Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:18])[CH:17]=2)[CH3:11])=[O:8])=[CH:5][N:6]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[Cl:18][C:16]1[CH:17]=[C:12]([CH:10]([NH:9][C:7]([C:4]2[O:3][C:2]([NH:1][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[N:6][CH:5]=2)=[O:8])[CH3:11])[CH:13]=[N:14][C:15]=1[O:19][CH2:20][C:21]([F:23])([F:22])[F:24]
Reactant: O=C(Cl)C1CC1
Reactant: CC(NC(=O)c1cnc(N)o1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(NC(=O)c1cnc(NC(=O)C2CC2)o1)c1cnc(OCC(F)(F)F)c(Cl)c1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)oxazole-5-carboxamide (30 mg, 0.08 mmol, Step-1, single enantiomer) and cyclopropanecarbonyl chloride (13 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)Cc1cccs1
Product: ClCc1coc(Cc2cccs2)n1
Yield: 27 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-thiopheneacetamide was reacted with 1,3-dichloroacetone to give 4-chloromethyl-2-(2-thienylmethyl)oxazole. The yield was 27%. Oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.CN(C)C.C1(C)C=CC=CC=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([OH:37])[CH:33]=[CH:34][C:35]=1[F:36]>C1(C)C=CC=CC=1.O>[F:39][C:29]([F:28])([F:38])[C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[F:36])[O:37][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(-c2ccc(Cl)c(Cl)c2)n1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Oc2ncc(Cl)c(-c3ccc(Cl)c(Cl)c3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
To a solution of 0.5 g (1.7 mmol) of 3B in 10 mL of toluene was added 4.0 mL of 10% trimethylamine/toluene solution and the mixture stirred at room temperature for 20 min. To the resulting mixture was added 0.36 g (20 mmol) of 3-trifluoromethyl-4-fluorophenol and the mixture stirred overnight. The reaction mixture was diluted with H2O and transferred to a separatory funnel and extracted with 40 mL of methylene chloride. The organic layer was washed sequentially with 5% NaHCO3 solution and water, dried and evaporated to yield 0.52 g (70.3%) of 2-(3-trifluoromethyl-4-fluorophenoxy)-4-(3,4-dichlorophenyl)-5-chloropyrimidine (m.p. 90-92)
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Oc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1c(Cl)nsnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a stirred solution of 12.8 grams (0.07 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one and 6.7 grams (0.07 mole) of 3-hydroxypyridine in 300 ml of tetrahydrofuran was added dropwise 7.1 grams (0.07 mole) of triethylamine. During the addition the exothermic reaction caused the reaction mixture temperature to rise to 34° C. Upon complete addition, the reaction mixture was stirred for 16 hours during which time it cooled to ambient temperature. The reaction mixture was filtered to remove triethylamine hydrochloride. The filter cake was washed with tetrahydrofuran. The filtrate and wash were combined and evaporated under reduced pressure to a residual solid. The residue was triturated with 300 ml of distilled water and the insolubles collected by filtration. The filter cake was washed with water and recrystallized twice from ethanol. A sample of the recrystallized solid was dissolved in chloroform and subjected to analysis by thin layer chromatography. This analysis indicated that the solid contained impurities. The filtrates from the recrystallizations were combined and evaporated under reduced pressure to a residue. The residue was combined with the twice-recrystallized solid and dissolved in chloroform. The solution was slurried with silica gel in an effort to remove the impurities. The mixture was filtered and the filtrate was evaporated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to give 7.0 grams (42%) of 3-chloro-5-(3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 134.5°-135.5° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=O)C.NC(N)=[S:19]>C(O)C>[OH:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13]([SH:19])[N:8]2[N:7]=1
Reactant: NC(N)=S
Reactant: CC(=O)OCc1nc2nc(C)cc(Cl)n2n1
Solvent: CCO
Product: Cc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
In 400 ml of ethanol was dissolved 23.7 g of 2-acetoxymethyl-7-chloro-5-methyl-s-triazolo[1,5-a]pyrimidine, and 19 g of thiourea was added thereto and the mixture was stirred for 30 minutes under reflux. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration, washed with ethanol and dried. After the obtained crystals were dissolved in a 10 % potassium hydroxide aqueous solution and stirred for 30 minutes, pH was adjusted to 2 with addition of a 2N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 15.3 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO[C:23]([CH3:25])=O>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][CH:25]3[CH2:23][CH2:15][CH2:16][NH:8][CH2:6]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(NC3CCCNC3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 5-nitro-indazole-1-carboxylic acid tert-butyl ester (300 g, 1.1 mol, 1.0 eq) in THF (3 L) was added Pd/C (30 g). The reaction mixture was stirred at 40° C. for 16 hours under pressure of H2 (50 psi). TLC (PE:EtOAc=4:1) showed complete conversion. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1-carboxylic acid tert-butyl ester (252 g, 95%) which was used directly for next step without purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]=2)(=[O:3])[CH3:2].[N:20]1([CH2:26][CH2:27][N:28]([CH2:37][CH3:38])[C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1.C1(C)C=CC=CC=1>O>[CH2:15]([N:14]([CH2:17][CH3:18])[C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([C:1](=[O:3])[CH:2]=[CH:33][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:37][CH3:38])[CH2:27][CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:36][CH:35]=3)[C:5](=[O:19])[O:6]2)=[CH:11][CH:10]=1)[CH3:16]
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Reactant: CCN(CCN1CCCCC1)c1ccc(C=O)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)c1ccc2cc(C(=O)C=Cc3ccc(N(CC)CCN4CCCCC4)cc3)c(=O)oc2c1

Procedure:
3-acetyl-7-diethylaminocoumarin (1.04 g, prepared according to the procedure described in U.S. Pat. No. 4,147,552), 1.20 g N-(2-piperidinoethyl)-N-ethyl-4-aminobenzaldehyde, 0.10 g piperidinium acetate, and 40 ml toluene were placed in a 100 ml round-bottomed flask fitted with a Dean-Stark trap and condenser. The solution was refluxed for 16 hr with removal of collected water. The toluene was evaporated under reduced pressure and a mixture of 20 ml water and 5 ml ethanol was added to the resultant viscous material. Upon stirring a solid precipitated which was isolated by filtration and drying to give 1.5 g of 7-diethylamino-3-(3-(N-ethyl-N-(2-piperidinoethyl)-4-aminophenyl)propenoyl)coumarin (4) as a red solid; λmax (ethanol)=475 nm. ##STR10##
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1Cl)COC2=O
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-5-ethenyl-2-benzofuran-1(3H)-one (1.1 g, 5.7 mmol) in DCM (40 mL) was added mCPBA (1.9 g, 8.5 mmol). The solution was allowed to stir at RT for 16 hours. Analysis by TLC and LC showed formation of the desired product. The reaction was diluted with DCM (200 mL), washed with aqueous Na2S2O3 and Na2CO3, dried over sodium sulfate, concentrated, and purified by silica gel flash chromatography to afford title compound. 1H-NMR (500 MHz, CDCl3) δ ppm 7.86 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 5.34 (s, 2H), 4.33 (m, 1H), 3.33 (m, 1H), 2.75 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[OH:17])[C:5]1=[O:28])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:34][O+](C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[O:17][CH3:34])[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1OC
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccc(OC)c(OC)c1
Reaction time: 3 h

Procedure:
4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate as well as 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then a further 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][S:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:28])=[O:27])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CCCCC1

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with cyclohexanesulfonyl chloride (0.053 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0195 g (50%) of the compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:51]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][N:61]([C:34](=[O:36])[C:33]2[CH:32]=[CH:31][C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=6)[CH2:40][C:41]6[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:38][CH:37]=2)[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and 1-Boc-piperazine (36.1 mg, 0.194 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, a crude product of 4-{4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid (89.9 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-141) as a yellow powder (29.6 mg, 60%).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][NH2:29])[CH3:27])=[CH:22][CH:21]=1>CO>[CH3:7][O:6][CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[CH:1]=[N:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:21][CH:22]=1)[CH3:27]
Reactant: CC(=NN)c1ccc(C(F)(F)F)cc1
Reactant: COC(c1cc(C)no1)c1ccccc1C=O
Solvent: CO
Product: COC(c1cc(C)no1)c1ccccc1C=NN=C(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To 0.23 g (1 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylisoxazole in 2 ml of methanol was added 0.22 g (1.1 mmol) of 4′-(trifluoromethyl)acetophenone hydrazone and stirred at room temperature for 3 hours. After completion of the reaction, methanol was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-{4-(4-trifluoromethylphenyl)-2,3-diaza-1,3-pentadienyl}benzyl]-3-methylisoxazole (0.23 g, 55.4%) as oil.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Brc1ncnc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C

Procedure:
A mixture of 6-bromopurine (2.0 g, 10 mmol), 3,4-dihydro-2h-pyran (1.0 ml, 11 mmol), and p-toluenesulfonic acid monohydrate (0.050 g, 0.26 mmol) in EtOAc (30 mL) was stirred at reflux under a reflux condenser for 48 h. The reaction mixture (suspension) was allowed to cool to room temperature and the solid was removed by suction filtration and washed with EtOAc (50 mL). The combined wash was concentrated in vacuo to afford 2.1 g as oil. The oil was chromatographed through a Redi-Sep® pre-packed silica gel column, eluting with a gradient of 30% to 60% EtOAc in hexane, to provide product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[F:13][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC1
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Product: CC(=O)c1ccc(-c2ccccc2S(=O)(=O)N2CCCC2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those described in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and 1-(2-bromo-phenylsulfonyl)pyrrolidine. MS (ESI): mass calcd. for C18H18FNO3S, 347.10; m/z found, 348.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J=7.9, 1.3, 1H), 7.95-7.89 (m, 1H), 7.63-7.58 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.27 (m, 2H), 7.26-7.25 (m, 1H), 2.98-2.90 (m, 4H), 2.69 (d, J=4.9, 3H), 1.76-1.67 (m, 4H).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH2:21]>CO>[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH:21][C:3]([C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)=[O:17]
Reactant: COC(=O)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Reactant: NCC(O)CO
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(1,2-dihydroxyethyl)benzoic acid methyl ester (0.40 g, 1.69 mmol) and 2,3-dihydroxypropylamine (0.17 g, 1.86 mmol) were dissolved in methanol (2 ml) and the solution was stirred at 75° C. for 1 h. The pressure was then reduced to 200 mm Hg and stirring was continued at 95° C. for 2 h . The crude reaction mixture was purified by preparative HPLC. Yield: 0.40 g (78%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>C(O)(C)C>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4c(C)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A microwave vessel was charged with 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (56.8 mg, 0.182 mmol) 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (49.5 mg, 57%) as a white powder that had the following properties: m.p: 210-212° C.; LC/MS (ESI+): 479 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.29-9.20 (m, 2H), 8.30 (m, 1H), 8.14 (s, 1H), 7.48-7.40 (m, 2H), 7.36 (d, J=8.3, 1H), 7.29-7.20 (m, 2H), 6.93 (d, J=8.3, 1H), 3.55 (br s, 2H), 2.70 (d, J=4.1, 3H), 2.50 (m, 2H), 2.15 (s, 3H), 2.10-1.85 (m, 4H), 0.92 (t, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](OC)=[O:13])=[C:4]([N+:22]([O-])=O)[CH:3]=1>CCO.[NH4+].[Cl-].[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](=[O:13])[NH:22]2
Reactant: CCOC(=O)CC(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC1C(=O)Nc2cc(F)cc(N)c21

Procedure:
A solution of (±)-4-ethyl 1-methyl 2-(4-fluoro-2,6-dinitrophenyl)succinate from Step C (7.23 g, 21.0 mmol) and iron powder (5.86 g, 105 mmol) in EtOH (60 mL) and saturated aqueous NH4Cl (15 mL) was stirred at reflux for 4.5 h. The warm reaction mixture was filtered through Celite, rinsing the filter cake with ethyl acetate. The crude product solution was washed with saturated aqueous NaHCO3 (300 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=253 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: Fc1ccc(-n2cccn2)cc1
Product: CC(C)C(O)c1ccnn1-c1ccc(F)cc1
Yield: 45 %

Procedure:
This compound was prepared from 1-(4-fluorophenyl)-1H-pyrazole and isobutyraldehyde using the method described in example 10B and isolated as an oil in 45% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (m, 1H), 7.57 (m, 2H), 7.37 (t, 2H, J=8.9 Hz), 6.41 (m, 1H), 5.41 (m, 1H), 4.13 (m, 1H), 1.85 (m, 1H), 0.87 (d, 3H, J=6.6 Hz), 0.61 (d, 3H, J=6.8 Hz).
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([C:16](=[O:18])[CH3:17])[C:14](=[O:19])[C@H:13]2[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[N:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([C:16](=[O:18])[CH3:17])[C:14](=[O:19])[C@H:13]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])=[N:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:1]
Reactant: O=[O+][O-]
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
Ozone was passed through a -78° C. methylene chloride solution of compound 27 (0.7 g, 1.2 mmol) until a blue color was maintained. Excess ozone was removed by purging the solution with N2. Dimethyl sulfide (1 mL) was added. The solution was warmed to room temperature, allowed to stand for 72 h, and concentrated. The residue was purified by silica gel chromatography (EtOAc:Et2O/1:3) to afford 230 mg (38%) of the title product.