Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[C-:10]#[N:11].[K+].O>CS(C)=O>[C:10]([CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1ccnc(CCl)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(CC#N)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 1112.3 %

Procedure:
2-chloromethyl-4-methylpyridine (3.70 g, 2.17 mmol) was dissolved in dimethyl sulfoxide (9 ml) and herein potassium cyanide (1.70 g, 2.60 mmol) was added. After stirring for 17 hours at room temperature, water was added and it was extracted twice with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain the desired product (3.19 g, yield=95%).
Reaction SMILES: [H-].[Na+].[CH3:3][N-:4][CH3:5].[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=[O:12])[CH3:7].[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)(=[O:17])[CH3:16]>CN(C)C=O>[CH3:3][N-:4][CH3:5].[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=[O:12])[CH3:7].[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:17])[CH3:16]
Reactant: CC(=O)OCCCCCCCCCCCBr
Agent: CCOC(=O)CC(=O)O
Agent: C[N-]C
Agent: [H-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOC(C)=O
Temperature: 22 °C
Yield: 79.7 %

Procedure:
A suspension of 0.6 g of sodium hydride and 3 g of malonic acid ethyl ester dimethylamide in 30 ml of dimethylformamide is stirred for an hour at 22° C., mixed with 6.9 g of 1-acetoxy-11-bromoundecane and stirred for 16 hours at 50° C. Then the reaction mixture is stirred in 200 ml of ice water, extracted with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation in vacuum. Thus, 5.3 g of 11-acetoxyundecane malonic acid ethyl ester dimethylamide is obtained as light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClCCl.O=[Pt]=O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: C[C@H]1N[C@@H](c2ccccc2)COC1=O
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (35) (1.70 g, 9.0 mmol, 1.0 equiv.) in anhydrous dichloromethane (60 mL) under an atmosphere of nitrogen was added PtO2 (170 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by recrystallization from dichloromethane, diethyl ether and hexane to furnish the title compound as a colourless needles (1.26 g, 74%); m.p. 81.0-82.0° C. (lit. m.p. 81.0-82.0° C.); v(max)(KBr) 3314 (N—H), 2981 (C—H), 1736 (C═O), cm−1, δH (250 MHz, CDCl3) 7.43-7.26 (5H, m, Ph); 4.42-4.23 (3H, m, CHCH2), 3.88 (1H, q, /6.76 Hz, CHCH3), 1.80 (1H, br. NH), 1.50 (3H, d, J 6.76 Hz, CH3); δc (62.5 MHz, CDCl3) 170.7, 138.1, 129.3, 129.1, 127.5, 75.4, 58.2, 55.4, 19.0; m/z (CL, NH3), 192 (MH+, 30%), 147 (68%), 132 (64%), 104 (100%), and 91 (10%); HRMS for C11H13NO2 requires 192.1025 found 192.1019. [α]D20 +88.8 (c 0.96 CHCl3) (lit. [α]D20 +92.3 (c 0.84 CHCl3)).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide (Intermediate 10, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CCO.CO>[CH2:14]([O:16][C:17]1[C:20](=[O:21])[C:19](=[O:24])[C:18]=1[NH:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH3:15]
Reactant: CN(C)C(=O)c1cccc(N)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 g of 3-amino-2-hydroxy-N,N-dimethyl-benzamide are dissolved in 880 ml of EtOH. 46 g of 3,4-diethoxy-3-cyclobuten-1,2-dione and 4.4 g of K2CO3 are added and the reaction mixture obtained is stirred overnight at rt. Solvent is evaporated. A residue obtained is purified by column chromatography over 500 g of silica using CH2Cl2/MeOH 98/2 as eluent. The product-containing fractions are combined and solvent is evaporated. A residue obtained is suspended in 1 l of MeOH and filtered. This process is repeated a further 3 times. The title compound is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([C:13](OC)=[O:14])=[CH:10][CH:11]=3)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH2:13][OH:14])=[CH:10][CH:11]=3)[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(cnn2C2CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(cnn2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 1-cyclopropyl-1H-indazole-5-carboxylate (400 mg, 1.8 mmol, step-1 of Example 28) in THF (15 mL) was added LiAlH4 (70 mg, 1.8 mmol) at 0° C. The reaction mixture was stirred for 1 hr at room temperature, and quenched with saturated aqueous NH4Cl (20 mL). The mixture was diluted with DCM (80 mL), dried over Na2SO4, filtered through a pad of Celite (registered trademark) the filtrate was concentrated to give 386 mg (quant.) of the titled compound as pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[CH3:23].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.[NH4+].[Cl-].[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[C:15]([CH3:23])=[CH:16][C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:18][N:19]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Cc1cc(B(O)O)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 1-iodo-4-(trifluoromethoxy)benzene (288 mg, 1.0 mmol) and 6-chloro-5-methylpyridin-3-ylboronic acid (223 mg, 1.3 mmol) in DMF (2 mL) was added K2CO3 (552 mg, 4.0 mmol) and H2O (0.5 mL). The reaction mixture was stirred for 5 min under an atmosphere of dry N2. Pd(PPh3)4 (10 mg, 0.009 mmol) was added, and the resulting mixture was subjected to irradiation at 120° C. for 10 min. Cooled, diluted with EtOAc (20 mL), filtered through a layer of celite, washed with 10% DMF in EtOAc (50 mL), transferred to a separation funnel, organic phase was washed with 2N Na2CO3 (20 mL, 4.00 mmol), H2O (20 mL), 30% aqueous NH4Cl (50 mL) and brine (50 mL), and dried and concentrated. The crude mixture was subjected to preparative HPLC with a gradient MeCN/H2O (5% to 98%) containing 0.1% TFA to afford 2-chloro-3-methyl-5-(4-(trifluoromethoxy)phenyl)pyridine,
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].C(=O)(O)[O-].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:3]1[N:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH3:27])[C:6]([CH3:7])=[CH:5][CH:4]=1)=[O:16]
Reactant: Cc1ccc(C(=O)c2ccccc2Cl)n1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1c(C)ccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred slurry containing 1-amino-2-(2-chlorobenzoyl)-5-methylpyrrole (27.1 g, 0.115 mol) and sodium bicarbonate (16.8 g, 0.20 mol) in 300 ml of dichloromethane was added ethyl chloroformate (21.7 g, 0.20 mol) over 5 minutes. The reaction mixture was stirred at room temperature overnight and thereafter quenched with 500 ml of H2O. The organic layer was washed with brine, dried (MgSO4), charcoaled, filtered, and evaporated to an oil. This oil crystallized in hexane, which was recrystallized from ether-hexane to give 31.9 g (90%) of powder, m.p. 82°-84°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=O)=[N:3]1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: CN
Reactant: COC(=O)c1nn(C)c2ccccc12
Solvent: CO
Product: CNC(=O)c1nn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A suspension of methyl 1-methyl-1H-indazole-3-carboxylate (3.88 g, 20.4 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (5 mL) was stirred at RT for 4 hr, during which time a homogeneous solution formed. The solution was concentrated to approximately ⅓ volume and the precipitated solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.42 g. 89%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.24 (m, 1H), 7.47 (m, 2H), 7.34 (m, 1H), 6.95 (br s, 1H), 4.19 (s, 3H), 3.05 (d, J=12.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:22])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[N:11]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[C:10]=2[CH3:22])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Product: COC(=O)c1ccc2c(c1)c(Sc1ccc(Cl)cc1)c(C)n2CC(=O)OC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 11 part (ii) using the product of part (ii) and t-butylbromoacetate. The product was purified using flash column chromatography (14% EtOAc/hexane as eluent).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([CH2:21][CH2:22][Cl:23])[C:7]1=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)n1c(=O)[nH]c2cc(OC)ccc21
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(=O)n(CCCl)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-methoxy-2-oxo-2,3-dihydrobenzimidazole-1-carboxylic acid ethyl ester and 80% NaH (0.38 g; 0.013 mol) in anhydrous DMF was stirred 20 minutes at room temperature. Then 1-bromo-2-chloroethane (1.1 ml; 0.013 moles) was added and the solution was stirred overnight. After cooling, the reaction mixture was poured into water and the separated oil was extracted into ethyl acetate. The organic layer was dried over MgSO4 and evaporated under vacuum to give the crude title compound which was crystallized with diisopropyl ether. White solid. 1.35 g; m.p. 116-118° C.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6].COCCOCCOC>O>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+:2].[Na+:2].[Na+:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
An aqueous solution of sodium citrate was prepared by adding 38.8 gms. of sodium hydroxide to 620 gms. of water with stirring. When the sodium hydroxide dissolved, 880 gms. of anhydrous citric acid were added as stirring was continued. When the citric acid dissolved, 60 gms. of POLY-TERGENT SL-62 surfactant, 90 gms. of POLY-TERGENT SL-42 surfactant and 80 gms. of POLY-SOLV DPM glycol ether were added. An additional amount of 300 gms. of water containing 38.8 gm. sodium hydroxide was added. Stirring was continued until the mixture is homogeneous. The resulting formulation had a pH greater than 2.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10]CC=C)=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[CH:20]=CC=C[C:16]=1Cl>>[CH2:20]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[OH:10])[CH:15]=[CH2:16]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc2c(c1)OCO2
Product: C=CCc1cc2c(cc1O)OCO2
Yield: 92 %

Procedure:
A solution of allyl 3,4-(methylenedioxy)phenyl ether (2.4 g, 13 mmol), was dissolved in 30 ml of 1,2-dichlorobenzene and the solution was refluxed for 18 h. The solvent was removed under high vacuum in a water bath set at 60° C. The remaining oil was extracted into ether, washed with brine and dried over MgSO4. The solvent was removed under vacuum to give a yellow oil which was further purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes gave 2.2 g (92%) of the pure compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2]>[Pd](Cl)Cl.C(O)(=O)C>[C:1]([O:4][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])(=[O:3])[CH3:2]
Reactant: C=COC(C)=O
Agent: Cl[Pd]Cl
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 3 h
Yield: 2504.6 %

Procedure:
The procedure of Example 9 was repeated except that 0.451 g of palladium chloride was used in place of palladium supported on activated carbon and the reaction was effected for 3 hours. GC analysis showed that 1.51 g of vinyl acetate and 32.1 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.[OH-].[K+]>CCOCC>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3(O)CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.5 %

Procedure:
A mixture of (E)-N-methyl-2-(1H-indole-5-yl)ethenesulphonamide (2.0 g), 1-methyl-4-piperidone (1.62 g) and potassium hydroxide (0.7 g) in IMS (20 mL) was stirred at ambient temperature for 22 hr. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel. Eluting with dichloromethane/ethanol/ammonia (25:10:1) gave an oil which solidified on standing to a brown solid. Trituration with ether provided the product as a white powder (1.85 g, 64% of theory).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N:27]=[C:28]=[N:29][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11]/[C:10]/3=[N:29]\[C:28]#[N:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (240 mg, 0.804 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 608.6 mg, 3.2 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (380.6 mg, 3.12 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (20 mg, 10%), which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:26]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:26]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Reaction of 5-chloro-3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][CH2:15][CH2:16][C:17](O)=[O:18].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][O:14][CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCC(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-methoxypropanoic acid (204.2 μL, 2.174 mmol) and triethylamine (605.9 μL, 4.347 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (202.7 mg, 2.174 mmol). The mixture was stirred at room temperature for 24 hours. 2M LiOH.H2O in water (3 mL) was then added and stirred for 30 minutes. The precipitate formed was filtered, washed with CH2Cl2 (3×2 mL), and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (115 mg, 42% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.05 (br s, 1H), 9.55 (s, 1H), 8.34 (d, 1H), 7.63 (s, 1H), 3.63 (t, 2H), 3.26 (s, 3H), 2.58 (t, 2H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.57 minutes (Method 2).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97 %

Procedure:
To an ice-cooled solution of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate and imidazole (2 eq.) in DMF (0.4 M), chloro(triisopropyl)silane (2 eq.) was added dropwise. The mixture was stirred at RT for 7 h, diluted with EtOAc, washed with sat. aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 6:1). After evaporation of the solvents the product was obtained as colourless oil (97%). MS (ES−): 519.7 (M−H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1ccoc1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and furane