Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH:18][N:19]=[C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[N:23][NH:22][C:21]2=[O:35])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:42][CH2:43][CH2:44][NH:45][CH3:46]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:24]2[C:20](=[N:19][NH:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:45]([CH2:44][CH2:43][OH:42])[CH3:46])=[CH:7][CH:8]=3)[C:21](=[O:35])[NH:22][N:23]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: CNCCO
Reactant: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCBr)c(-c3ccccc3)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCN(C)CCO)c(-c3ccccc3)c2)cc1OC
Temperature: 50 °C

Procedure:
4-{[6-(3-Bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (s) and Cs2CO3 were dissolved in 1 mL (2-hydoxy)ethylmethyl amine and the resulting soultion was heated to 50° C. for one hour. The solvent was evaporated and the residue was purified by silica gel chromatography eluent: 10% methanol/DCM) to afford 15 mg 5-(3,4-dimethoxy-phenyl)-4-[(6-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one (compound 120): HPLC (Rt): 5.525 minutes; m/e: 531.24, MS (ES+): 532.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2c(Cl)cccc2Cl)ccn1
Yield: 49.8 %

Procedure:
Using the method of Example 3, Step A, 2,6-dichlorobenzenethiol (1.69 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(2,6-dichlorophenylthio)pyridine (1.37 g, 50% yield) as a white powder. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.53 (d, 2H), 7.41 (t, 1H), 6.84 (s, 1H), 6.79 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([NH2:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7][N:6]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(O)(=O)C.C(Cl)Cl.C(Cl)Cl>[CH3:18][S:17]([C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH2:20])([CH3:1])[CH3:19])=[N:6][CH:7]=2)[CH:16]=[CH:15][N:14]=1)=[O:29]
Reactant: CSc1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1

Procedure:
1,1-Dimethyl-3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-2-yl]-prop-2-ynylamine (500 mg, 1.76 mmol) in acetic acid/DCM (2.6 ml/8.8 ml) was treated at 0° C. with mCPBA (content 70%, 455 mg, 2.64 mmol) for 10 minutes. The reaction mixture was diluted with DCM and washed with 2N-solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered, evaporated to give the title compound as brownish crystals. Yield: 500 mg (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(OCC)(=O)C.C(=O)([O-])O.[Na+].O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1CNC1=Nc2ccc(N)cc2CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)C3CC3)cc2CO1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 60.1 %

Procedure:
To a vigorously stirred solution of N2-(2-methoxy-benzyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 4) (128 mg, 0.45 mmol; HPLC 0.41 min) in ethyl acetate (2 ml) and sat. sodium hydrogen carbonate-sol. (1.2 ml) at 23° C. was dropwise added cyclopropanecarbonyl chloride (50 ul, 0.54 mmol) and the mixture was stirred at 23° C. for 20 min. Diluted with ethyl acetate and water, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left an off-white solid which was purified by silica gel column chromatography with heptane/ethyl acetate 1:1 to 0:1 followed by trituration with diethyl ether to give the title compound as a white solid (95 mg, 55%, HPLC 0.998 min 100%), MS (ISP) m/e=352.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
To a solution of 100 mg (0.345 mmol) of (2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate in tetrahydrofuran (3 mL) was added water (3 mL), followed by cooling to 0° C., and 15.2 mg (0.362 mmol) of lithium hydroxide monohydrate was added, followed by stirring at the same temperature for 15 minutes. The reaction mixture was washed with ethyl acetate, and the aqueous layer was made acidic with saturated aqueous sodium dihydrogen phosphate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and subsequently the solvent was concentrated under reduced pressure to afford 93.1 mg of the title compound as a colorless foamy solid (yield 98%). Instrumental data were consistent with those of Example 9.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4]1.[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(C)C>[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][CH:28]([NH:2][C@H:3]2[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[CH2:4]2)[CH2:27][CH2:26]1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of N-{2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride (22.10 g, 47.1 mmol) and 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (12.7 g, 47.1 mmol) in isobutyl alcohol (80.0 mL) was added triethylamine (19.7 mL, 141 mmol). The reaction mixture was cooled in an ice bath and stirred for 30 minutes. To it was added sodium triacetoxyborohydride (11.0 g, 51.8 mmol) in portion. After being stirred at room temperature for 4 hours, the solvent was removed by evaporation under reduced pressure. Saturated aqueous NaHCO3 solution was added and the solution was extracted with ethyl acetate (150×3). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was columned on silica gel, eluting with ethyl acetate (1% NH4OH aqueous solution)/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated to give the title compound as a white powder (17.77 g). MS (M+H) 569.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:32])[CH2:27][CH2:28]2)[N:3]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(o-tolyl)-piperazine dihydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-o-tolyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=398.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)[CH3:35])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH3:35])[C@@H:36]4[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CN([C@@H]1CCCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CN([C@@H]1CCCNC1)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (R)-tert-butyl 3-(2-bromo-N-methylphenylsulfonamido)piperidine-1-carboxylate. MS (ESI): mass calcd. for C27H32FN5O4S, 541.21; m/z found, 542.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1([CH3:11])[C:7](=[O:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:19]=[CH:20][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][C:4]=2[O:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)Oc2cc(N)ccc2N(c2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-amino-2,2-dimethyl-4-phenyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(3), 50 mg) in chloroform (2 mL) were added dropwise successively methanesulfonyl chloride (22 μL) and pyridine (30 μL) under ice-cooling and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water, 10% HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (solvent; n-hexane/ethyl acetate=1/1→ethyl acetate) to give N-(2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanesulfonamide (55 mg) as a colorless powder. MS (APCI) m/z: 347 [M+H]+
Reaction SMILES: C[O:2][S:3]([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][N:8]=1)(=O)=[O:4].C1(C)C=CC=CC=1.C[N:24](C=O)C.C(Cl)(=O)C(Cl)=O>O>[CH:13]1[CH:14]=[CH:15][C:10]2[O:9][N:8]=[C:7]([CH2:6][S:3]([OH:2])(=[O:4])=[NH:24])[C:11]=2[CH:12]=1
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)Cc1noc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A 250 ml three necked flask, equipped with mechanical stirrer, Dean-Stark trap and condenser, was charged with 1,2-benzisoxazole-3-methanesulfonic acid methyl ester (10 grams, 0.044 mole, obtained from a commercial vendor) and toluene (100 ml). The suspension was heated to reflux while azeotropic distillation of water was performed, during 2 hours. The mixture was thereafter cooled under nitrogen atmosphere to 10° C. and DMF (0.36 ml, 0.0044 mole, 0.1 molar equivalent) was added to the mixture. Oxalyl chloride (4.1 ml, 0.047 mole, 1.07 molar equivalent) was then added drop-wise at 10-15° C. during 30 minutes and the reaction mixture was heated to 40° C. and was kept at this temperature for 4 hours. Ammonia (gas) (3.0 grams, 4 molar equivalents) was then bubbled into the reaction mixture at 10-18° C. during 2 hours and the reaction mixture was kept at ambient temperature overnight. The obtained precipitate was collected by filtration and slurried in 25% ammonium hydroxide (40 ml) at ambient temperature for 2 hours. The obtained solid was collected by filtration, washed with water and dried under reduced pressure at 50° C., overnight to obtain crude zonisamide (7.4 grams, 80.4% yield) having a purity of 98.7%, as determined by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18]O)[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][F:27])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1OC[C@@H](CO)N1c1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Product: O=C1OC[C@@H](CF)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
(4R)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(hydroxymethyl)-1,3-oxazolidin-2-one (0.71 g, 2.0 mmol), prepared in Example 71, was dissolved in 20 mL methylene chloride and cooled to 0° C. (Diethylamino)sulfur trifluoride (0.295 mL, 2.20 mmol) was added dropwise. The mixture was warmed to 25° C. and stirred for 2.5 h. The reaction was quenched with water and saturated NaHCO3 and the mixture was extracted with methylene chloride. The organics were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (8% acetone/hexane) afforded the title compound (243 mg, 34%) as a white solid. mp 148-150° C. HRMS: calcd for C13H10BrFN2O2S+H+, 356.97031; found (ESI, [M+H]+), 356.9705. Analytical HPLC: retention time 10.2 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH 3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[NH2:5].N1C=CC=CC=1.[C:30]([O:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37])(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:36]([CH2:35][CH2:34][O:33][C:30](=[O:32])[CH3:31])(=[O:38])=[O:37])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: Cn1c(Cc2ccc(N)cc2F)ccc1C(=O)c1ccccc1
Reactant: CC(=O)OCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCS(=O)(=O)Nc1ccc(Cc2ccc(C(=O)c3ccccc3)n2C)c(F)c1
Yield: 57.7 %

Procedure:
3-Fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]aniline (0.75 g, 2.43 mmol) [prepared as described in Example 1, but substituting ethyl 1,4-dimethylpyrrole-2-acetate with methyl 1-methylpyrrole-2-acetate in Step (a)], and pyridine (0.39 ml, 4.88 mmol) were dissolved in methylene chloride (8 ml). 2-Acetoxyethanesulfonyl chloride (681 mg, 3.65 mmol) was added to the solution and after 15 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness. Purification of the residue by flash chromatography (hexane-ethyl acetate, 3:2) gave N-{3-fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]-phenyl}-2-(acetoxy)ethanesulfonamide, (643 mg, 58%) as a solid. ##STR57##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=1)[NH2:23]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N)cc(CSC)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(CSC)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1

Procedure:
Intermediate 32.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-methoxy-5-[(methyl-sulfanyl)methyl]aniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 7:3) to give the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1>>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C

Procedure:
1-Methylpiperazine (492 μL, 4.44 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 612 mg, 1.48 mmol). The mixture was heated at 120° C. for 1 h and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (25 mL) and washed with water (2×25 mL) and sat. brine (25 mL), then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound as an orange gum. This gum was dissolved in ethanol (25 mL) and a solid precipitated. This solid was collected by filtration and washed with ethanol and diethyl ether to give the title compound (365 mg, 50%) as a yellow/orange solid; 1H NMR: 2.26 (3H, s), 2.47-2.55 (4H, m), 3.07-3.13 (4H, m), 3.93 (3H, s), 6.85 (1H, s), 6.99 (1H, t), 7.16-7.22 (1H, m), 7.48 (1H, d), 8.26 (1H, d), 8.36 (1H, s), 8.42 (1H, d), 8.51 (1H, s), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+ MH+ 494.46.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C[Al](C)C.[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20](OCC)=[O:21].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][C:20]([CH:19]2[CH2:25][CH2:26][CH2:27][CH2:28][NH:18]2)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1cc(NC(=O)C2CCCCN2)c(F)cc1Cl
Reaction time: 48 h

Procedure:
The product of Example 1, Step A (4.25 g, 26.37 mmol) was dissolved in CH2Cl2 (200 mL). A solution of 2.0M trimethylaluminum (52.75 mmol) was added dropwise under nitrogen at 0° C. The resultant mixture was stirred at room temperature overnight. Ethyl pipecolinate (4.15 g) was added dropwise to the mixture and the mixture was stirred for 2 days. To the reaction mixture 6N HCl (100 mL) was added dropwise at 0° C. 200 mL of H2O was added, followed by the addition of 150 mL of methylene chloride. The aqueous layer was separated and basicified to pH 10 with 50% aqueous NaOH. 500 mL of CH2Cl2 was added. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to give the title compound of Step A as a white solid, 4.7 g. m.p. 96°-98° C. 1H NMR (CDCl3): δ9.25 (br s,1H), 8.17 (d,1H), 7.13 (d,1H) 4.58 (m,1H), 3.20 (M,1H), 3.10 (m,1H), 2.79 (m,1H), 2.00 (m,1H), 1.89 (m,2H), 1.60-1.40 (m,4H), 1.36 (d,6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.[CH3:29][N:30]([CH2:32][C:33](O)=[O:34])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:29][N:30]([CH3:31])[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1)=[O:34]
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(N)cc2NC3=O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(NC(=O)CN(C)C)cc2NC3=O)ccc1[N+](=O)[O-]

Procedure:
A mixture of Example 120 (38 mg, 0.10 mmol), dimethylaminoacetic acid (17 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol) and Et3N (0.1 g) in 1 mL of DMF was stirred overnight. The reaction mixture was partitioned between H2O and ethyl acetate, and the organic layer was separated, washed with brine, dried, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product. MS (DCI) m/e 462 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.03 (s, 1H), 8.10 (s, 1H), 8.01 (d, J=8.59 Hz, 1H), 7.80 (d, J=8.29 Hz, 1H), 7.53 (d, J=1.23 Hz, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 4H), 7.03 (d, J=8.59 Hz, 1H), 4.11 (s, 2H), 4.03 (s, 3H), 2.86 (s, 6H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33]([N:8]1[C:9]2[C:5](=[C:4]([F:3])[C:12]([C:13]3[C:21]4[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=4[N:15]([CH3:23])[CH:14]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:34]
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Yield: 36 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), 2,5-difluorophenylacetic acid (48.3 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and a precipitate formed. The precipitate was collected by filtration, and dried at the pump for 1 hour. The residue was adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtAc) to afford 5-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (44.2 mg, 36.0% yield) as a white solid. LC-MS (ES) m/z=438 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 4.36 (t, J=8.34 Hz, 2H), 5.78-6.19 (m, 2H), 7.13-7.32 (m, 5H), 7.89 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).