Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]3)C(=O)[NH:10][C:5]2=[N:4][CH:3]=1.BrC1C(N)=NC=C(Br)N=1.Cl.CC1(C)CC(CCN)CCO1.C(N(C(C)C)CC)(C)C>CS(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][C:16]([CH3:20])([CH3:21])[CH2:15]2)[C:5]([NH2:10])=[N:4][CH:3]=1
Reactant: CC1(C)CC(CCn2c(=O)[nH]c3ncc(Br)nc32)CCO1
Agent: CC1(C)CC(CCN)CCO1
Agent: Cl
Agent: Nc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(CCNc2nc(Br)cnc2N)CCO1
Yield: 42 %

Procedure:
6-Bromo-1-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 3,5-Dibromopyrazin-2-amine (161 mg, 0.6 mmol), 2-(2,2-dimethyl-tetrahydro-pyran-4-yl)-ethylamine hydrochloride (100 mg, 0.5 mmol), diisopropylethylamine (0.5 mL), and dimethylsulfoxide (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor to 150° C. for 2 h to give crude 6-bromo-N2-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl)pyrazine-2,3-diamine. MS (ESI) m/z 329.5, 331.5 [M+1]+. 1,1′-Carbonyldiimidazole (194 mg, 1.2 mmol) was added to the reaction mixture and then heated again in a Biotage Emrys Optimizer microwave reactor to 150° C. for 10 min. The product was purified by reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Product containing fractions were concentrated and then triturated with ether to give a white solid (90 mg, 42% yield over two steps). MS (ESI) m/z 355.4 [M]+, 357.4 [M+2]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:11]O)[CH:7]=1.N1C=CC=CC=1.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]2([C:14]([F:17])([F:16])[F:15])[CH2:11][O:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol (8.15 g) and pyridine (21.2 mL) in 50 mL of methylene chloride (CH2Cl2) at 0° C.-5° C. was added dropwise methanesulfonyl chloride (2.63 mL). The mixture was warmed to room temperature, stirred overnight and methanol (80 mL) and K2CO3 (36.2 g) were added. The mixture was stirred 4 hours, diluted with diethyl ether, washed with water, dilute HCl, and brine, and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue that was purified by flash silica gel chromatography using 5% EtOAc in hexanes as the eluent. The product-rich fractions were collected and the volatiles removed in vacuo to provide 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[N:5]2[N:4]=[C:3]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=3)=[C:10]2[CH:9]=[N:8][N:7]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (60.2 mg, 0.149 mmol), 3-trifluoromethylbenzeneboronic acid (42.3 mg, 0.223 mmol) and cesium carbonate (96.9 mg, 0.297 mmol) in anhydrous 1,4-dioxane (5 ml) was degassed using three freeze-pump-thaw cycles. Tris(dibenzylideneacetone)palladium(0) (13.8 mg, 0.0151 mmol) and a 0.1 M solution of tri-tert-butylphosphine in 1,4-dioxane (0.357 ml, 0.357 mmol) was added, and the mixture was further degassed with two more freeze-pump-thaw cycles before heating at 90° C. under nitrogen for 17 h. The mixture was filtered through glass fibre paper, washing well with ethyl acetate (25 ml). The filtrate was washed with saturated aqueous NaCl (10 ml), and the aqueous layer was further extracted with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to give 56.3 mg (81%) of the title compound as a yellow solid: mp=152-155° C. (EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 3.79 (3H, s), 5.58 (2H, s), 7.31 (1H, m), 7.41 (1H, td, J=7.6 and 0.9 Hz), 7.63-7.68 (3H, m), 7.80 (1H, m), 7.85-7.86 (2H, m), 7.93 (1H, s), 9.44 (1H, s); MS (ES+) m/e 470 [MH]+. Anal. Found C, 56.22; H, 3.35; N, 20.59%. C22H15F4N7O requires C, 56.29; H, 3.22; N, 20.89%.
Reaction SMILES: S(O)(O)(=O)=O.C[NH:7][C:8](=[NH:10])S.[OH-].[K+].C([O:15][C:16](=O)[CH2:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)C.O1C=CC=CN1>O>[NH2:10][C:8]1[O:26][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:17][C:16](=[O:15])[N:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: CNC(=N)S
Agent: C1=CNOC=C1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1nc(=O)cc(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 16.6 g (0.597M) of methylthiopseudourea sulfate is added 66 ml of H2O+13.0 g of KOH. With vigorous stirring, 20 g (71.9 mM) of ethyl-m-fluorobenzoylacetate is added and the reaction mixture is allowed to stir, at ambient temperature, for 18 hours. The solids are filtered and washed well with H2O followed by diethylether. The crude title compound is dried at 60° C. in a vacuum over to yield 16.0 g (>100 percent). To 6.8 g of crude powdered oxazine is added 100 ml of H2O and heated to 70° C., cooled, filtered and washed solids. Yield of 2-amino-6-m-fluorophenyl-1,3-oxazine-4-one of 3.60 g (53 percent of rec. yield).
Reaction SMILES: [CH3:1][C:2]1([C:39](O)=[O:40])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:22]([N+:36]([O-:38])=[O:37])[CH:21]=3)(=[O:19])=[O:18])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.COCCOC>[OH:40][CH2:39][C:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:22]([N+:36]([O-:38])=[O:37])[CH:21]=3)(=[O:19])=[O:18])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC1(C(=O)O)CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(CO)CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 532H (35 mg, 0.06 mmol), 4-methylmorpholine (0.007 mL, 0.06 mmol), and DME (0.3 mL) at −15° C. was treated dropwise with isobutyl chloroformate (0.008 mL, 0.06 mmol), stirred for 15 minutes, and filtered. The filter cake was washed with DME and the filtrate and washings were combined. The solution was cooled to −15° C., treated sequentially with NaBH4 (3.5 mg, 0.09 mmol) water (0.03 mL), and additional water (50 mL), and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purifed by flash column chromatography on silica gel with 1-2% methanol/dichloromethane to provide the desired product. MS (ESI(−))) m/e 583 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ11.92 (s, 1H), 8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 2H), 7.38 (d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 6.90 (d, 2H), 4.53 (t, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 3.30 (m, 2H), 3.16 (m, 4H), 1.50 (m, 2H), 1.25 (m, 2H), 0.91 (s, 3H).
Reaction SMILES: [Cl:1]OC(C)(C)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=1>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH:17][Cl:1])=[O:16])=[CH:10][CH:9]=1
Reactant: NC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: O=C(NCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
t-Butyl hypochlorite (7.5 g, 0.070 mole) was added to 1,1-di(p-fluorophenyl)urea (17.5 g, 0.071 mole) in 440 ml methanol at 0°-5° and the mixture stirred for 1 hour at that temperature to produce a solution containing step (a) title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=5[F:18])=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)c(F)c1
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)c(F)c1

Procedure:
The title compound, white solid (40 mg, 30%), MS (ISP) m/z=407.4 [(M+H)+], mp 152° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(2,4-difluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate K) (0.1 g, 0.324 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.39 mmol).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[C:25]#[N:26]>>[C:25]([C:21]1[N:22]=[CH:23][NH:24][C:20]=1[NH:19][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1)#[N:26]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: N#Cc1nc[nH]c1N
Product: N#Cc1nc[nH]c1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-amino-1H-imidazole-4-carbonitrile as the starting materials.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:37][NH:38][OH:39].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:38]([OH:39])[CH3:37])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(O)C(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 5 °C
Reaction time: 1.17 h
Yield: 79.6 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (9.0 g 23.50 mmol) in anhydrous DMF (285 mL) was added CDMT (4.95 g 28.20 mmol 1.2 eq.) and NMM (N-methyl morpholine) (2.85 g 28.2 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 70 min. N-Methylhydroxylamine hydrochloride (23.6 g 282.0 mmol 12.0 eq) was added and stirring continued for 3 hours. The reaction was judged to be complete by HPLC-MS analysis, and was quenched by adding water (100 mL) to the reaction mixture. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a residue. Saturated aqueous sodium bicarbonate (120 mL) was added to neutralize to pH 7. White solid precipitated out, and the mixture was cooled to 5° C. The solid was filtered, washed with cold water (100 mL), and dried in vacuo to afford 7.7 g (85%) of 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide at >95% purity by 1HNMR analysis. To obtain 99% purity, 7.7 g of the product was dissolved in a boiling mixture (700 mL) of methanol and isopropanol (1:9). The hot solution was filtered to remove trace impurities, and the filtrate was allowed to cool to room temperature. The product crystallized out as needle-like crystals, which was filtered, washed with isopropanol, and dried in vacuo to afford (3.0 g) 99% purity. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—2.27 min, m/e=412.30 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.29 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.32 (s, 3H) 3.73 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.71 (s, 1H) 7.83 (s, 1H) 8.09 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: CN(C)C=O.Br[C:7]1[C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)CCC>[Cu]=O.O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:16]1[C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Agent: O=[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 4-(2-bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (35 mg), tetrakistriphenylphosphine palladium (9.8 mg), tri-n-butyl-(2-pyridyl)-tin (63 mg), and copper(II) oxide (14 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone. The purification product was then dissolved in methanol, and the solution was added dropwise to water. The precipitate was collected by filtration to give the title compound (5.1 mg, yield 15%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C2CCC(C(=O)O)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCC(C(=O)O)CC2)cc1

Procedure:
In analogy to example 1, step 2, from (S)-4-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)cyclohexanecarboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI−): m/z=471.4 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:35])[F:34])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:34])([F:35])[F:36])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: CCOC(=O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of ethyl 3-({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}ethynyl)benzoate (0.19 g, 0.33 mmol) in CH3OH-THF (1:1, v/v) containing 1.0 mL of 1 N NaOH was stirred overnight at ambient temperature, then neutralized with dilute acid and partitioned with ethyl acetate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 0.15 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OC)ccc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2s1
Reaction time: 2 h
Yield: 49.5 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (0.86 g, 1.96 mmol) in CH2Cl2 (15.0 mL) at 0° C. is treated with BBr3 (3.0 mL, 2.94 mmol). The mixture is stirred for 2 h and quenched with water (10 mL). The aqueous layer is extracted with CH2Cl2 (30 mL). The organic layer is concentrated and purified using silica gel column chromatography (25% EtOAc/Hex) to afford the title compound (0.412 g, 50%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CCO.C1COCC1>[CH3:29][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])=[CH:15][CH:16]=2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(C)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CCc2ccc(Nc3ccc([N+](=O)[O-])cc3C(=O)O)cc2)cc1C
Yield: 95.3 %

Procedure:
The title compound was prepared 2-{4-[2-(3,4 dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid methyl ester (1.12 g, 2.76 mmol), 1N NaOH (50 mL) in EtOH (50 mL) and THF (50 mL) using the procedure described in Example 2. This procedure yielded a yellow solid, 1.03 g (2.63 mmol, 81%) of the desired product. mp 214-216° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(F)c1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1cccc(N=C=S)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Into a solution of 2,3-difluoroaniline (1.0 g, 7.74 mmol) in 30 mL of toluene at room temperature, thiophosgene (0.91 mL, 11.6 mmol) and triethylamine (1.3 mL, 11.6 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (910 mg, 68%). 1H NMR (CDCl3) δ 6.98 (m, 2H), 7.11 (m, 1H).
Reaction SMILES: CC([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>CO>[CH2:32]([N:34](/[CH:18]=[C:17]1/[C:23](=[O:24])[O:25][C@H:26]([CH2:27][O:28][CH3:29])[C@@:15]2([CH3:30])[C:16]/1=[C:20]([OH:19])[C:21](=[O:22])[C:13]1[C@H:8]3[C@:7]([CH3:31])([CH2:6][C@@H:5]([OH:4])[C:14]2=1)[C@@H:11]([OH:12])[CH2:10][CH2:9]3)[CH2:35][CH3:36])[CH3:33]
Reactant: CCNCC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: CO
Product: CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](O)C[C@]2(C)[C@@H](O)CC[C@@H]12)CC

Procedure:
To a solution of 17-hydroxywortmannin (1100 mg) in methanol (5 mL) is added diethylamine (0.72 mL). After 48 hours the reaction mixture is concentrated under vacuum. The residue is dissolved in EtOAc and precipitated with hexane. A yellow powder is obtained (0.29 mg). MS: 462.2 (M+H)+.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22].C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]4[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=4)=[O:22])[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.30 g, 0.0010 mol), p-nitrophenyl chloroformate (0.25 g, 0.0012 mol), and N,N-diisopropylethylamine (540 μL, 0.0031 mol) in methylene chloride (4 mL, 0.06 mol) was stirred at rt for 16 h. The crude reaction mixture was purified by flash column chromatography to afford 120 mg of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19](I)[C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:23]1[CH:28]=[C:27]([C:19]2[C:9]3[N:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:11]=[N:12][C:8]=3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCCO
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cccc(N)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
This was prepared analogously to the above product from 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (2.1 g, 5.36 mmol), 3-aminophenylboronic acid (1.1 g, 8.04 mmol), 1,3-propanediol (1.9 ml, 26.8 mmol), potassium carbonate (3.7 g, 26.8 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (5 ml). The title product was obtained as an off-white solid (1.30 g, 68%) m/z, 358.2 (M+H)+.