Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]=2[C:22]([NH:24][CH3:25])=[O:23])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]=2[C:22]([NH:24][CH3:25])=[O:23])[CH:18]=1
Reactant: COc1ccccc1B(O)O
Reactant: CNC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)nn2cc(-c3ccccc3OC)ccc12
Temperature: 150 °C
Yield: 39.9 %

Procedure:
To a microwave vial equipped with a magnetic stir bar was charged 2-methoxyphenylboronic acid (12.09 mg, 0.080 mmol), 6-iodo-N-methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carboxamide (15 mg, 0.040 mmol), sodium carbonate (7.38 mg, 0.070 mmol), palladium(II) acetate (0.893 mg, 3.98 μmol) and dimethylforamide (1.0 mL). This mixture was placed under an argon atmosphere and heated at 150° C. for 10 minutes. The title compound (5.7 mg, 36%) was isolated by reverse phase HPLC: Start % B=30 to Final % B=80, Gradient time=10 minutes, Flow Rate=35 mL/minute, Wavelength=220 nm, Solvent A=10% methanol, 90% water with 0.1% TFA; Solvent B=90% methanol, 10% water with 0.1% TFA, Column=Phenomenex-Luna 30×50 mm S10, Product peak at 7.6 minutes. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.85 (d, J=4.88 Hz, 3H) 3.86 (s, 3H) 7.03 (d, J=7.93 Hz, 1H) 7.08 (t, J=7.02 Hz, 1H) 7.39 (m, 2H) 7.54 (m, 3H) 7.63 (dd, J=9.16, 1.53 Hz, 1H) 7.69 (m, 1H) 8.36 (dd, J=9.16, 0.61 Hz, 1H) 8.76 (m, 1H). LCMS: 2.0 minutes, M+1=358.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[OH:39].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[O:39][C:8]1[CH:9]=[CH:10][C:11]([N+:28]([O-:30])=[O:29])=[C:12]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:27])[CH:13]=1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Reactant: Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 38 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (1.14 g, 8.25 mmol) is added to a solution of methyl 3-(5-fluoro-2-nitrophenyl)-tetrahydro-2,4,6-trioxo-s-triazine-1(2H) -acetate (0.93 g, 2.74 mmol) and 2,4-dichlorophenol (0.66 g, 4.07 mmol) in N,N-dimethylformamide at 38° C. The reaction mixture is stirred at 38° C. for 3 days, cooled to room temperature and poured into 1M hydrochloric acid. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and 30% to 40% ethyl acetate in hexanes solutions gives the title product as a yellow foam which is identified by NMR spectral analysis.
Reaction SMILES: [OH:1][C:2](=[C:20]1[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])OC1=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:30](O)(C)(C)C>>[O:1]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][C:25]([O:24][C:23]([CH3:27])([CH3:28])[CH3:30])=[O:26]
Reactant: CCCCCCCCC=CCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)O
Product: CCCCCCCCC=CCCCCCCCC(=O)CC(=O)OC(C)(C)C

Procedure:
Starting from 5-(1-hydroxy-9-octadecenylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (18 g) and tert-butyl alcohol (200 ml), tert-butyl 3-oxo-11-eicosenoate was obtained as an oil according to a similar manner to that of Preparation A-2(2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[C:8]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.CC(OC)(C)C>C(Cl)(Cl)(Cl)Cl.C1CCCCC1>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:17])=[C:9]([F:14])[C:8]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COC(C)(C)C
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)c(F)c1F
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 2,3-difluoro-4-methyl-benzoic acid tert-butyl ester (17.3 g, 75.9 mmol) and N-bromosuccinimide (13.5 g, 75.9 mmol) in carbon tetrachloride (250 mL) was degassed for 10 minutes. AIBN (1.2 g, 7.32 mmol) was added and the reaction mixture was stirred at reflux for 18 hours before being cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue which was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to afford the title compound as a colourless oil (16.7 g, contaminated by 25% of starting material). 1H NMR (CDCl3, 400 MHz) 7.61 (1 H, ddd, J=8.3, 6.4, 2.1 Hz), 7.18 (1 H, ddd, J=8.1, 6.4, 1.8 Hz), 4.49 (2 H, d, J=1.3 Hz), 1.59 (9 H, s).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][CH2:37][NH2:38]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH:32]2[CH2:33][CH2:34][CH2:35][N:31]2[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCCC1CCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC3CCCN3C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by the procedure analogous to Example 1. MS (APCl, m/z): 454 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4].O1CCC[CH2:17]1>>[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To the cooled solution of sodium hydride (91 mg, 2.285 mmol, 60% suspension in oil) in anhydrous tetrahydrofuran was added a solution of methyl 2-(3-cyanophenyl)acetate (400 mg, 2.285 mmol) dropwise at 0° C. Reaction mixture was stirred at room temperature for 1 h. TLC showed complete consumption of starting material. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic part was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography to afford methyl 2-(3-cyanophenyl)propanoate (180 mg, 48%).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)C(=O)C2=CC=CC=C12.C(OCC)(=O)C>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Hydrazine monohydrate [2.99 ml (61.6 mmol)] was added to a suspension of 5.0 g (20.5 mol) of 4-(3-phthalimidopropyloxy)pyridine in 50 ml of ethanol, and the mixture was stirred at room temperature for 3 hours. 100 ml of ethyl acetate was added and insoluble materials were filtered off. The volatile component in the filtrate was distilled off and then chloroform was added to the residue. The mixture was washed with brine and dried over potassium carbonate. The solvent was distilled off to obtain 2.99 g of the desired compound (yield: 99.5%, pale yellow oil).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of 1-[3-(1H-benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-4-one (0.05 g, 0.17 mmol) in methanol (50 mL) was added sodium borohydride (NaBH4) (0.01 g, 0.17 mmol) and the resulting mixture was stirred for 1 h at room temperature and then quenched with few drops of water. The solvent was removed under reduced pressure, the crude dissolved in EtOAc (5 mL) and filtered, then the organic phase was evaporated under reduced pressure to afford 0.02 g (36%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].Cl.C(OC(C)C)(=O)C>CCCCCCC>[C:1]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Product: CC(=O)c1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][CH:18]=[CH2:17])[C:3]=1[O:9][CH3:10]
Reactant: C=CCBr
Reactant: COc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(F)c1OC
Temperature: 25 °C

Procedure:
A mixture of 3-fluoro-2-methoxyphenol (19.5 g; 0.137 m) potassium carbonate (85 g), allyl bromide (15 ml) and acetone (100 ml) was refluxed for 4 hours. The reaction was cooled to room temperature and evaporated to dryness. The residue was partitioned between water and dichloromethane. The organic layer was separated, dried and evaporated affording 19.0 g of the desired product as an oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:36])([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=2)[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:36])([C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)cc(P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
NBS (13.5 g, 76 mmol) was added to a solution of (3,5-dimethoxyphenyl)bis(3,5-dimethylphenyl)phosphine oxide (30 g, 76 mmol) in CH2Cl2 (400 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 300 ml) was added to quench the reactions. It was stirred at RT for 30 min and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (100 ml×2). The combined organic layer washed with water (150 ml×2), brine (200 ml×1) and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g) which was sufficiently pure for the next step. The pure product (34.2 g, 93% yield) was obtained by crystallization from ether/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.32 (br, 2H), 7.28 (br, 2H), 7.21 (br, 2H), 6.67 (d, J=2.7 Hz, 1H), 6.52 (dd, J1=2.7 Hz, J2=14.1 Hz, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 2.34 (s, 12H). 31P NMR (121.5 MHz, CD2Cl2) δ: 31.35.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:43][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and cyclopentylamine (10 mmol) according to conditions described in general procedure C. Compound is produced (25 mg) as a light yellow solid; Mp: 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 1.23-1.38(m, 4H), 1.53-1.88(m, 4H), 3.22-3.25(m, 4H), 3.84-3.86(m, 4H), 4.08-4.15(m, 1H), 5.06(bs, 1H), 6.07(bs, 1H), 6.76(d, J=11.7 Hz, 1H), 7.07(d, J=8.4 Hz, 1H), 7.25-7.31(m, 2H), 7.48-7.58(m, 2H), 7.85-7.98(m, 3H), 8.14(s, 1H), 8.25(s, 1H); MS: 528 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:5][C:6]([CH2:19][CH3:20])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:10]=2[O:17]C)[N:8]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[C:4]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:5][C:6]([CH2:19][CH3:20])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:17])[N:8]=1)[CH3:2]
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1NC(CC)CC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1nc(-c2ccc(O)cc2O)c(CC)nc1NC(CC)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a solution of 3,6-diethyl-5-(2,4-dimethoxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amine (910 mg, 2.54 mmol) (obtained in example 23) in dichloromethane was added BBr3 (1N,6 ml)at −78° C. The mixture is stirred for 10 min then gradually warmed to room temperature and stirred for 3 hr before being poured into ice-water and extracted with dichloromethane. The aqueous layer was basified with sat. NaHCO3 and extracted with dichloromethane. The combined extracts were dried (sodium sulfate), filtered, concentrated and the residue is purified by column (20% EtOAc in hexane) to give 3,6-diethyl-5-(2,4-dihydroxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amine as a yellow oil(590 mg, 71%): 1H NMR (CDCl3, 400 MHz) δ 0.94 (t, 6H), 1.30 (t, 3H), 1.36 (t, 3H), 1.57 (m, 2H), 1.67 (m, 2H), 2.62 (q, 2H), 2.86 (q, 2H), 4.15 (m, 2H). 6.41 (t, 1H), 6.51 (d, 1H), 7.27 (d, 1H). LC-MS: 330 (M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](OS(OCC)(=O)=O)[CH3:13]>CN(C)C=O>[CH2:12]([N:1]1[C:5]2[C:4](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:3]=[CH:2]1)[CH3:13]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc2ncccc21
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
To a flask were added 0.5 g 4-azabenzimidazole and 10 ml N,N-dimethylformamide and the mixture was cooled to 10 C under nitrogen. 0.18 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 0.71 g Diethylsulfate were added and the mixture was allowed to warm to 22 C and was stirred for 16 hours. The mixture was quenched slowly with 30 ml 1M hydrochloric acid and the aqueous layer was washed with ethyl acetate. After basification with sodium hydroxide, the product was extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 5% methanol in ethyl acetate to 12% methanol in ethyl acetate. 0.4 g Of an oil was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>C1COCC1.CN(C=O)C>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=C1CCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 5-hydroxy-1-indanone (4.27 g, 0.0288 mol) in THF/DMF (5 mL/10 mL) at 0° C. was added NaH (60%, 1.21 g, 0.0303 mol) followed by allyl bromide (2.7 mL, 0.0317 mol). The reaction was warmed to room temperature and stirred overnight The reaction mixture was quenched with water and extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography eluted with EtOAc/hexane (1:1) to give 4.29 g (79%) of the desired product as brown oil. MS (DCI/NH3) m/z: 189.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.53-2.64 (m, 2H), 2.96-3.11 (m, 2H), 4.64-4.72 (m, 2H), 5.29 (dd, J=10.51, 1.36 Hz, 1H), 5.42 (dd, J=17.29, 1.70 Hz, 1H), 6.06 (m, 1H), 6.98 (dd, J=8.48, 2.37 Hz, 1H), 7.10 (d, J=2.03 Hz, 1H) 7.56 (d, J=8.48 Hz, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][C:15](=[O:36])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH2:34][OH:35])[CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[CH3:13]>ClCCl>[CH2:12]([O:14][C:15](=[O:36])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH:34]=[O:35])[CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1(CCC(CO)Cc2ccc(C(=O)OC)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CC1(CCC(C=O)Cc2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1247 mg (5.79 mmol) of pyridinium chlorochromate (PCC) are added to a solution of 1680 mg (4.82 mmol) of methyl 4-[4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-(hydroxymethyl)butyl]-benzoate in 100 ml of dichloromethane, and the mixture is stirred at room temperature for 12 hours. After complete conversion, 10 g of silica gel are added and the solvent is carefully removed to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 1270 mg (76% of theory) of a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:15]3[C:20]([C:21]=2I)=[CH:19][CH:18]=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:31]1([C:34]#[CH:35])[CH2:33][CH2:32]1.C(N(CC)CC)C.CN(C=O)C>CCOC(C)=O.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.[Cu]I>[CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:15]3[C:20]([C:21]=2[C:35]#[C:34][CH:31]2[CH2:33][CH2:32]2)=[CH:19][CH:18]=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C#CC1CC1
Reactant: CCOc1ccc2c(I)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc2c(C#CC3CC3)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Reaction time: 8 h
Yield: 24.2 %

Procedure:
[4-(1-Cyclopropylmethyl-6-ethoxy-3-iodo-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.19 mmol), cyclopropylacetylene (50 μL, 70% in toluene, 0.4 mmol), Pd(PPh3)2Cl2 (6.7 mg, 0.0096 mmol), CuI (5 mg, 0.026 mmol), triethylamine (600 μL), and DMF (600 μL) was stirred at room temperature for 5 h. Additional Pd(PPh3)2Cl2 (5 mg), and cyclopropylacetylene (30 μL) was then added and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with H2O and aq. HCl. The organic layer was dried, concentrated and purified by silica gel chromatography (3:1 CH2Cl2/hexane), followed by a second chromatography (7:3 hexane/ether) to provide [4-(3-cyclopropylethynyl-1-cyclopropylmethyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (21 mg, 24%) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:21][CH2:22][O:23][CH:11]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=[C:2]2[I:1]
Reactant: OCCO
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21

Procedure:
6.11 g (15.2 mmol) 3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-5-carbaldehyde (Example 4A), 2.82 g (45.6 mmol) ethylene glycol and a trace amount of p-toluenesulfonic acid in toluene (100 ml) were heated to reflux overnight using a Dean-Stark trap. After cooling, the mixture was extracted twice with saturated aqueous sodium bicarbonate solution and washed with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining substance was purified by preparative RP-HPLC (acetonitrile/water gradient) yielding 3.94 g (58% of th.) of the pure title compound.