Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)(C)C.[CH3:6][O:7][C:8]([CH3:13])=[CH:9][C:10](=O)[CH3:11].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[C:17]([CH3:18])[C:16]2[C:10]([CH:9]=1)=[CH:11][CH:19]=[CH:20][CH:15]=2
Reactant: Brc1ccccc1
Reactant: COC(C)=CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COc1cc(C)c2ccccc2c1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of t-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).
Reaction SMILES: [CH3:1][CH:2]([C:7]([F:10])([F:9])[CH3:8])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)[OH:12]>O>[CH3:1][C:2]([OH:12])([C:7]([F:10])([F:9])[CH3:8])[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C(C)(F)F)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(F)(F)C(C)(O)C(F)(F)F

Procedure:
As another example, 2-methyl-1,1,1,3,3-pentafluoro-2-butanol may be prepared by fluorinating commercially available 2-methyl-1-buten-3-yne to form 2-methyl-1,2,3,4-tetrafluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,2,3,3,4-pentafluorobutane. The 2-methyl-1,2,3,3,4-pentafluorobutane may then be dehalogenated to form 3-methyl-2,3,4-trifluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,2,3,3-tetrafluorobutane. The 2-methyl-1,2,3,3-tetrafluorobutane may then be dehalogenated to form 2-methyl-1,3,3-trifluoro-1-butene which may then be fluorinated to form 2-methyl-1,1,2,3,3-pentafluorobutane. The 2-methyl-1,1,2,3,3-pentafluorobutane may then be dehydrohalogenated to form 2-methyl-1,1,3,3-tetrafluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,1,1,3,3-pentafluorobutane. The 2-methyl-1,1,1,3,3-pentafluorobutane may then be dehydrogenated and then reacted with sulfuric acid and water to form 2-methyl-1,1,1,3,3-pentafluoro-2-butanol.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]2[CH2:12][N:13]([CH2:14][C:15]([O:17]CC)=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.CCO.[OH-].[Li+:24].Cl>C1COCC1.O>[O:1]=[C:2]1[CH2:11][CH:10]2[CH2:12][N:13]([CH2:14][C:15]([O-:17])=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Li+:24]
Reactant: CCOC(=O)CN1CC2CC(=O)Nc3cccc1c32
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])CN1CC2CC(=O)Nc3cccc1c32
Reaction time: 0.25 h

Procedure:
To a solution of ethyl (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B, from Step E (55 mg, 0.211 mmol) in THF (1 mL), EtOH (1 mL) and H2O (1 mL) was added 1.0 N lithium hydroxide (0.232 mL, 0.232 mmol). After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7 and the mixture was concentrated in vacuo to give the title compound. MS: m/z=233 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][C:41]=5[CH3:48])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][C:41]=5[CH3:48])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCN3CC(C)C)cc1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (460 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (175 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (236 mg) (Compound 388) as yellow amorphous.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=474.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][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.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[N:46][CH:45]=[C:44]([S:48]([N:51]6[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]6)(=[O:50])=[O:49])[CH:43]=5)[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:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(S(=O)(=O)c2cncc(Br)c2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(S(=O)(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(5-bromo-pyridine-3-sulfonyl)-4-methyl-piperazine (prepared from 5-bromo-pyridine-3-sulfonyl chloride and N-methylpiperazine, 65 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[5-(4-methyl-piperazine-1-sulfonyl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-249) as a milky white powder (66 mg, 66%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:35][OH:36].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH:35][OH:36])=[NH:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:36])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(C(F)(F)F)c1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(N)=O)c(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
To a solution of 180 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-benzonitrile in 5 mL of tetrahydrofuran and 10 ml of methanol was added 267 mg of hydroxylamine hydrochloride followed by 0.55 mL of triethylamine. The resulting mixture was heated to 60° C. overnight. The solvents were removed in vacuo, the resulting residue was poured into water and extracted with ethylacetate. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 1/ethyl acetate 1) to give 90 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-trifluoromethyl-benzamidine and 50 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].[H-].[Na+].[H][H].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl>COC(C)(C)C>[C:36]([O:35][C:33]([CH2:32][O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime and 10 ml of tert-butyl methyl ether are placed in a reaction vessel, to which 48 mg of 60% sodium hydride (in oil) is slowly added with stirring at room temperature in a stream of nitrogen gas. The mixture is stirred at room temperature until the evolution of hydrogen gas ceases, to which 0.29 g of tert-butyl bromoacetate is added at room temperature, and the mixture is further stirred with heating under reflux. After completion of the reaction, the reaction mixture is poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(tert-butoxycarbonylmethyl)oxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]#[C:16][C:17]([O:19]CC)=[O:18])[CH2:7][CH2:6]2.[OH-].[K+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]#[C:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C#CC1=Cc2cc(OC)c(OC)cc2CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)CCC(C#CC(=O)O)=C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Added to a solution of 65.2 mg (0.23 mmol) of ethyl 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate synthesized by the process described in Referential Example 13 in methanol-tetrahydrofuran (1:1; 1 ml) was 0.5 ml (2.5 mmol) of a 5N aqueous solution of potassium hydroxide, and the mixture was stirred for 30 minutes at room temperature. A saturated saline solution and 0.25 ml (3.0 mmol) of concentrated hydrochloric acid were added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant concentrated residue was purified by column chromatography on silica gel to obtain 61.4 mg (quantitative) of 3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid as a colorless amorphous powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C1(P(=[CH:39][C:40]([O:42][CH3:43])=[O:41])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(C)C=CC=CC=1>>[C:40]([CH:39]=[CH:7][C:6]1[N:2]([CH3:1])[C:3]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:4][C:5]=1[CH3:9])([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1ccc(CSc2nc(C)c(C=O)n2C)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CCOC(=O)C=Cc1c(C)nc(SCc2ccc(OC)cc2)n1C

Procedure:
A mixture of 1,4-dimethyl-5-formyl-2-(4-methoxybenzylthio)imidazole (1.7 g, 6 mmoles) and methyl (triphenylphosphoranylidene)acetate (4.8 g, 14 mmoles) in toluene (50 ml) was heated to reflux for 16 hours, cooled and concentrated in vacuo. The residue was triturated with ether, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica eluted with hexane-ethyl acetate (3:2) to give 5-[2-(carbethoxy)-ethenyl]-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (mp 165°-167° C.).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:3]12.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.Cl>CN(C)C=O.O1CCOCC1>[CH:28]1([CH2:27][N:8]2[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]3[CH2:13][CH2:14][NH:15][CH2:16][CH:3]3[C:2]2=[O:1])[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3CNC(=O)C2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1C2CNCCN2c2ccccc2CN1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate (100 mg, 0.315 mmol, Example 1) in anhydrous N,N-dimethylformamide (2 mL) was added sodium hydride (13.86 mg, 0.347 mmol). After stirring for 1 hour at room temperature, (bromomethyl)cyclopropane (102 mg, 0.756 mmol) was added to the reaction mixture. The reaction was stirred for 20 hours. The reaction was then quenched carefully with water and extracted with ethyl acetate. The organic layer was separated, dried with MgSO4, and concentrated. The residue was purified via flash chromatography (0-40% ethyl acetate/hexanes). The material obtained was dissolved in 1,4-dioxane (0.8 mL) and 4 M HCl in 1,4-dioxane (0.8 mL). The mixture was stirred for 20 hours. at room temperature. The title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.07-6.94 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (s, 1H), 4.17 (d, J=16.1 Hz, 1H), 3.51-2.79 (m, 8H), 0.66 (m, 1H), 0.15-0.05 (m, 1H), 0.05-−0.08 (m, J=4.1 Hz, 1H); MS (DCI) m/z 221.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH:18]=[CH:17][CH:16]=[N:15][C:13]=3[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH2:20](I)[CH3:21]>CN(C=O)C>[CH2:20]([O:19][C:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[N:15][C:13]=2[NH:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:3])[C:9]=2[N:10]=1)[CH3:21]
Reactant: Cc1cccc2c1NC(=O)c1cccnc1N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1=Nc2c(C)cccc2Nc2ncccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Sodium hydride (80% oil dispersion, 0.13 g, 5.5 mmol) was added at room temperature to a suspension of 6,11-dihydro-7-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (1.12 g, 5.0 mmol) in DMF (20 mL) under argon. The reaction mixture was heated at 60° C. for 1 h and then was cooled in an ice-bath before the addition of ethyl iodide (0.86 g, 5.5 mmol). Stirring was continued at room temperature overnight, followed by warming to 60° C. for 1 h. The solution was concentrated in vacuo to near dryness, the residue was poured over ice-water, and the resulting solid was collected, washed with water, and dried. Purification by chromatography (elution with 1% MeOH/CH2Cl2) afforded 0.23 g (18%) of the title compound, which crystallized as yellow needles from petroleum ether (30°-60° C.): m.p. 135°-136° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:33])[F:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:32])[F:33]
Reactant: C=C(c1cc(Cl)c(C(F)F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(C(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of crude N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (156 mg, 0.65 mmol) and 1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (210 mg, 0.72 mmol) in DMF (8 mL) at rt was added TEA (100 μL, 0.72 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (90 mg; yield 28% over 3 steps) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.268 (s, 1 H), 7.796 (s, 2H), 7.757-7.771 (m, 2 H), 7.694-7.710 (m, 1H), 7.389 (t, J=52.0 Hz, 1 H), 4.451 (d, J=18.0 Hz, 1 H), 4.344 (d, J=18.0 Hz, 1 H), 1.476 (s,6 H); HPLC purity: 99.28% at 220 nm and 100% at 254 nm; MS: m/z=494.0 (M+1, ESI+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].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.[CH2:60]([NH2:64])[CH:61]([CH3:63])[CH3:62]>CN(C=O)C>[CH2:60]([NH:64][C:24]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:15]=1[NH:14][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:13])[NH:21][CH:20]=[CH:19]2)=[O:25])[CH:61]([CH3:63])[CH3:62]
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 μL, 0.2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, 66%). 1H-NMR (400 MHz, DMSO-d6) δ 12.66 (d, J=7.4 Hz, 1H), 12.42 (s, 1H), 11.21 (s, 1H), 8.81 (d, J=6.6 Hz, 1H), 8.47 (s, 1H), 8.36 (t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.72-7.71 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (m, 1H), 6.48 (m, 1H), 3.10 (t, J=6.2 Hz, 2H), 1.88 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); HPLC ret. time 2.73 min, 10-99% CH3CN, 5 min run; ESI-MS 403.3 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 1-(3-methoxyphenyl)ethanone (5.5 mL, 40 mmol) in chloroform (100 mL) was added dropwise a solution of bromine (2.05 mL, 40 mmol) in chloroform (20 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted in methylene chloride (50 mL) and washed with water (2×25 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. Purification by column chromatography using methylene chloride as eluent gave the title compound (8.44 g, 84%) as oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]1[C:22](=[C:23]=[O:24])[CH:21]=[CH:20][C:19]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:18]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:18]=[C:19]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:20]=[CH:21][C:22]=1[CH:23]([OH:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCNC1=CC(c2ccc(Cl)cc2Cl)C(=C=O)C=C1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C(O)c2ccccc2)c(-c2ccc(Cl)cc2Cl)c1
Yield: 75 %

Procedure:
Phenylmagnesiumbromide (1M in THF) (2eq) is added to a solution of 8 (50 mg) in THF (10 ml) at 78° C. under argon with stirring. The reaction is allowed to stir for 15 min. at 78° C. after the addition of Grignard at which time sat; aq. NH4Cl (4 ml) is added to quench the reaction. The mixture is diluted with EtOAc (60 ml) and water (2 ml), and the layers are separated. The organic layer is washed with sat. aq. NH4Cl (10 ml), water (10 ml), brine (10 ml), dried (Na2SO4), filtered and concentrated. The residue is purified by silica column chromatography eluting with EtOAc/hexane to give 13.