Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C2CC2)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C2CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-tert-Butyl 4-((1-(5-cyclopropyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (30 mg, 0.061 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 21.8 mg (91%). LC/MS (HPLC method 3): tR=2.235 min, 394.10(MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH2:17])[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:17][S:25]([CH3:24])(=[O:27])=[O:26])[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccc(N)c2sc(C(N)=O)c(N)c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(NS(C)(=O)=O)c2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a stirred mixture of the above amide (0.2 g, 0.8 mmol) and pyridine (2.0 mL) in THF at 0° C. was added methanesulfonyl chloride (0.46 g, 4.0 mmol). The reaction was stirred at room temperature overnight. It was next diluted with water and extracted with dichloromethane (20 mL). The solvent was removed and purified by preparative TLC (5% EtOAc in CH2Cl2) to afford the title compound (20 mg, 7.6%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)C.C(=O)([O-])[O-:40].[K+].[K+]>CC(C)=O.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([NH:15][C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[C:4]([OH:3])=[O:38])=[CH:8][CH:9]=1)(=[O:40])[NH2:14]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ccc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)cc1

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from example 10 (0.120 g, 0.235 mmol) was dissolved in a mixture of acetone (5 mL) and water (3 mL). Urea-hydrogen peroxide complex (1.0 mmol, 0.094 g) and potassium carbonate (10 mg) were added and the mixture stirred until completion (HPLC). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMSO (1.5 mL) and 5 N NaOH (0.2 mL) was added. After stirring for 30 min at room temperature, TFA (0.5 mL) was added and the product isolated by prep HPLC (18 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@:17]([CH3:21])([CH2:19][CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:19]([C@@:17]1([CH3:21])[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:20]
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-isovalinamide (Intermediate 99, 42 mg) in dry dichloromethane (6 mL), TEA (0.089 mL, 0.638 mmol) was added. The mixture was cooled down to 0° C. and a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (1.500 mL) was added dropwise. The mixture was stirred at that temperature for 1 hour, then a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (DCM) (1.500 mL) was added dropwise again. The reaction was stirred for 30 minutes, it was maintained in the ice-bath and quenched with water (10 mL). The mixture was allowed to reach the room temperature then it was extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 80/20 to 50/50 (Biotage system). This afforded the title compound as a white solid (24 mg).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.22 ml) was added to methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in DCM (4 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butyl benzoyl chloride (230 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 235 mg (53%). 1H NMR (DMSO-d6, 300 MHz): δ 10.31 (s, 1H), 8.83 (d, 1H), 8.36 (s, 1H), 8.10 (d, 2H), 7.91 (dd, 4H), 7.56 (d, 2H), 4.38 (t, 1H), 3.68 (s, 3H), 2.35 (m, 1H), 1.31 (s, 9H), 0.98 (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][NH:11][NH2:12]>CO>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:11]([CH3:10])[NH2:12])[N:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CNN
Solvent: CO
Product: CN(N)c1cc(N)nc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a refluxing solution of 6-chloro-2,4-diaminopyrimidine (4.0 g) in anhydrous methanol (40 ml) was added methylhydrazine (3.2 g). After 18 hours the refluxing mixture was allowed to cool to room temperature under a nitrogen atmosphere in order that the product could crystallise out. The white solid (3.0 g) was collected by filtration and dried under reduced pressure at 70° C. Recrystallisation of the product from methanol/methylhydrazine (50/l) gave straw-coloured crystals of 2,4-diamino-6-(1-methylhydrazino)pyrimidine (1.92 g; 56% of theoretical yield; M.P. 214°-217° C. decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:15]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[O:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]3[CH2:29][CH2:28]3)=[C:3]([CH:15]3[C:16](=[O:26])[C:17]([CH3:24])([CH3:25])[O:18][C:19]([CH3:22])([CH3:23])[C:20]3=[O:21])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2C2CC2)C1=O
Temperature: 100 °C
Yield: 3.1 %

Procedure:
To a stirred solution of 4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.390 g, 0.90 mmol), cyclopropylboronic acid (0.100 g, 1.16 mmol), potassium phosphate (0.665 g, 3.14 mmol) and tricyclohexylphosphine (0.025 g, 0.09 mmol) in a mixed solvent system of toluene (4 ml) and distilled water (0.2 ml) is added palladium acetate (0.010 g, 0.044 mmol). This mixture is then heated at 100° C. overnight. After cooling to room temperature the solution is diluted with ethyl acetate and distilled water, then filtered through diatomaceous earth (additional washing with ethyl acetate/distilled water). The aqueous phase is acidified with 2M aqueous hydrochloric acid to pH3, then the organic phase is separated and the aqueous phase extracted again with ethyl acetate (×2). All organic fractions are combined, washed with brine, then dried over anhydrous magnesium sulfate and filtered. After concentration in vacuo the crude oil is purified by preparative reverse phase HPLC then triturated with hexanes to afford 4-(4′-chloro-4-cyclopropylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.011 g) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]3[C:19]([N:20]=[CH:21][CH:22]=2)=[C:18]2[C:13]([C:14]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[CH:25][CH:24]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:36](Br)[CH:37]=[CH2:38].O>CN(C=O)C.C(OCC)(=O)C>[CH2:38]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:14]2[C:13]3[C:18](=[C:19]4[C:10](=[CH:11][CH:12]=3)[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:22][CH:21]=[N:20]4)[N:17]=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: OCCCCCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCCCCCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
A 60% dispersion of NaH in mineral oil (76.1 mg) is suspended in DMF (10 ml). To this suspension is added 6-[4-(7-phenyl-1,10-phenanthrolin-4-yl)phenyl]hexan-1-ol (657 mg) followed by mixing at room temperature for 3 hrs. Allyl bromide (242 mg) is then added and the mixture is stirred at 35° C. for 24 hours, or until the reaction is judged complete by TLC. Excess NaH is carefully reacted with water and the reaction mixture is then diluted with ethyl acetate. The organic layer is washed with aqueous 6 M NaCl, dried over MgSO4, concentrated by roto-evaporation, and purified by column chromatography on silica gel to give the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH3:14]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)CCC4)c2cc1OCC
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 205 mg (1.54 mM) of 5-Aminoindan in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The brown solid was dissolved digested in 200 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the warm solution and washed with ethanol followed by ether and dried under vacuum at 80° C. to yield 435 mg of 6,7-Diethoxy-4-(indan-5-ylamino)-quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 374.0, mp=85-88° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48]([C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[C:53](Cl)=[O:54])#[N:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:53](=[O:54])[C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([C:48]#[N:49])[CH:51]=2)[CH2:42][CH2:41]1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 14 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-cyanobenzoyl chloride as starting materials in 14% yield. LCMS for C32H30ClN8O2 (M+H)+: m/z=593.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[N+:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([CH2:45][C:46](O)=[O:47])[C:38]2=[O:49])([O-:34])=[O:33]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:46](=[O:47])[CH2:45][N:39]1[C:38](=[O:49])[C:37]2[C:41](=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=2)[C:40]1=[O:44]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol) was placed in a 50 ml round bottom flask and dissolved in DMF (3 ml), EDC (45.6 mg, 0.238 mmol), and 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetic acid (60 mg, 0.238 mmol) were added to it followed by DMAP (29.1 mg, 0.238 mmol). The reaction was stirred at RT for 6 hours. The reaction was quenched by adding 30 ml of HCl/H2O (1M) and extracted with EtOAc (30 ml). The organic phase (EtOAc) was extracted with HCl/H2O (1M; 30 ml; ×3) and subsequently with K2CO3/H2O (15% w/w; 20 ml; ×3) by using a 100 ml extracting funnel. The resulting organic extract was dried over Na2SO4 (0.5 g), filtered on a filter paper, and the solvent removed under reduced pressure. The oil residue was purified by preparative HPLC (Method 2) to yield 120 mg of desired product (yield=77%). 1H NMR (400 MHz, acetone) δ ppm 8.35 (d, J=7.50 Hz, 1H), 8.24-8.30 (m, 1H), 8.16-8.24 (m, 3H), 7.16-7.25 (m, 2H), 7.05 (dd, J=8.16, 1.98 Hz, 1H), 6.94 (t, 1H, CHF2), 6.14 (dd, J=9.48, 4.63 Hz, 1H), 4.52 (s, 2H), 4.01 (dd, J=6.62, 3.97 Hz, 2H), 3.54 (dd, J=14.33, 9.48 Hz, 1H), 3.26-3.40 (m, 1H), 1.25-1.38 (m, 1H), 0.56-0.73 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=652.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[N:13]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12](=[O:24])[CH:11]1[CH3:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[N:13]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[C:12](=[O:24])[CH:11]1[CH3:25])[CH:8]=[O:9]
Reactant: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(CO)cc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(C=O)cc1Br
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]-2-[2-(trimethylsilyl)ethoxy]-methylisothiazolidin-3-one 1,1-dioxide (0.70 g, 1.6 mmol) in methylene chloride (15 mL) was added Dess-Martin periodinane (725 mg, 1.71 mmol) at room temperature. After stirring for 1 h, reaction solution was diluted with diethyl ether, quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with diethyl ether once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified with silica gel chromatography (5%–50% ethyl acetate/hexanes) to afford product as oil (0.69 g, 99%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.6 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.38 (m, 4H), 5.60 (dd, J=8.2, 6.2 Hz, 1H), 5.09 (dd, J=15.0, 11.3 Hz, 2H), 3.66 (dd, J=9.2, 7.4 Hz, 2H), 3.56 (dd, J=17.6, 8.2 Hz, 1H), 3.28 (dd, J=17.6, 6.2 Hz, 1H), 0.96 (dd, J=8.6, 7.0 Hz, 2H), 0.01 (s, 9H). LCMS found for C16H23BrNO5SSi (M+H)+: m/z=448, 450.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>CC(C)=O.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: [H][H]
Reactant: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 82 %

Procedure:
3-(3-Nitrophthalimido)-3-methylpiperidine-2,6-dione (0.5 g, 1.57 mmol) was dissolved in acetone (250 mL) with gentle heat and then cooled to room temperature. To this solution was added 10% Pd/C (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50 psi of hydrogen for 4 hours. The mixture then was filtered through Celite and the pad washed with acetone (50 mL). The filtrate was concentrated in vacuo to yield a yellow solid. The solid was slurried in ethyl acetate (10 mL) for 30 minutes. The slurry then was filtered and dried (60° C., <1 mm) to afford 0.37 g (82%) of 3-(3-aminophthalimido)-3-methylpiperidine-2,6-dione as a yellow solid: mp 268–269° C.; 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 7.44 (dd, J=7.1 and 7.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.52(s, 2H), 2.71–2.74(m, 3H), 2.08–1.99 (m, 1H), 1.87 (s, 3 H); 13C NMR (DMSO-d6) δ 172.48, 172.18, 169.51, 168.06, 146.55, 135.38, 131.80, 121.51, 110.56, 108.30, 58.29, 29.25, 28.63, 21.00; HPLC Water Nova-Pak/C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 5.62 min (99.18%). Anal. Calcd For C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.60; H, 4.41; N, 14.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]=[O:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.O1CCC[CH2:25]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]([OH:23])[CH3:25])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:13][CH:12]=2
Reactant: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring hetereogeneous mixture of 3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline-2-carbaldehyde (0.2129 g, 0.632 mmol) in tetrahydrofuran (6.32 mL, 0.632 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.632 mL, 1.90 mmol) dropwise at 0° C. (started at 11:20 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown syrup. The brown syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1 H, d, J=8.6 Hz), 8.31 (1 H, d, J=7.0 Hz), 8.05 (1 H, t, J=8.0 Hz), 7.48-7.71 (4 H, m), 5.33 (1 H, br. s.), 4.84 (1 H, br. s.), 1.28-1.55 (3 H, m); LC-MS (ESI) m/z 353.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:27]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][C:31]1=[O:40])[C:28]#[CH:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][CH2:27][N:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][C:31]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Fc1ccccc1C1=NCc2nnc(C(F)(F)F)n2-c2ccc(I)cc21
Reactant: C#CCN1C(=O)CCc2ccccc21
Product: O=C1CCc2ccccc2N1CC#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C(F)(F)F)n1-2

Procedure:
The title compound was prepared by coupling 6-(2-fluorophenyl)-1-(trifluoromethyl)-8-iodo-4H-[1,2,4]triazolo [4,3-a][1,4]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was purified by chromatoqraphy over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions were combined and evaporated and the residue was crystallized from ethyl acetate to yield colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 193°-196°.