzamide (I-227) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.16 g, 73.3%).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.[NH2:38][C:39]1[CH:54]=[CH:53][C:42]2[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([CH2:49][OH:50])([OH:48])[CH2:46][O:47][C:41]=2[CH:40]=1>C(O)(C)C>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])=[N:22][C:17]([NH:38][C:39]2[CH:54]=[CH:53][C:42]3[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([OH:48])([CH2:49][OH:50])[CH2:46][O:47][C:41]=3[CH:40]=2)=[N:18][CH:19]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(O)(CO)COc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCC(O)(CO)CN3CC)ncc1Cl

Procedure:
10-Camphorsulfonic acid (107 mg, 0.462 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (142 mg, 0.420 mmol), and 3-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.100 g, 0.420 mmol) in Isopropyl alcohol (3.0 mL) and the mixture was irradiated in a CEM microwave (120° C., 40 min). The reaction mixture was then purified by HPLC and lyophilized to afford 2-[5-Chloro-2-(9-ethyl-7-hydroxy-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a yellow lyophilate (2 mg, 1%). LCMS: 541.31 (M+H); 1HNMR (CDCl3): 9.33 (s, 1H), 8.02 (s, 1H), 7.46 (d, J=5.32 Hz, 4H), 7.33 (s, 1H), 6.97 (s, 1H), 6.65 (d, J=7.80 Hz, 1H), 4.05 (m, 4H), 3.87 (s, 2H), 3.51 (s, 2H), 3.13 (s, 2H), 1.12 (t, J=7.04 Hz, 3H);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:12])[CH:6]2[CH3:13])#[N:2].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:14][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[S:12]
Reactant: CC1C(=S)Nc2ccc(C#N)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC1(Cl)C(=S)Nc2ccc(C#N)cc21

Procedure:
A solution of 5-cyano-3-methylthiooxindole (950 mg, 4.66 mmol) and N-chlorosuccinimide (800 mg, 5.95 mmol) in 100 ml of methylene chloride was stirred at room temperature for 24 hours. The solvent was removed in vacuo, yielding 3-chloro-5-cyano-3-methylthiooxindole and the residue, which was dissolved in a minimum of tetrahydrofuran, was added to a vigorously stirred slurry of red mercuric oxide (1.00 g, 4.7 mmol) and boron trifluoride ethereate (670 mg, 4.7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After 2 hours, the reaction mixture was filtered through a pad of Celite. The pad was washed with three 100-ml portions of chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform-ethanol (9:1 v/v) gave 5-cyanoisatin as an orange solid (525 mg, 65%), mp 270°-272° (dec); ir (KBr) 3100 (NH), 2220 (C≡N), 1730 (C=O) and 1710 cm-1 (C=O); nmr (DMSO-d6)π-1.30 (1H, b, s, NH), 2.00 (d of d, 1H, J4,6 =2 Hz, J6,7 =8.5 Hz, H6), 2.10 (d, 1H, J4,6 =2 Hz, H4), and 2.90 (d, 1H, J6,7 =8.5 Hz, H7); mass spectrum, m/e obs. 172.0238 (calc. 172.0272).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:4]=1[CH2:5]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32](Cl)[CH:33]([CH3:35])[CH3:34]>>[CH:33]([C:35]1[O:2][C:3]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:4]=2[CH:5]=1)([CH3:34])[CH3:32]
Reactant: O=[N+]([O-])c1ccc(O)c(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)CCl
Agent: [Br-]
Product: CC(C)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
Reaction of 2-hydroxy-5-nitrobenzyl triphenylphosphine bromide (prepared as described in Example 1(a) (40 g, 0.08 mol) and isobutyl chloride (10,6, 0.1. mol) was carried out with the method described in Example 1(b) to produce 19.7 g of 2-isopropyl-5-nitrobenzofuran.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C@H:47]5[CH2:51][CH2:50][O:49][CH2:48]5)=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O[C@@H]1CCOC1
Reactant: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(O[C@H]2CCOC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a 10 ml tetrahydrofuran suspension of 150 ml (0.423 mmol) of the compound obtained in Example 36, 133 mg (0.508 mmol) of triphenylphosphine, 51 μl (0.635 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 80 μl (0.508 mmol) of diethyl azodicarboxylate were slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour. Further, 44 mg (0.169 mmol) of triphenylphosphine, 17 μl (0.212 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 27 μl (0.169 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1˜1/2) to obtain 124 mg (69%) of the captioned compound.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:52]=1[CH2:61][C:62]([OH:64])=O>>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:51]([O:50][CH3:49])[C:52]=1[CH2:61][C:62]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:64]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: COc1cc(OC)c(CC(=O)O)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: COc1cc(OC)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(OC)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,4,6-trimethoxyphenylacetic acid, mp 159°-163° C.