Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28].N1CCCCC1>C(O)C>[OH:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32](/[CH:35]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:31][C:30]=1[CH3:37])=[O:28]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCO
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCO

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (150 mg, 0.42 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-ethyl)-amide (88 mg, 1 eq. 0 and piperidine (18 mg, 0.5 eq.) in ethanol (2 mL) was stirred at rt for 5 days. The reaction was concentrated and triturated with ethanol to give the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](Cl)=[C:18]([C:20]#[N:21])[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([F:26])[CH:28]=3)=[C:18]([C:20]#[N:21])[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(C#N)c(Cl)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2c(C#N)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(C)c2=O)cc1F
Temperature: 145 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A mixture of [1-(5-chloro-4-cyano-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (200 mg, 0.54 mmol), 3-fluoro-4-methoxybenzeneboronic acid (278 mg, 1.63 mmol), Pd(dppf)2Cl2 (119 mg, 0.16 mmol), and Na2CO3 (173 mg, 1.63 mmol) in dioxane (5 mL) and H2O (1 mL) was degassed with N2 and stirred at 145° C. in the microwave for 2 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo and the residue purified by preperative HPLC to give 110 mg of the desired product (45%). [M+H] Calc'd for C23H28FN5O4, 458. Found, 458.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.OO.[OH-:32].[Na+]>CS(C)=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]([NH2:19])=[O:32])=[N:16][CH:17]=1
Reactant: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C(N)=O)c1
Reaction time: 16 h

Procedure:
To a solution of 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile TFA salt (166 mg, 0.404 mmol) in DMSO (3 ml) were added hydrogen peroxide (35% aqueous solution, 0.053 ml, 0.61 mmol) and sodium hydroxide (4.0 M aqueous solution, 0.32 mL, 1.3 mmol) at 20° C. After 16 hour, the reaction mixture was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA) to give 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 3.72-3.49 (m, 1H), 3.52-3.33 (m, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 1.39 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH3:28].O>CN(C=O)C>[CH2:27]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[CH3:28]
Reactant: CCI
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.42 mmol) was dissolved in DMF (3 mL) and K2CO3 (220 mg, 1.6 mmol) and ethyl iodide (37 μL, 0.46 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 290.1, found 290.2.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][CH2:14][CH2:13]2.C(N(CC)CC)C.ClCCl>O>[F:1][C:2]([F:8])([F:7])[S:3]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][CH2:14][CH2:13]2)(=[O:5])=[O:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1NCCc2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1NCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonyl chloride (1.0 ml) was added dropwise to a mixture of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1.52 g), triethylamine (1.3 ml) and dichloromethane (5 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 50:50), and the solvent was evaporated under reduced pressure to obtain, as a colorless powdery solid, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.56 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
To a solution of 4-fluoro-2-hydroxy-benzaldehyde (560 mg, 4 mmol) in DMF (10 ml) were added benzyl chloride (0.5 ml, 4.33 mmol), and K2CO3 (860 mg, 6.22 mmol). After heating at reflux for an hour, the reaction mixture was allowed to cool to room temperature and was poured into a mixture of EtOAc/H2O. The organic layer was separated, washed with H2O and dried over MgSO4. The resulting oil was purified by flash chromatography to give 2-benzyloxy-4-fluoro-benzaldehyde as pale oil (628 mg, 68%), 1H NMR (CDCl3, 300 MHz) δ: 5.17 (s, 2H), 6.74 (m, 2H), 7.36 (m, 5H), 7.88 (m, 1H), 10.51 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:22]1([P:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1.0 mole of n-butyllithium in hexane at -78° C under an inert atmosphere is added dropwise and with efficient stirring 236g of p-dibromobenzene in dry tetrahydrofuran (total volume 500 ml). The resulting solution is stirred at -78° C for 1 hour, then treated dropwise at this temperature with 220.5g of chlorodiphenylphosphine. When this addition is complete, the mixture is allowed to warm to room temperature, then solvent is removed under vacuum. The residue is triturated with two 400-ml portions of methanol, then distilled through a Vigreux column. The cut with bp 165°-170° C (0.15 mm) is recrystallized from ethanol to give 100.5g of p-diphenylphosphinobromobenzene, mp 78°-80° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6](C(C(O)=O)C)[C:5]1=[O:17])=[N+]=[N-].NC1CCCCCNC1=O.C(O)(=O)C.O=[C:33]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(O)C.[Pd]>[CH2:37]([O:36][C:34]([CH:33]([NH:1][CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C(=O)O)N1CCCCCC(N=[N+]=[N-])C1=O
Agent: [Pd]
Agent: NC1CCCCCNC1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCCNC1=O

Procedure:
Reduce 3-azidoperhydroazocin-2-one (Example 3) to 3-aminoperhydroazocin-2-one using 10% Pd/C in ethanol. NMR (CDCl3, TMS): δ 1.67 (broad s, 8H), δ 2.25 (broad s, 2H), δ 3.35 (m, 2H), δ 3.8 (m, 1H), δ 7.0 (broad, 1H). Hydrogenate a solution of 1.42 g of this amine, 0.59 g acetic acid and 3.09 g ethyl 2-oxo-4-phenylbutyrate in 50 ml ethanol over 10% Pd/C catalyst. AFter filtration and concentration of the reaction, purify the product by chromatography over silica gel to isolate 3-[(1-ethoxycarbonyl-3-phenyl-1-propyl)amino]perhydroazocin-2-one.
Reaction SMILES: Cl.NC1C(Cl)=CC=CC=1C.C(C1C(N)=CC=CC=1C)=O.Cl.NC1C=CC(Cl)=CC=1C.[CH:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37](Cl)=[CH:36][C:35]=1[CH3:41])=[O:32]>>[CH:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[O:32]
Reactant: Cc1cc(Cl)ccc1NC=O
Agent: Cc1cc(Cl)ccc1N
Agent: Cc1cccc(Cl)c1N
Agent: Cc1cccc(N)c1C=O
Product: Cc1ccccc1NC=O

Procedure:
An improved process for the production of 2-amino-chlorotoluene hydrochloride comprising chlorination of 2-formyl-amino-toluene, splitting off the formyl group of the 2-formyl-amino-chlorotoluenes and isolation of crystalline 2-amino-5-chlorotoluene hydrochloride is disclosed, in which process the 2-formylamino-5-chlorotoluene formed by chlorination of 2-formylamino-toluene in an inert solvent is reacted with methanol to form 2-amino-5-chlorotoluene and methyl formate, and the 2-amino-5-chlorotoluene is isolated as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>CS(C)=O.CCOC(C)=O>[CH3:22][C:21]1[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cccnc1Oc1ccc(N)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-aminophenol (0.87 g, 8.0 mmol) in DMSO (12 mL) was added cesium carbonate (3.1 g, 9.6 mmol) and 2-fluoro-3-picoline (0.89 g, 8.0 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide 4-(3-methylpyridin-2-yloxy)benzenamine as tan solid. MS (ESI, pos. ion) m/z: 201.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:23][CH2:22][CH2:21]1>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: O=C1C(Br)CCCC1c1cc(F)ccc1F
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(F)ccc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (63 mg, 0.24 mmol) and of crude 6-bromo-2-(2,5-difluoro-phenyl)-cyclohexanone (73 mg, 0.25 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (53 mg, 49%) as an off-white solid. MS ISP (m/e): 453.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.88 (s, 1H), 7.50 (s, 1H), 7.09 (d, 1H), 6.99 (m, 1H), 6.80-6.88 (m, 2H), 6.75 (d, 1H), 6.67 (m, 1H), 4.35 (m, 1H), 3.59 (s, 3H), 2.76 (m, 2H), 2.37 (s, 3H), 2.22 (m, 1H), 1.70-1.98 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[ClH:17]>C(C(C)=O)C(C)C.O>[Cl:17][CH:12]([CH2:11][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)=[O:16])[C:13]([OH:15])=[O:14]
Reactant: Cl
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1c(Cl)cc(C(=O)CC(Cl)C(=O)O)cc1Cl
Yield: 100 %

Procedure:
A suspension of 5.18 g (0.02 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, prepared as described in Example 1(b), in 50 ml of methyl isobutyl ketone was saturated with dry hydrogen chloride gas, by blowing the gas through the suspension whilst ice-cooling and stirring it. The mixture was then stirred at room temperature for a further 1 hour, after which it was diluted with 30 ml of cold water and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous sodium sulphate, after which the solvent was distilled off and the residue was washed with a small amount of hexane and then dried, giving 5.91 g (yield 100%) of the desired 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid, melting at 129°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.O>C(OCC)(=O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
76.6 mg (0.50 mmol) of 1-methoxy-4-nitrobenzene (10), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 48.2 mg (0.39 mmol) of 4-amino-1-methoxybenzene (11). The yield was 78%. The reaction is expressed by the following scheme.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate (1.2 g, 3.4 mmol) and 3.75 M sodium hydroxide in water (10 mL, 38 mmol) in methanol (10 mL) was stirred at room temperature overnight. The mixture was neutralized with HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was used directly in next step (704 mg, 61%). LCMS calculated for C17H15ClFO4 (M+H)+: m/z=337.1. found: 337.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:11])[C:3]=12.[H-].[Na+].[CH3:14][CH:15]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:14])[CH:9]=[C:10]([I:11])[C:3]=12
Reactant: Clc1ccnc2[nH]cc(I)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(Cl)ccnc21
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (5.00 g, 17.9 mmol, US 2006128661 Example 1) in DMF (50 mL) was treated with 60 wt % NaH (0.790 g, 19.7 mmol) then stirred for about 15 min. The TIPSCl (4.18 mL, 19.8 mmol) was then added to the mixture and the mixture was stirred for about 30 min. The solvents were evaporated under reduced pressure then the material was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). The layers were separated then the aqueous layer was extracted with EtOAc (25 mL). The combined organics were washed with water (25 mL) then brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 120 g silica column and eluting with heptane to give 4-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.34 g, 68%): LC/MS (Table 2, Method g) Rt=2.58 min; MS m/z 435 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:18]=[O:19]
Reactant: Cc1cc(F)cc(F)c1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(F)c(C=O)c(F)c1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of 1,3-difluoro-5-methylbenzene (10.2 g, 80 mmol) in anhydrous ether (80 mL) was added n-BuLi (2.5 M solution in hexane, 48 ml, 120 mmol) over a 20 min period while the internal temperature was maintained at around −50° C. After stirring at that temperature for 1.5 hr, DMF (14.6 g, 200 mmol) was added over a 20 min period. After stirring at the same temperature for an additional 1.5 h, the reaction mixture was slowly poured into 1N aqueous sulfuric acid (300 mL) and extracted with ether three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give the title compound (11.2 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 10.25 (s, 1H), 6.75 (d, 2H, J=9.9 Hz), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:15])=[CH:10]2)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([Cl:24])[C:22]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:22]1[C:21]([Cl:24])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[Cl:16])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cc(O)cnc12
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cnc12
Temperature: 25 °C

Procedure:
To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (97) (256 mg, 1.26 mmol) and 3,4,5-trichloronitrobenzene (294 mg, 1.30 mmol) in acetone (40 mL) was added K2CO3 (870 mg, 6.30 mmol). This mixture was refluxed for 3.5 h. The reaction mixture was cooled to room temperature and insoluble materials were removed by Celite filtration. The filtrate was concentrated and the residue was purified by column chromatography. (hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 98. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (3H, s), 7.67 (1H, dd, J=7.3 Hz), 7.79 (1H, d, J=2.9 Hz), 7.88 (1H, dd, J=1.5, 7.3 Hz), 9.05 (1H, d, J=2.9 Hz).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:44])[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O:47][C:48]([CH3:50])=[CH2:49]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([OH:44])[CH2:49][C:48](=[O:47])[CH3:50])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)O[Si](C)(C)C
Reactant: CC(C)(C)[Si](OCCCC(=O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)CC(O)(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.17 h
Yield: 10.3 %

Procedure:
A solution of 50 (160 mg, 0.257 mmol) in anhydrous CH2Cl2 (0.3 mL) was cooled in an ice bath under argon for 10 min. TiCl4 (25 μL) was added, and the resulting mixture was stirred for 10 min. 2-(Trimethylsilyloxy)prop-1-ene (33.4 mg, 0.257 mmol, 0.43 μL) was added. Stirring was continued for 20 min. The reaction mixture was diluted with ice-cold water. CH2Cl2 was added, and the phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4). Concentration of the sample under reduced pressure yielded a pale yellow oil, which was purified by column chromatography [silica, hexanes/ethyl acetate (10:1→3:1)] affording a colorless oil (18 mg, 10%): 1H NMR δ 1.04 (s, 18H), 1.85-1.89 (m, 4H), 2.18 (s, 3H), 2.61 (s, 2H), 3.65 (m, 4H), 7.37-6.42 (m, 12H), 7.65-7.67 (m, 8H).
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:21][NH2:22]>C(O)C>[NH:9]1[CH:10]=[C:6]([CH2:5][C:4]([NH:21][NH2:22])=[O:3])[N:7]=[CH:8]1
Reactant: NN
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NNC(=O)Cc1c[nH]cn1
Temperature: 70 °C

Procedure:
To a solution of 4-imidazoleacetic acid methyl ester hydrochloride (3.95 g, 22.4 mmol) in ethanol (150 ml) is added N,N-diisopropylethylamine (2.90 g, 16.6 mmol) and hydrazine (1.79 g, 36 mmol). The solution is refluxed at 70° C. overnight. The solution is concentrated and recrystallized from methanol to give 4-imidazoleacetic acid hydrazide as a white solid. The yield is 2.46 g, 78%.