Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[O:18]1CCCC1>C(O)(=O)C.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:17]=[O:18])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a mixture of 7 g 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL each of tetrahydrofuran (THF), acetic acid (AcOH) and water at −10° C. was added 70 g of ceric ammonium nitrate in portion over 20 minutes, the reaction temperature being maintained at about 5° C. The resulting mixture was them cooled to 0° C., stirred for another 2 hr and then diluted with 250 mL of brine. The mixture was then extracted with 2×300 mL 10% MeOH in dichloromethane (DCM). The organic extracts were combined and dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The residue was purified on silica gel column with hexanes(hex)/ethyl acetate (EtOAc)/AcOH (6:4:0.05) followed by crystallization in EtOAc to give 1.5 g of 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)CCC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
2-Ethoxycarbonyl-2-phenylpentanedioic acid diethyl ester (670 mg) was dissolved in THF (2 mL) and EtOH (2 mL), and thereto was added 1N sodium hydroxide (2 mL). The solution was stirred at room temperature for 1 hour and concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and concentrated to give 2-ethoxycarbonyl-2-phenylpentanedioic acid 1-ethyl ester (517 mg).
Reaction SMILES: CC([O-])(C)C.[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[C:14]1[CH:15]=[C:16]2[N:25]([CH3:26])[CH:24]=[CH:23][C:17]2=[N:18][C:19]=1[C@@H:20]([NH2:22])[CH3:21]>CC1CCCO1.C1(C)C=CC=CC=1>[CH3:26][N:25]1[C:16]2[C:17](=[N:18][C:19]([C@@H:20]([NH2:22])[CH3:21])=[C:14]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH:15]=2)[CH:23]=[CH:24]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 92.5 °C
Yield: 5.2 %

Procedure:
To a 100-mL three-neck round bottom flask equipped with an overhead stirrer, thermocouple, and condenser with gas inlet for nitrogen, was charged with KOt-Bu (95%, 8.3 g, 70.40 mmol, 4.0 eq) and 2-methyltetrahydrofuran (36 mL) followed by morpholine (18.5 mL, 210.6 mmol, 12.0 eq). The mixture was heated to 90-95° C. and then a solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (4.46 g, 210.6 mmol) in 2-methyltetrahydrofuran (9 mL) was added dropwise via a syringe pump over a period of one hour. Following addition of the amine, the transfer vessel was rinsed with 2-methyltetrahydrofuran (5 mL). The rinse was added to the reaction mixture, which was stirred at reflux for one hour. HPLC analysis indicated the reaction was complete. The slurry was then cooled to 60° C. and water (15 mL) was added, which dissolved the solids. The organic and aqueous phases were separated at 40-50° C. The aqueous phase was extracted with 2-methyltetrahydrofuran (20 mL) at 50° C. The organic layers were combined and concentrated under reduced pressure to afford crude product (9.0 g) which contained residual morpholine. The crude product was heated in hot toluene (30 mL). Some undissolved solids remained and the hot solution was decanted into a clean receiver. The toluene solution was cooled, resulting in crystallization of solids. The solution was further cooled in a refrigerator at 2-8° C. for one hour. The solids were filtered, washed with toluene (10 mL), and dried to afford the title compound as a tan solid (2.85 g).
Reaction SMILES: [CH3:1][Si:2]([CH2:5]Cl)([CH3:4])[CH3:3].[Mg].[CH3:8][N:9]([CH3:28])[CH2:10][CH2:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1.[Cl-].[NH4+]>CCOCC>[CH3:28][N:9]([CH3:8])[CH2:10][CH2:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])([OH:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1
Reactant: CN(C)CCC1Cc2ccccc2C(=O)c2ccccc21
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)CCC1Cc2ccccc2C(O)(C[Si](C)(C)C)c2ccccc21

Procedure:
A Grignard reagent is prepared by conventional techniques from 12.2 g. (0.1 mole) trimethylsilylmethyl chloride and 24.3 g. magnesium metal (0.1 atom) and 200 ml. ether. The resulting solution is treated with 27.9 g. (0.1 mole) of 10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 100 ml. ether. Stirring is initiated and the mixture is heated at reflux for 5 hours, then cooled in ice and hydrolyzed with 150 ml. of saturated ammonium chloride. The layers are separated and the ether dried over anhydrous magnesium sulfate and evaporated to give 10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:17][F:18]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:17][F:18])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: FCCl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FCOc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a tared, sealed 350 mL round-bottomed pressure flask containing a suspension of 3,5-dibromophenol (10.0 g, 39.7 mmol; see step (ii) above) and Cs2CO3 (20.7 g, 63.5 mmol) in DMF (150 mL) at −78° C. was added chlorofluoromethane via bubbling for 5 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 9.0 g (131 mmol) of chlorofluoromethane. The solution was heated in an oil bath set at 70° C. overnight. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with water (100 mL). The aqueous layer was extracted with Et2O (3×200 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (7.9 g, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([OH:15])[C:8]=3[C:6]=2[CH:7]=1.[Br:16]Br.O>CC(O)=O>[Br:16][C:12]1[C:13]2[S:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[C:8]=2[C:9]([OH:15])=[N:10][CH:11]=1
Reactant: Oc1nccc2sc3ccc(Cl)cc3c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1ncc(Br)c2sc3ccc(Cl)cc3c12
Temperature: 120 °C

Procedure:
To 8-chloro[1]benzothieno[3,2-c]pyridine-1-ol in AcOH (0.3 M) was added Br2 (1.1 equiv). The resulting mixture was heated at 120° C. for 1 h, cooled to room temperature, poured into H2O and filtered. The solid was suspended in acetone, sonicated and filtered to provide the title compound.
Reaction SMILES: [C:1]([C:9]1[C:17]2[O:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([Br:20])[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([C:9]1[C:17]2[O:16][CH2:15][C:14]([CH3:18])([CH3:19])[C:13]=2[CH:12]=[C:11]([Br:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COc2c(C(=O)c3ccccc3)cc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)COc2c(Cc3ccccc3)cc(Br)cc21

Procedure:
Following General Procedure J and using 7-benzoyl-5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (Intermediate 38, 2.15 g, 6.53 mmol), anhydrous dichloromethane (10 mL), trifluoroacetic acid (4.12 mL, 53.5 mmol) and triethyl silane (8.4 mL, 52 mmol) followed by flash column chromatography, the title compound was obtained (1.57 g, 76%). 1H NMR (300 MHz, CDCl3): δ 7.23-7.14 (m, 5H), 7.02 (d, 1H, J=1.9 Hz), 6.97 (d, 1H, J=1.9 Hz), 4.17 (s, 2H), 3.85 (s, 2H), 1.36 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:4]=1[F:11].FC1C=C(C)C=C(F)C=1>>[F:10][C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([CH3:2])[C:4]=1[F:11]
Reactant: Fc1cc(F)c(F)c(CBr)c1
Agent: Cc1cc(F)cc(F)c1
Product: Cc1cc(F)cc(F)c1F

Procedure:
The title compound was prepared from 1-bromomethyl-2,3,5-trifluoro-benzene by a procedure analogous to that for 3,5-difluorotoluene, above. 1H NMR (400 MHz, CDCl3) δ ppm; MS (APCI, m/z): [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH:30](O)[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][CH:30]3[CH2:31][CH2:32][N:28]([CH3:27])[CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C)C1
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Diethyl azodicarboxylate (793 mg, 4.56 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (800 mg, 3.80 mmol), 1-methylpyrrolidin-3-ol (422 mg, 4.18 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) in dichloromethane (16 ml). The reaction mixture was stirred for 1 hour and then a further portion of diethyl azodicarboxylate (360 ul) and triphenylphosphine (0.65 mg) were added. The mixture was stirred for 1 hour and the resulting orange solution was purified directly by silica gel chromatography eluting with a 0-10% mixture of methanol in dichloromethane to 4-chloro-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline (330 mg, 28% yield) as a tan coloured solid:
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([OH:25])=[O:24].C=O>C1COCC1>[Cl:19][C:20]1[C:21]2[CH2:1][O:24][C:23](=[O:25])[C:22]=2[CH:26]=[CH:27][N:28]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: C=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OCc2c1ccnc2Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (4.05 ml, 24 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (8.8 mL of a 2.5 M solution in hexanes, 22 mmol) and the reaction is let stir at −50° C. for 0.5 h. Solid 2-chloro-isonicotinic acid, (1.58 g, 10 mmol) is added as a solid to the reaction mixture at −50° C. The reaction is stirred at −50° C. for 0.5 h. The reaction mixture is treated with paraformaldehyde (7 equivalents) dropwise at −50° C. The reaction is stirred at −50° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until the pH of aqueous layer is ˜5 and is then extracted with ether (2×40 mL). The aqueous solution is treated with aqueous 1N HCl solution until the pH ˜2. An oily residue separated which from solution is collected to give the title compound as a yellow oil (0.62 g, 36%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]=[CH2:6])[CH3:2].C12BC(CCC1)CCC2.O1CCCC1.Br[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH2:6][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2)[CH3:2]
Reactant: C=CC(OCC)OCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CCc1ccc2ncccc2c1)OCC
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
3,3-Diethoxy-1-propene (548 g, 4.2 mol, 1.75 equiv) was added to a 22 L flask charged with 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (9-BBN solution in THF, 8.4 L, 4.2 mol, 1.75 equiv) at room temperature (the internal temperature raised to 40° C.) over 1 h. The resulting reaction mixture was stirred at room temperature for overnight. At which time 1H NMR of an aliquot of the reaction mixture indicated that all the 3,3-diethoxy-1-propene had been consumed. 6-Bromoquinoline (8, 500 g, 2.4 mol, 1.0 equiv), potassium carbonate (K2CO3, 662 g, 4.8 mol, 2.0 equiv), tricyclohexylphosphine (67.4 g, 0.24 mol, 0.1 equiv), palladium acetate (Pd(OAc)2, 27 g, 0.12 mol, 0.05 equiv) and water (90 mL) were added to the reaction mixture in that order followed by degassing with nitrogen for 0.5 h. The reaction mixture was then heated to reflux for 4 h. Once TLC and LC/MS showed that the starting material had been consumed, the reaction mixture was cooled to room temperature with stirring before being quenched with water (7.5 L) and ethyl acetate (EtOAc, 7.5 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 4 L). The combined organic layers were washed with a saturated brine solution (NaCl, 4 L), dried over magnesium sulfate (MgSO4) and concentrated under the reduced pressure. The residue was purified by column chromatography (SiO2, 10-60% of ethyl acetate in heptane gradient elution) to afford 6-(3,3-diethoxypropyl)quinoline (23, 520 g, 622.4 g theoretical, 83.5% yield) as a colorless oil. For 23: 1HNMR (DMSO-d6, 300 MHz) δ ppm 8.81 (dd, 1H, J=4.23 Hz, 1.73 Hz), 8.28 (d, 1H, J=8.07 Hz), 7.91 (d, 1H, J=8.62 Hz), 7.75 (s, 1H), 7.61 (dd, 1H, J=8.63 Hz, 1.92 Hz), 7.46 (dd, 1H, J=8.25 Hz, 4.22 Hz), 4.46 (t, 1H, J=5.60 Hz), 3.61-3.38 (m, 4H), 2.79 (t, 2H, J=8.53 Hz), 1.95-1.85 (m, 2H), 1.11 (t, 6H, J=6.84 Hz); C16H21NO2 (MW 259.34), LCMS (EI) m/e 260.2 (M++H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(C)C(O)c1ccc(Br)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C(c1ccc(Br)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
To a flame-dried flask containing a near-solution of 324 mg of 4-hydroxycoumarin and 573 mg of 1-(4-bromophenyl)-2-methylpropan-1-ol of Preparation 14 in 10 mL of dioxane under an argon atmosphere is added 1.2 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 50% to 60% ethyl acetate in hexanes to yield 28 mg of the title product as a tan solid.
Reaction SMILES: CSC.B.[N:5]1[S:9][N:8]=[C:7]2[CH:10]=[C:11]([CH2:14][C:15](O)=[O:16])[CH:12]=[CH:13][C:6]=12.CO>O1CCCC1.C(OCC)(=O)C>[N:5]1[S:9][N:8]=[C:7]2[CH:10]=[C:11]([CH2:14][CH2:15][OH:16])[CH:12]=[CH:13][C:6]=12
Reactant: O=C(O)Cc1ccc2nsnc2c1
Agent: B
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CSC
Product: OCCc1ccc2nsnc2c1
Temperature: 10 °C
Reaction time: 1.25 h
Yield: 71.3 %

Procedure:
Borane methylsulfide (1.6 ml) was added dropwise to a cold solution (8–10° C.) of crude benzo[1,2,5]thiadiazol-5-yl-acetic acid (b) (2.8 g, 14 mmol) in tetrahydrofuran (20 ml). Stirring was continued for 1.25 hours while maintaining the temperature below 30° C. The mixture was cooled to 10° C. then methanol was added (1.4 ml) and the mixture was left 15 hours in the refrigerator. The mixture was diluted with ethyl acetate, washed with water then with a saturated aqueous solution of sodium hydrogencarbonate and again with water. The organic phase was separated, dried over magnesium sulfate and evaporated. The residue was triturated in pentane, collected by filtration and dried to give crude 2-benzo[1,2,5]thiadiazol-5-yl-ethanol (1.8 g, 71%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][N:45]=[CH:44]2)=[NH:40]>CN(C=O)C>[NH:46]1[C:47]2[C:43](=[CH:42][C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:49][CH:48]=2)[CH:44]=[N:45]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (1.52 g), EDAC (2.14 g) and HOBt (1.51 g) were dissolved in DMF (30 ml) and then stirred for 5 minutes. N-hydroxy-1H-indazole-5-carboximidamide (D2) (1.3 g) was added and the reaction was heated to 80° C. for 6 hours and left to cool overnight. The solvent was removed in vacuo and the crude was partitioned between EtOAc and aq. sodium bicarbonate. The organic layer was separated, dried and evaporated to dryness in vacuo. The resulting solid was triturated with ether and ethyl acetate, washed with methanol and ether to give the title compound (816 mg) as a pink solid. MS (ES): C19H15N5O2 requires 345; found (MH+) 346
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([O:11][CH3:12])=[CH:7][C:8]=1[CH2:9]Cl.[OH-].[Na+].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH2:17]([N:24]1[CH2:9][C:8]2[C:3](=[CH:4][C:5]([O:13][CH3:14])=[C:6]([O:11][CH3:12])[CH:7]=2)[CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CN(Cc1ccccc1)C2
Reaction time: 20 h

Procedure:
2.35 g (10 mmol) of 4,5-bis(chloromethyl)veratrol was added at room temperature to a suspension comprising 5 ml of a 50% sodium hydroxide aqueous solution, 25 ml of toluene, 1.25 g (11.66 mmol) of benzylamine and 0.2 g of Starks catalyst (a 90% aqueous solution), and the mixture was stirred for 20 hours. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crystal residue was washed with diisopropyl ether to obtain 1.87 g of the above identified compound as colorless needle crystals.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Li+]>C1COCC1.CO.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1854.3 %

Procedure:
A solution of methyl 3-(2-cyanopropan-2-yl)benzoate 2 (72 g, 5.9 mmol) in THF (900 mL), MeOH (300 mL) and water 300 (mL) was treated with lithium hydroxide (47.6 g, 1.13 mol). The mixture was stirred overnight at rt. Concentrated to ±300 mL in vacuo and the resulting solution was acidified with 1N HCl solution. The resulting white precipitate was collected, washed with water and dried. Purification by column chromatography (5% methanol in CH2Cl2) gave pure 3-(2-cyanopropan-2-yl)benzoic acid 3 (20.7 g, 31%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), (t, J=7.5 Hz, 1H), 7.80 (m, 1H), 8.09 (m, 1H), 8.20 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 41.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0295 g, 0.0639 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.383 mmol) and 4-chlorobenzenesulfonyl chloride (0.0400 g, 0.192 mmol) to obtain 4-(4-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0167 g, yield 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26]([CH3:27])=[CH:25][C:24]([NH2:28])=[N:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26]([CH3:27])=[CH:25][C:24]([NH:28][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N)nn1Cc1ccc(F)cc1
Product: COc1cc(Nc2cc(C)n(Cc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-fluoro-benzyl)-5-methyl-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow oil (Yield=41%). MS ISP (m/e): 392.2 (100) [(M+H)+].