Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].C(#N)C.C(N(CC)CC)C.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](OC2C=CC=CC=2)=[N:46][C:47]#[N:48])=[CH:40][CH:39]=1>>[C:47](/[N:46]=[C:45](\[O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)/[N:20]1[CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:27])[CH2:10][CH2:11]2)=[O:16])[C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]1)#[N:48]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 85 °C

Procedure:
To a stirred solution of methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (386.500 mg, 1.04334E-3 mol) in anhydrous acetonitrile (6.000 mL, 0.1149 mol) at rt was added triethylamine (0.2923 mL, 0.002087 mol) and diphenyl cyanocarbonimidate (384.4 mg, 0.001565 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product (60% in yield). MS (ESI): (M+H)+=515.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
step b To a solution of 120 (4.29 g, 18.40 mmol) in MeOH (50 mL) and toluene (75 mL) was added dropwise trimethylsilyldiazomethane (15.64 mL, 31.3 mmol) until the yellow color persisted. The resulting solution was stirred for 30 min then the reaction was quenched with several drops of HOAc until the yellow color disappeared. The solvents were evaporated to afford methyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (122) which was used in the next reaction without further purification.
Reaction SMILES: [Cl-].[C:2]1([I+:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:15](OC)([O:19][CH3:20])([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][PH:15](=[O:16])[O:19][CH3:20].[C:9]1([I+:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COP(=O)(OC)OC
Agent: [Cl-]
Agent: c1ccc([I+]c2ccccc2)cc1
Product: CO[PH](=O)OC

Procedure:
Diphenyliodonium chloride (315 mg; 1 mmol) and trimethyl phosphate (1 g) were stirred at 170° C. for 10 minutes. After the reactants were dissolved, the mixture was cooled, to thereby yield solid matter. The solid matter was washed with ether, to thereby yield 250 mg of the target compound as white crystals (yield: 81.6%). The anion content of the resultant compound was determined by ion chromatography. The chloride anion content was determined to be not greater than 10 ppm.
Reaction SMILES: CO[C:3]1C=C(C)[C:6](CC2OC(C(OC)=O)=CC=2)=[C:5]([CH3:20])[CH:4]=1.[CH3:21][O:22][C:23]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[C:24]=1[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:27]=1.ClCC=C(C)C.CC(C)([O-])C.[K+].CC1C=C(OCCC(C)=C)C=C(C)C=1CC1OC(C(OC)=O)=CC=1>O.CS(C)=O>[CH3:40][C:35]1[CH:36]=[C:37]([CH3:39])[CH:38]=[C:23]([O:22][CH2:21][CH2:3][CH2:4][C:5]([CH3:20])=[CH2:6])[C:24]=1[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(Cc2c(C)cc(OC)cc2C)o1
Reactant: COC(=O)c1ccc(Cc2c(C)cc(C)cc2OC)o1
Agent: C=C(C)CCOc1cc(C)c(Cc2ccc(C(=O)OC)o2)c(C)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)=CCCl
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)CCCOc1cc(C)cc(C)c1Cc1ccc(C(=O)OC)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
In a 500-mL round-bottom flask, a mixture of methyl 5-(4-methoxy-2,6-dimethylbenzyl)-2-furoate (202) and methyl 5-(2-methoxy-4,6-dimethylbenzyl)-2-furoate (203) (4.52 g, 17.38 mmol) and anhydrous DMSO (50 mL) were placed. To this solution, 1-chloro-3-methylbut-2-ene (1.91 g, 18.25 mmol) and potassium tert-butoxide (2.25 g, 20.07 mmol) were added. The reaction mixture was placed under nitrogen and stirred at room temperature for 3 hours. The reaction mixture was poured into, water and extracted with ethyl acetate. The separated organic layer-was washed with water (2×) and brine and dried over MgSO4 then concentrated to yield a mixture of methyl 5-{2,6-dimethyl-4-[(3-methylbut-3-enyl)oxy]benzyl}-2-furoate (204) and methyl 5-{2,4-dimethyl-6-[(4-methylpent-4-enyl)oxy]benzyl}-2-furoate (205) (3.64 g, 64% yield).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[CH:9]([CH:13](OC)OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC(C)C
Reactant: COC(OC)C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.6 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 22.8 g (0.108 mol) of 3-bromo-4,4-dimethoxy-2-butanone and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 20 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 9.63 g (yield: 54%) of 5-acetyl-1-isopropyl-2-methylimidazol as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39]#[CH:40].CCO>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][S:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCSc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CSc3ccccc3)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and Cu (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and phenyl propargyl sulfide (0.082 mL). The reaction is stirred at room temperature for 7 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous. phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 3% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.12 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 1% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.16 g of the title compound as light tan product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[CH:19](O)[CH2:20]CC2C=CC=CC=2)[CH2:14][CH2:13]1.[C:31]1(CCC(O)=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C=CC=CC=1[C@@H](CC)C(O)=O>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[CH2:19][CH2:20][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)CCc1ccccc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)C(O)CCc2ccccc2)CC1
Agent: CC[C@@H](C(=O)O)c1ccccc1O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)CCc2ccccc2)CC1

Procedure:
Compound 12 was prepared in the manner of compound 7 substituting 3-phenylpropanoic acid for (R)-2-hydroxy-phenylbutyric acid in part C to afford compound 12: Mass spectrum (M+1)=380.40.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:32][CH2:31][CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=CCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CCCN)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 5, Step C, 0.118 g, 0.5 mmol) and N,N-diisopropylethylamine (0.071 g, 0.55 mmol) in 10 mL MeOH was stirred at room temperature for 30 minutes and 3-(3-chloro-phenyl)-propionaldehyde (from Preparation 3, 0.093 g, 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0° C., NaBH4 (30.3 mg, 0.801 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with 1:1 NaHCO3:H2O and was washed with CH2Cl2. The CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (171 mg). MS 352 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([N:24]([CH2:29][CH2:30][O:31]C)[CH2:25][CH2:26][O:27]C)(=[O:23])=[O:22].[Br-].[Al+3].[Br-].[Br-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([N:24]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:26][OH:27])(=[O:23])=[O:22]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Agent: [Al+3]
Agent: [Br-]
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N(CCO)CCO)c1O)Nc1cccc(Cl)c1Cl
Yield: 14.3 %

Procedure:
Following the deprotection procedure outlined in example 58, N-[4-chloro-3-[N″,N″-di-(2-methoxyethyl)aminosulfonyl]-2-hydroxyphenyl]-N′(2,3-dichlorophenyl) urea (15 mg, 0.028 mmol) and aluminum bromide (18.7 mg, 0.07 mmol) were reacted to give the desired product (2 mg, 14%). LC-MS 500.0 (M+).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27].[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41]N(C)[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41][N:23]([CH:24]([CH2:25][C:26]([NH2:27])=[O:28])[C:29]([OH:31])=[O:30])[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C(CC(N)=O)C(=O)O)C1
Yield: 6 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and asparagine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (12 mg, 6% yield). 1H NMR (300 MHz, DMSO) δ: 13.1 (bs, 1H), 11.05 (bs, 1H), 7.62 (d, 1H, J=8.42), 7.53 (s, 1H), 7.51 (s, 1H), 7.25 (bs, 1H), 6.97 (s, 1H), 4.90 (m, 1H), 4.58 (s, 2H), 4.07 (s, 2H), 2.96 (s, 3H), 2.73 (m, 2H). HRMS (M−H) calcd for C17H16N3Cl2O6: 428.0416. found: 428.0415.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:12]([CH3:14])[CH3:13])[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:15][C:16]1[CH:21]=[C:20]([NH:2][C@H:3]([CH:12]([CH3:14])[CH3:13])[C:4]([NH:6][CH2:7][C:8]([F:9])([F:10])[F:11])=[O:5])[CH:19]=[N:18][CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)[C@@H](N)C(=O)NCC(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Temperature: 120 °C
Yield: 46.4 %

Procedure:
In a round bottomed flask equipped with a magnetic stirrer, (R)-2-amino-3-methyl-N-(2,2,2-trifluoroethyl)butanamide hydrochloride (1-3b) (20 g, 85 mmol), 3,5-Dibromopyridine (30.3 g, 128 mmol), Potassium carbonate (35.3 g, 256 mmol) were suspended in DMSO (71 ml, 1.2M) and reaction mixture was purged with nitrogen for 20 minutes, then Copper(I) Iodide (0.974 g, 5.1 mmol) was added and the reaction mixture was slowly heated to 120° C. overnight. The cooled reaction mixture was then partitioned between Isopropanol (IPA):Chloroform (1:3) and Water, the aqueous layer was extracted with three times with IPA:Chloroform mixture. The combined organic layers were extracted with 1M solution of EDTA disodium salt, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude sample. Purification on a silica gel column using a gradient 0-40% ethyl acetate:hexane gave an orange solid which was taken up in ethyl acetate and concentrated to an oil, hexane was added dropwise while stirring, a white solid crystallized which was filtered, washed with hexane and dried under vacuum to give 14 g, (46.4%) the title compound, I-3, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.C(O)(C)(C)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CO)cc3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.8 %

Procedure:
To a solution of 6-chloro-5-(4-hydroxymethyl-phenyl)-1H-indole-3-carbaldehyde (422 mg, 1.48 mmol) in MeCN (18 mL), tert-butanol (18 mL) and 2-methyl-2-butene (12 mL, 110 mmol) at 0° C. was added a solution of sodium chlorite (1.25 g, 14.8 mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol) in water (9 mL) dropwise. The ice bath was removed and the solution was stirred at room temperature. After 5 hours, additional 2-methyl-2-butene (3 mL, 27.5 mmol) was added, followed by sodium chlorite (1.25 g, 14.8 mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol) in water (9 mL) dropwise. The resulting solution was stirred at room temperature. After 27 hours total reaction time, the solution was concentrated in vacuo to afford a pale yellow solid. Water (5 mL) was added to the solid and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were concentrated in vacuo and purified by flash chromatography (35-90% EtOAc/heptane, with 0.2% formic acid modifier) to afford a pale yellow solid. The solid was stirred in EtOAc (5 mL) at 55° C. for 6 hours, and the resulting slurry was cooled to room temperature. The precipitate was filtered and washed with EtOAc (1 mL) to afford the title compound (182 mg, 41% yield) as a cream-colored crystalline solid. MS (ES+) 300.0 (M−H)+. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H) 7.98 (s, 1H) 7.56 (s, 1H) 7.40 (m, 4H) 4.65 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Oc1ccccc1Br
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromophenol (6.0 mL, 51.7 mmol) in DMF (80 mL) was added potassium carbonate (7.16 g, 51.7 mmol), and the mixture was allowed to stir for 10 min ar rt. 2-Fluorobenzonitrile (5.62 mL, 82.6 mmol) was added and the mixture was heated to 100° C. for 40 h. The mixture was allowed to cool to rt, poured onto ice, filtered, washed with water, and dried to yield 13.0 g (91.7%) of title compound 2-(2-bromophenoxy)-benzonitrile 1j.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 71.4 %

Procedure:
A solution of octylbromide (4.19 g), 4-hydroxybenzoic acid (3 g) and potassium carbonate (3 g) in dimethylformamide (100 ml) was stirred at 130° C. for two hours. The solution was poured in water and neutralized with dilute aqueous hydrochloric acid solution. Diethylether was added to effect extraction. After the extracted layer was distilled to remove the solvent, the residue was added to a solution of sodium hydroxide (3.3 g), water (10 ml) and ethanol (50 ml). The solution obtained was refluxed for about a day and neutralized with dilute aqueous hydrochloric acid solution. The solution was distilled to remove the solvent and concentrated. The solid obtained was collected and recrystallized from water/ethanol to obtain the titled compound (3.88 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]=2[N:13]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C)c2nc(-c3ccccc3F)[nH]c(=O)c12
Product: Cc1nn(C)c2nc(-c3ccccc3F)nc(Cl)c12
Yield: 51 %

Procedure:
6-(2-Fluoro-phenyl)-1,3-dimethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.0 g, 7.74 mmole) was treated with 40 ml phosphorous oxychloride and heated to reflux overnight. The excess phosphorous oxychloride was removed under vacuum and ice water was added to the residue. The product was extracted with ethyl acetate, washed with 10% sodium carbonate, water, dried over sodium sulfate (anh) and the solvent was removed to give crude product. Crude product was chromatographed on silica gel column eluting with chloroform to give 1.10 g of pure product (yield: 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[Si:20](OS(C(F)(F)F)(=O)=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (1.20 g, 5.55 mmol, prepared according to the method in Tetrahedron Lett. 2000, 41, 4335) and 2,6-lutidine (1.29 mL, 11.11 mmol) in CH2Cl2 (12 mL) was added TBSOTf (1.91 mL, 8.33 mmol). After stirring at room temperature for 2 h, the reaction was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The crude residue was purified on silica gel (0-10% EtOAc/hexanes) which afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:44][O:45][NH:46][CH3:47]>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([N:46]([O:45][CH3:44])[CH3:47])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc(C)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
To 0.500 g (2.91 mmol) 2-chloro-6-methyl-isonicotinic acid in 5.0 mL of anhydrous methylene chloride and 0.5 mL of anhydrous DMF was added 0.47 g (3.5 mmol) 1-hydroxybenzotriazole hydrate. The reaction mixture was stirred for 20 minutes at 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.67 g, 3.5 mmol) was added to the reaction mixture. Stirring was continued for 1 hour allowing the reaction mixture to slowly warm up to room temperature. The reaction mixture was re-cooled to 0° C. and 0.750 g (5.8 mmol) of diisopropylethylamine and 0.340 g (3.5 mmol) of O,N-dimethyl-hydroxylamine were added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was diluted with water and extracted with 50 mL of methylene chloride. The organic phase was washed with water, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel using 5:1 hexane:ethyl acetate to give 360 mg of the 2-chloro-N-methoxy-6,N-dimethyl-isonicotinamide.