Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[F:16][C:17]([F:36])([F:35])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)=[CH:21][CH:20]=1.[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]([F:16])([F:35])[F:36])=[CH:20][CH:21]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 4.75 h
Yield: 63 %

Procedure:
To a solution of 110 mg (0.52 mmol) (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) and 169 mg (0.52 mmol) methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) in 5 ml acetonitrile were added 15.7 mg (0.10 mmol) NaI and 188 mg (0.58 mmol) Cs2CO3. The mixture was stirred at room temperature for 2 days and for 4.75 h at reflux. After filtration, the solvent was evaporated. The residue was redissolved in dichloromethane, dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 95:5) yielded 143 mg of the title compound as light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:19]O>>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:19])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cc2ccc(O)cc2)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cc2ccc(O)cc2)cn1

Procedure:
One gram of 5-(4-hydroxybenzyl)-picolinic acid was suspended in 15 ml. of methanol. Then, hydrogen chloride gas was introduced therein till saturation. After heating under reflux for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was added with cold water to form crystals. The crystals were then recrystallized from ethyl acetate to obtain 0.85 g of methyl 5-(4-hydroxybenzyl)picolinate as colorless needlelike crystals of a melting point of 184°~186° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:25][P:26]([C:31]([F:50])([F:49])[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=2)=[C:36]([F:47])[C:35]=1[F:48])[OH:33])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:48][C:35]1[C:36]([F:47])=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=2)[CH:38]=[CH:39][C:34]=1[C:32](=[O:33])[C:31]([P:26](=[O:30])([O:27][CH2:28][CH3:29])[O:25][CH2:23][CH3:24])([F:49])[F:50]
Reactant: CCOP(=O)(OCC)C(F)(F)C(O)c1ccc(-c2ccc(F)cn2)c(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)C(=O)c1ccc(-c2ccc(F)cn2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin reagent (1.75 g, 4.1 mmol) was added to a solution of diethyl{2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-hydroxyethyl}phosphonate (876 mg, 2.1 mmol) in methylene chloride (30 mL) at room temp—solution darkens to deep red over 1 hr. After stirring at rt for 1 hr, a solution of saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate (1:1) (ca. 20 mL) was added and the solution stirred until clear. The reaction mixture was extracted with dichloromethane, dried (sodium sulfate) and concentrated to afford diethyl {2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-oxoethyl}phosphonate as an off white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:5][CH2:6][N:7]1[C@H:12]2[CH2:13][CH2:14][C@@H:8]1[CH2:9][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:11]2)[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][C:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:5][CH2:6][N:7]1[C@H:8]2[CH2:14][CH2:13][C@@H:12]1[CH2:11][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:9]2)[CH2:3][NH:4][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46]
Reactant: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of intermediate 24 (158 mg, 0.4 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (0.175 mL, 1.0 mmol) followed by phenylsulfonyl chloride (0.065 mL, 0.5 mmol) and the solution stirred at room temperature under nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 to give the title compound (150 mg, 70%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][NH2:16]>ClCCl>[CH3:15][NH:16][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(O)Cn1nc([N+](=O)[O-])cc1CBr
Reactant: CN
Solvent: ClCCl
Product: CNCc1cc([N+](=O)[O-])nn1CC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 250b (3.0 g, 11.4 mmol) in dichloromethane (30 mL) was added the solution of CH3NH2 (3.0 g, 34.2 mmol, 35% in water). This reaction mixture was stirred at room temperature for 1 h. Then the organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 250c (1.9 g, 78%) as yellow solid. MS-ESI: [M+H]+ 215.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21]C2CCCCO2)=[O:19])[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:32])([S:28]([CH3:31])(=[O:29])=[O:30])[C:18]([NH:20][OH:21])=[O:19])[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (536.3 mg, 1.12 mmol) was dissolved in methylene chloride (5 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 8.41 mL, 30 mmol) and the slurry was stirred at RT for 15 minutes. Methanol (1 mL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material purified via silica gel chromatography eluting with methylene chloride/methanol to afford title compound as a solid 117.8 mg. LCMS: (M+1) 395.3 1H NMR (CD3OD) 7.51 (1H, d, J=7.62 Hz), 7.42-7.32 (5H, m), 6.18 (1H, dd, J=7.42, J=2.73), 5.09 (2H, s), 4.21-4.13 (1H, m), 3.85-3.77 (1H, m), 3.08 (3H, s), 2.53-2.45 (1H, m), 2.32-2.25 (1H, m), 1.65 (3H, s) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([NH2:16])[CH:18]=[CH:19][C:20]=1[Cl:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(N)ccc1Cl
Yield: 15.1 %

Procedure:
(S)-2-(5-Amino-2-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (316 mg) was prepared from (S)-2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester-hydrochloride (1.5 g, 5.1 mmol) and 5-amino-2-chloro-benzoic acid (909 mg, 5.1 mmol) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 100 mL of 1N HCl and 50 mL of EtOAc. The organic layer was washed with 1N HCl, 10% sodium carbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM-EtOAc, 9-1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10](Cl)=[N:11][OH:12])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.[CH2:25]([O:27][CH:28]=[CH:29][CH3:30])[CH3:26].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:29]([CH3:30])[CH:28]([O:27][CH2:25][CH3:26])[O:12][N:11]=3)=[C:7]([C:14]([NH:15][CH3:16])=[O:17])[C:6]=2[CH:18]=1
Reactant: CNC(=O)c1c(C(Cl)=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CC=COCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1ON=C(c2oc3cc(N(C)S(C)(=O)=O)c(Br)cc3c2C(=O)NC)C1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 5-bromo-N-hydroxy-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carbimidoyl chloride (400 mg, 0.91 mmol), 1-ethoxyprop-1-ene (392 mg, 4.56 mmol) and NaHCO3 (153 mg, 1.82 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. It was concentrated, diluted with water, extracted with EtOAc, the organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (PE:EA=2:1) to get product 5-bromo-2-(5-ethoxy-4-methyl-4,5-dihydroisoxazol-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (370 mg, yield: 83%). MS (M+H)+: 488/490.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.O>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[C:9](=[O:13])[N:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2N1CCCC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)nc2c1cc(-c1cn[nH]c1)c(=O)n2N1CCCC1
Temperature: 100 °C

Procedure:
To a flask was added a 2-amino-6-bromo-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (21.0 mg, 0.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (20.9 mg, 0.07 mmol) potassium carbonate (25.6 mg, 0.19 mmol) in DMAC (1.20 ml):H2O (0.1 ml). The reaction mixture was degassed by alternating between N2 and vacuum. To the reaction mixture was added PdCl2(PPh3)2 (4.3 mg). After heating in microwave for 60 min at 100° C., the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reversed phase column eluted with acetonitrile: 0.1% acetic acid in water to give the titled compound weighted 2.5 mg
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:6]=1[CH3:28])([CH3:4])([CH3:3])[CH3:2].IB1C2CCCC1CCC2>ClCCl.CCCCC>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:25]([CH3:26])[CH3:27])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:6]=1[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: IB1C2CCCC1CCC2
Solvent: CCCCC
Solvent: ClCCl
Product: Cc1c(N(c2ccc(O)cc2)C(C)C)cc2c(c1C(C)(C)C)OCC2(C)C
Yield: 131.1 %

Procedure:
Following general procedure M and using 7-t-butyl-5-[isopropyl-(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 57, 0.032 g, 0.083 mmol) and 1M solution of 9-iodo-9-borabicyclo[3.3.1]nonane (B-iodo-9-BBN) in hexanes (0.2 mL, 0.2 mmol) in 0.6 mL of anhydrous dichloromethane and 1 mL of n-pentane, the title compound (0.04 g) was obtained as a brown oil that was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:34])=[O:33]
Reactant: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 167.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (13, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in 685 mL of dichloromethane was added to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, 63.8 g of triethylamine (0.629 mol, 1.2 equiv.) was added and the mixture was cooled to less than 5° C. temperature. 66 g (0.576 mol, 1.1 equiv.) of methanesulfonyl chloride was added dropwise while maintaining the temperature below 10° C. and after the addition was complete, the mixture was stirred for an additional 30 min and then warmed to approximately 20° C. temperature under nitrogen atmosphere. The reaction mixture was stirred for NLT 1 h and quenched with 261 mL of ice-water at below 25° C. temperature and mixed for NLT 15 min. The lower organic layer was separated and the upper aqueous layer was extracted with 2×135 mL of dichloromethane. The combined organic layers were washed with 3×327 mL of water, dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator under vacuum at NMT 60° C. temperature. The resulting crude product (viscous oil) was dried over night using a high vacuum pump to afford 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl) ((S)-1-phenylethyl)amino) acetate (14) as a viscous oil, which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 17.23 min; LC-MS (m/z): 398.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](I)[CH3:21]>>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: CCI
Product: CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and ethyl iodide to produce the above.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:19]Br.Cl>ClCCl>[Br:19][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:6]=2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran5-yl)-ethanone (1.69 g, 8.88 mmol) in dichloromethane (25 mL) was slowly added a suspension of AlCl3 (2.96 g, 22.2 mmol) in dichloromethane (30 mL). Bromine (1.61 g, 10.7 mmol) was added dropwise and the mixture was stirred at room temperature for 6 hours then cooled to 0° C. and aqueous HCl (1N) was added and the mixture extracted with dichloromethane, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: EtOAc/10:1 to 2:1) to give 1.94 g 1-(7-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran5-yl)-ethanone (81%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.39 (s, 6H), 2.56 (s, 3H), 4.37 (s, 2H), 7.69 (d, J=1.76 Hz, 1H), 7.95 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35]C)[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][OH:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 52.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide (prepared according to WO2002055517) as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (52 mg, 52.7%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH:20]([CH:24]([CH3:26])[CH3:25])[C:21](O)=[O:22])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.C[Si](C)(C)[O:45][NH2:46]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH:20]([CH:24]([CH3:25])[CH3:26])[C:21]([NH:46][OH:45])=[O:22])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)C(C(=O)O)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(C(=O)NO)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (66 mg; 0.18 mmol) was dissolved in THF (2 ml). At 0° C., diisopropylethylamine (DIEA; 124 μl; 0.71 mmol) and ethyl chloroformate (51 μl; 0.53 mmol) were successively added. The mixture was allowed to reach RT from 0° C. over the course of 2 h and then O-trimethylsilylhydroxylamine (80.43 μl; 1.07 mmol) was added. Stirring at RT for a further 3 h was followed by partitioning between dilute HCl (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 5 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Trituration of the residue with EtOAc (2 ml) resulted in 2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (22 mg; 0.06 mmol). MS: 384.25 (M+H); Rt: 1.94 min (method: gradient acetonitrile+0.08% formic acid: H2O+0.1% formic acid from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min); flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=1.O.[NH2:19][NH2:20]>CCO>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][CH2:10][CH2:9][O:8][C:4]1[CH:3]=[C:2]([NH:19][NH2:20])[CH:7]=[CH:6][N:5]=1
Reactant: NN
Reactant: Fc1ccnc(OCCOC2CCCCO2)c1
Solvent: CCO
Solvent: O
Product: NNc1ccnc(OCCOC2CCCCO2)c1
Temperature: 80 °C
Yield: 89 %

Procedure:
Intermediate 67a (633 mg, 2.62 mmol) was suspended in EtOH (5 mL) and hydrazine hydrate (50-60%, 5 mL) in a microwave vial fitted with a stirrer bar and sealed with a crimped septum, and heated to 80° C. for 18 h. The reaction was cooled, and partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4, and concentrated in vacuo to afford the title compound as a colorless oil (593 mg, 89%). LCMS (Method 3) Rt 0.41 and 1.71 min, m/z 276.2 [M+Na].
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH2:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:11]>C1COCC1>[CH2:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 215 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.339 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-ethylphenoxy)phenyl)pyridin-2-amine (312 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 hr. The mixture was quenched with water at 0° C. Water and EtOAc/THF were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and washed with IPE/EtOAc to give the title compound (295 mg) as a white solid. A part of this was recrystallized from THF/IPE.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:6][C:7]=1[C:8](OCC)=[O:9])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)sc1CC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution (100 mL) of ethyl 2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylate (5.18 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (721 mg) at 0° C., and the mixture was stirred for 1 hr. Water (720 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (3.60 mL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale-yellow oil. To a solution of the obtained oil in tetrahydrofuran (100 mL) was added activated manganese dioxide (24.6 g), and the mixture was stirred at room temperature overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (4.38 g, 98%) as a brown oil.