Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[CH:22]1([CH2:28][C:29](=[O:43])[CH2:30][C:31]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([CH2:28][C:29]([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:43])[CH2:30][C:31]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])([CH3:33])[CH3:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2ccccc2[nH]1)CC1CCCCC1
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 66.5 %

Procedure:
To a solution of the 2-methylindole (65 mg) in THF (1 mL) stirred under argon cooled on dry ice/acetone was added n-butyl lithium (2 M in pentane, 0.8 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 1 mL) was added and the mixture was allowed to warm to approximately −20° C. After 5 minutes, a precipitate was noted and the mixture was cooled to −70° C. 1-Cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 15) (100 mg) in THF (1 mL) was added dropwise and the mixture was stirred for 20 minutes at −70° C. The reaction was quenched with EtOH (0.5 mL). The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography over silica gel (methylene chloride-hexanes (1:2)) gave the title compound as an oil (0.095 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(F)(F)CCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3CC(F)(F)CCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 5-(4-bromo-phenyl)-4-(2,2-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (150 mg), ethyl 4-piperidinecarboxylate (63.0 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (10 mL) was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (255 mg) was added. The mixture was stirred at room temperature for 2 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was partitioned between ethyl acetate and water, washed with saturated brine. The organic phase was collected and evaporated, the residue was dissolved in DMF (5 mL) and 2M NaOH (2 mL) solution was added. The mixture was stirred at 50° C. for 1 h, then cooled to room temperature. This reaction mixture was acidified with 2M HCl to pH 5-6, extracted with ethyl acetate for three times. The combined organic phase was concentrated and the residue purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E42) (40 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.02 (3H, t), 1.78 (2H, m), 1.98 (2H, m), 2.07 (2H, m), 2.73 (2H, d), 2.83 (2H, m), 3.19 (2H, m), 3.46 (2H, m), 4.41 (2H, m), 7.48 (2H, t), 7.63 (2H, m), 7.96 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 9.23 (1H, br s), 12.58 (1H, br s). δF (DMSO-d6, 376 MHz): −74.2. MS (ES): C29H33N3O2S requires 487. found 488.3 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].Br.Br[CH2:19][CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:3]1[CH2:19][CH2:20][N:21]=[C:2]1[NH:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(c2ccc(N=C=S)cc2)=NN1
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(NC3=NCCS3)cc2)=NN1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
A mixture of 0.57 g of 4,5-dihydro-6-[4-(isothiocyano)phenyl]-3(2H)-pyridazinone, 0.51 g of 2-bromoethylamine hydrobromide and 0.34 g of anhydrous K2CO3 in 12 ml of DMF is heated at 80° C. for four hours. The reaction mixture is cooled, filtered, and the filtrate is concentrated under reduced pressure. The residue is treated with water, neutralized, and filtered to give 0.5 g of 6-[4-[(4,5-dihydro-2-thiazolyl)amino]phenyl]-4,5-dihydro-3(2H)-pyridazinone, mp 217°-218° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:23]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCN1CCCCCC1=O
Yield: 80.4 %

Procedure:
Following example 10, 15.3 g of 50% sodium hydride-mineral oil dispersion (7.65 g NaH, 0.319 M), 30 g (0.266 M) of azacycloheptan-2-one and 66.1 g (0.265 M) of 1-bromododecane on 20 hr. reflux gave 60 g (80%) of colorless product; b.p. 175°-180°/0.3 mm.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:21][CH:20]=2)[CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:23][CH:24]=2)[CH:18]=1)=[O:13])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CC(=O)OC(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a solution of N-{2-(tert-butyldimethylsilyloxy)ethyl}-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 67-(1) (0.700 g) in N,N-dimethylformamide (5.0 mL), sodium hydride (55% in mineral oil, 0.058 g) was added and stirred at room temperature for 20 minutes. To the reaction mixture, tert-butyl 2-bromoacetate (0.281 g) was added and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.220 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15].[C-:17]#[N:18].[Na+].C(OCC)C>CS(C)=O>[C:17]([CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15])#[N:18]
Reactant: [C-]#N
Reactant: CC1CC(C)(C)N(CCCl)C2CCCCC12
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1CC(C)(C)N(CCC#N)C2CCCCC12
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
1-(2'-cyanoethyl)-2,2,4-trimethyl decahydroquinoline was prepared via the post-reaction of the above chloroethyl substituted compound. 61.0 grams (0.25 mole) of 1-(2'-chloroethyl)-2,2,4-trimethyl decahydroquinoline dissolved in 50 milliliters of methyl sulfoxide was added dropwise over a period of 40 minutes at room temperature to a prepared solution of 12.25 grams (0.25 mole) of sodium cyanide in 150 milliliters of methyl sulfoxide. The mix was then heated to 95° C. and stirred for 2.5 hours. The reaction mixture was then cooled, poured into 500 milliliters of ice water, diethyl ether was added, the organic layer separated out. The aqueous layer was washed with four 100 milliliter portions of diethyl ether and the ether washes combined with the original organic layer. The solution was then concentrated and distilled using a 6" Vigreaux column to yield 43.0 grams of a liquid product boiling at 134°-136° C. at 3.3 mm Hg. The infrared spectrum of the product is consistent with the desired compound, 1-(2'-cyanoethyl)-2,2,4-trimethyl decahydroquinoline. Calculated values for the formula C15H26N2 are 76.87% carbon, 11.18% hydrogen, and 11.95% nitrogen and found contents were 76.71% carbon, 11.02% hydrogen, and 11.15% nitrogen.
Reaction SMILES: [CH2:1]1[C:17]2[C:5]([C:6]3[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=3[C:8]3[C:16]=2[CH:15]=[C:14]2[C:9]=3[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=32)=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:48]([O:50][C:51](=[O:70])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]Br)=[CH:54][CH:53]=1)[CH3:49]>O1CCOCC1.C(OCC)C>[CH:18]1[C:13]2[C:12](=[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]3=[C:9]3[C:14]=2[CH:15]([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:55]2[CH:56]=[CH:57][C:52]([C:51]([O:50][CH2:48][CH3:49])=[O:70])=[CH:53][CH:54]=2)[C:16]2[C:8]3=[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]3=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]3=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1

Procedure:
1H-Tetrabenzo[a,c,g,i]fluorene (13) (2.08 g, 5.68 mmol) was suspended in degassed dioxane 80 mL) and heated to reflux under an atmosphere of nitrogen. Tetrabutylammonium hydroxide (40% w/w in H2O, 3.50 g, 5.41 mmol) was added as a solution in dioxane (20 mL) via syringe which was then washed with dioxane (2×5 mL). A yellow precipitate formed immediately which was filtered under nitrogen and washed with warm dioxane (100 mL) and diethyl ether (100 mL). The salt was resuspended in dioxane (100 mL) and to it added 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (10) (2.08 g, 5.40 mmol). The reaction mixture was refluxed under an atmosphere of nitrogen after which time a dark solution had formed. Solvent was removed in vacuo to form a dark brown oil. This was dissolved in diethyl ether and the supernatant removed to leave a yellow slurry. This was washed with diethyl ether (2×30 mL) and all the diethyl ether extracts combined and concentrated. The resulting residue was purified by flash column chromatography using CH2Cl2 /hexane (1:1) as the eluting solvent. The product was isolated as a pale yellow airy solid which was washed with and concentrated from diethyl ether four times. The desired product was precipitated from diethyl ether as a pale yellow powder (2.46 g, 3.67 mmol, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Yield: 75.4 %

Procedure:
A solution of ethyl 8-(4-chlorobenzenesulphonamido)-2,2-dimethyloctanoate (1.0 g), sodium hydroxide (1.5 g) in ethanol (40 ml) and water (5 ml) was stirred at room temperature for 90 hours then refluxed for 3 hours. The solvent was removed and the residue was dissolved in dilute hydrochloric acid, the resulting solution then being extracted with chloroform (3×50 ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from isopropanol-water to give the title compound as a white solid (0.7 g) m.p. 95°-96° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11](=[O:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[C:1]([NH:9][CH:10]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:11]([OH:33])[CH2:12][NH:13][C@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:15]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCC[C@H](NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN1CCCC[C@H](NCC(O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of (S)-3-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]amino]-hexahydro-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester (2.5 mmole) in tetrahydrofuran (25 ml.) and water (2.5 ml.) is added sodium borohydride (10.0 mmole) portionwise over a 10 minute period. After the addition is completed, the reaction mixture is stirred for 4 hours, and slowly quenched with concentrated hydrochloric acid. The mixture is diluted with ethyl acetate (50 ml.), washed with water (2×), saturated sodium bicarbonate (2×), and saturated sodium chloride (2×), dried (Na2SO4), and concentrated under reduced pressure to give (S)-3-[[3-(benzoylamino)-2-hydroxy-4-phenylbutyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of benzenesulfonyl chloride in anhydrous CH2Cl2 (0.5M solution) cooled to 0° C. under N2 was added t-butylamine (2.2 equiv) slowly through a dropping funnel. After completion of addition, the reaction was stirred at toom temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was extracted into ether and washed with 2N NaOH, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled product, which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O>CN(C=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 95.3 %

Procedure:
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60% NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95%) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.59 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4]O[C:2]=1[CH2:9][OH:10].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: Cl
Product: O=c1cc(CO)n(-c2ccccc2)cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a suspension of kojic acid (1.421 g, 10.00 mmol) in diluted hydrochloric acid (0.52 mL of concentrated hydrochloric acid diluted with 25 mL of water) was added aniline (1.40 mL, 15.4 mmol). The resulting mixture was heated under reflux for 20 h. The mixture, while warm (60° C.), was washed with dichloromethane two times and the organic phase was discarded. The aqueous phase was neutralized with solid sodium carbonate, upon which much off-white precipitate appeared. The mixture stood in a hood overnight. The crude product was isolated by filtration and purified by recrystallization with methanol to give a pale solid (1.064 g, 49%). Mp: 236-238° C. (lit.85 237-240° C.). 1H NMR (d6-DMSO): δ 4.20 (2H, s), 6.47 (1H, s), 7.35 (1H, s), 7.5-7.6 (5H, m). 13C NMR (d6-DMSO): δ 70.9, 102.5, 114.8, 118.2, 118.9, 130.5, 138.7, 146.7, 165.3, 179.5.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 83 %

Procedure:
3.8 g of ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate, 13 ml of ethanol and 1.0 g of sodium hydroxide are heated in 13 ml of water for 1 hour for boiling. The pH is reduced to 10 and the alcohol is distilled off in vacuo. The aqueous solution is shaken up with ether and purified with active charcoal. Acidification is carried out with dilute hydrochloric acid and with a yield of 83% 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5°-181°.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Cl.[C:20]1([S:26]([N:29]2[C:33]3=[N:34][CH:35]=[C:36]([N+:45]([O-:47])=[O:46])[C:37]([NH:38][CH:39]4[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]4)=[C:32]3[CH:31]=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([NH:38][C:37]4[C:36]([N+:45]([O-:47])=[O:46])=[CH:35][N:34]=[C:33]5[N:29]([S:26]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)(=[O:28])=[O:27])[CH:30]=[CH:31][C:32]=45)[CH2:40]3)=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCNC1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Fmoc-Cl (3.16 g, 12.2 mmol) was added to a solution of crude (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl-amine hydrochloride (5.34 g, 12.2 mmol) and diisopropylethylamine (5.31 ml, 30.5 mmol) in CH2Cl2 (100 ml) at 0° C. The reaction mixture was warmed to 25° C. and stirred for 18 h, then was partitioned between half-saturated NaHCO3 (225 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0 to 70% EtOAc in heptanes) to afford 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (7.09 g, 93%) as a yellow solid. This material was used in the next step below without additional characterization or purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[C:26]=2[CH3:37])=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Product: Cc1c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc2n1C

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1,2-Dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=504.4.