Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2c(OCc3ccccc3)cccc21
Yield: 87.6 %

Procedure:
To a solution of 4.86 g of 5-hydroxy-1-tetralone in 50 ml of acetonitrile, 5.13 g of benzyl bromide and 6.22 g of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 6.62 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=2)[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-].CO>CCOC(C)=O>[NH2:20][C:18]1[CH:17]=[C:10]([CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:19]=1)[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)COc1cc(-c2ccnc(C)c2)cc([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(N)cc(-c2ccnc(C)c2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a rt solution of 65.D (476 mg, 1.58 mmol) in EtOAc (9 mL) was added SnCl2-2H2O (1.88 g, 7.93 mmol). The reaction solution was refluxed for 2.0 hr, cooled to rt, and treated with concentrated NH4OH (2.5 mL). To the resulting mixture was added MeOH (10 mL) followed by celite. Solid was filtered off and washed with MeOH, the liquid layers was collected and concentrated. Purification of the residue by flash chromatography on silica gel using 0-20% MeOH/CH2Cl2 for elution gave title product 65.E as colorless syrup (282 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:29]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(C3(O)CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-hydroxypiperidine-1-carboxylate (270 mg, 0.500 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (1.25 mL). The mixture was stirred at rt for 17 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (25 mL). The mixture was washed with saturated, aqueous NaHCO3 (25 mL), brine, dried (Na2SO4) and concentrated to dryness to afford 211 mg (96%) of the desired product, which was approximately 50% pure. ES-MS m/z 440.19 [M+H]+, HPLC RT (min) 1.97. 50 mg of material was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg of pure desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.89 (s, 1 H), 7.80 (d, 1 H), 7.58 (s, 1 H), 7.27-7.37 (m, 5 H), 7.13 (dd, 1.36 Hz, 1 H), 6.69 (s, 1 H), 5.64 (s, 2 H), 5.19 (s, 1 H), 2.77-2.93 (m, 2 H), 2.43-2.54 (m, 3 H), 2.12 (br s, 1 H), 1.68-1.88 (m, 2 H), 1.33-1.46 (m, 1 H); ES-MS m/z 439.92 [M+H]+, HPLC RT (min) 2.06.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C=O)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%)
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C.C(N(CC)CC)C>[C:29]([CH2:28][CH2:27][CH2:26][NH:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1)([OH:31])=[O:30]
Reactant: CCCc1csc(/C=C/c2cccc(N)c2)n1
Reactant: CCOC(=O)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1csc(/C=C/c2cccc(NCCCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 63.5 %

Procedure:
To 20 ml of toluene were added 732 mg of 2-(trans-3-aminostyryl)-4-propylthiazole, 1170 mg of ethyl 4-bromobutyrate and 606 mg of triethylamine, and the reaction was carried out at 100° C. for 21 hours. After the reaction mixture was cooled to room temperature, 10 ml of ethanol and 10 ml of an aqueous 5% sodium hydroxide solution were added and the mixture was stirred at room temperature for 1.5 hours to effect hydrolysis of the ester. After completion of the reaction, ethanol was evaporated under reduced pressure and the residue was adjusted to pH 1-2 with addition of 10% hydrochloric acid, followed by extraction with ethyl ether. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the solid formed was recrystallized from ethyl ether to give 629 mg (yield 64%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>O>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][OH:20]
Reactant: CNCCCO
Reactant: Brc1ccn2c(n1)nc1ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CCCO)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.2 %

Procedure:
2-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), 3-(methylamino)propan-1-ol (0.072 g, 0.806 mmol) and N,N-Diisopropylethylamine (0.141 ml, 0.806 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted reaction with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated to afford crude 3-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl(methyl)amino)propan-1-ol (0.207 g, 0.808 mmol, 100% yield).
Reaction SMILES: CC1(C)COB([C:8]2[C:17]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[CH3:27])=[C:16]3[C:11]([NH:12][C:13]([CH3:31])([CH3:30])[C:14](=[O:29])[N:15]3[CH3:28])=[CH:10][CH:9]=2)OC1.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1I)([O-:35])=[O:34].C(=O)([O-])O.[Na+].CN(C)C=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.O.C(OCC)(=O)C>[F:26][C:24]1[CH:23]=[CH:22][C:21]([CH3:27])=[C:20]([CH:25]=1)[O:19][CH2:18][C:17]1[C:8]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:28])[C:14](=[O:29])[C:13]([CH3:31])([CH3:30])[NH:12]2
Reactant: Cc1ccc(F)cc1OCc1c(B2OCC(C)(C)CO2)ccc2c1N(C)C(=O)C(C)(C)N2
Reactant: O=[N+]([O-])c1ccccc1I
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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(F)cc1OCc1c(-c2ccccc2[N+](=O)[O-])ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 7-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 21, 68.2 mg, 0.155 mmol), 2-nitro-1-iodobenzene (79.0 mg, 0.317 mmol), sodium hydrogen carbonate (41.5 mg, 0.494 mmol) and tetrakis(triphenylphosphine)palladium (0) (19.0 mg, 0.0164 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.5 ml) and water (0.5 mL), and stirred at 120° C. for 30 minutes by irradiated microwave. After cooling down, ethyl acetate (15 mL) and water (15 mL) were added and partitioned. The organic layer was washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (42.6 mg) as a yellow solid. (Yield 61%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[CH:18]=1)=[O:8])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][N:12]2[C:18]=1[Cl:20])=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Yield: 57.2 %

Procedure:
0.86 g of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester was suspended in 30 ml of ethyl acetate; 1.2 g of N-chlorosuccinimide was added, followed by thermal refluxing for 20 hours. After cooling, 30 ml of tetrahydrofuran was added; the mixture was washed with an aqueous solution of sodium thiosulfate and saline, dried over magnesium sulfate and concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.552 g of the title compound.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[BrH:15]>O1CCOCC1.O.[Cu]Br>[Br:15][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5]
Reactant: Br
Reactant: N#Cc1c(N)cccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
2-Amino-6-fluorobenzonitrile (18.0 g, 132 mmol) was dissolved in hot 1,4-dioxane (20 ml), 48% hydrobromic acid (200 ml) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (10.5 g, 152 mmol) in water (20 ml) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 ml). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (1200 ml) and extracted with ethyl acetate (2×400 ml). The combined organics were washed with 10% aqueous ammonia solution (400 ml), water (400 ml) and brine (500 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-6-fluorobenzonitrile (18.5 g, 70%) as a white solid: δH (400 MHz, CDCl3) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: COCCCCCCOc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCCCCOC)cc3)CC2)cc1
Temperature: 150 °C
Yield: 70.8 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (1.90 g) and 1-[4-(6-methoxyhexyloxy)phenyl]piperazine (3.00 g) in dimethylsulfoxide (45 ml) was treated with potassium carbonate (4.25 g), and the mixture was heated at 150° C. for 22 hours. After cooling, water (200 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with water and dried under reduced pressure at 50° C. for 7 hours to give ethyl 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.20 g) as an ocher solid.
Reaction SMILES: ClC1C=CC=CC=1C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][C:23]([CH3:30])([C:27](O)=[O:28])[C:24]([OH:26])=[O:25].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[NH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1>C(Cl)Cl.CN1C(=O)CCC1.C(Cl)Cl.CN1C(=O)CCC1>[CH3:22][C:23]([CH3:30])([C:27]([NH:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)=[O:28])[C:24]([OH:26])=[O:25]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: NCc1ccccn1
Agent: CC(C)N=C=NC(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C(=O)O)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[C:13]([F:20])([F:19])C(OCC)=O.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:13]([F:20])[F:19]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(OC(F)F)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a N2 purged round bottom flask was added 2-bromo-5-nitrophenol (29.0 g, 133 mmol, 1.0 eq.) followed by 16.8 mL (133 mmol, 1.0 eq) of ethyl chlorodifluoroacetate and 18.8 g of K2CO3 (133 mmol, 1.0 eq.). Anhydrous DMF (300 mL) was added and the mixture was stirred at 70° C. for 5 h. The mixture was cooled to RT and the solvent was removed. The obtained crude mixture was dissolved in CH2Cl2 (500 mL) and washed with 1 N NaOH (aq.). The organic layer was dried (MgSO4), filtered and evaporated. The crude material was further purified by column chromatography (0-5% EtOAc in hexanes) providing pure 1-bromo-2-difluoromethoxy-4-nitro-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[N:19]O.N>CO.[Ni]>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:18][NH2:19]
Reactant: COc1c(C=NO)ccc2c1ncn2C1CCCCO1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1c(CN)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A 1 L autoclave was cooled under a stream of nitrogen and charged with 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde oxime (14.50 g, 0.052 mol, 1.0 equiv.) and aqueous ammonia (30 mL) in MeOH (300 mL). To this was added Raney Nickel (15.0 g, w/w) and the reaction was stirred at RT under hydrogen (pressure ˜60 psi) overnight. The reaction mixture was then filtered through a Celite® pad and the filtrate was concentrated in vacuo. The crude material was purified by neutral alumina column chromatography using a MeOH/DCM gradient (5 to 10% MeOH to afford (4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (97, 8.0 g, 57%) as a brown viscous oily liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)CCc1ccc(-c2ccccc2)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(O)CCc1ccc(-c2ccccc2)c(Cl)c1
Yield: 78 %

Procedure:
4-(2-Chloro-4-biphenylyl)-2-butanol was prepared analogous to Example 26 from 4-(2-chloro-4-biphenylyl)-2-butanone with a yield of 78% of theory. The product was obtained as a colorless, viscous, non-crystallizing oil after chromatography on silicagel (Rf -value 0.60, prepared silicagel plates, thickness of layer 0.25 mm; benzene/ethyl acetate, ratio by volume 1:1, as eluant), which was characterized by IR-, UV-, NMR-spectra and by elementary analysis.
Reaction SMILES: [NH:1]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[C:2]1[C:8]1[O:9][CH2:10][C:11](=[O:19])[C:12]=1[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1>CC(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:10]2[O:9][C:8]([C:2]3[NH:1][CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[C:11]2=[O:19])=[CH:21]1
Reactant: CC(C)OC(=O)C1=C(C2=CC=CC=CN2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(C2=CC=CC=CN2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a stirred solution of isopropyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.12 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.019 g, 0.13 mmol) in 2-propanol (1.0 mL), hexamethyleneimine (0.0014 mL, 0.012 mmol) was added at ambient temperature. The mixture was refluxed for 12 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.024 g, y. 49%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=1)(=O)=O.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:33]1([C:7]2[C:15]3[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[N:8]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(OS(=O)(=O)C(F)(F)F)nn(COCC[Si](C)(C)C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(COCC[Si](C)(C)C)c2C1
Temperature: 160 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (440 mg, 0.88 mmol) in 1,4-dioxane (9 mL) was added phenylboronic acid (331 mg, 2.63 mmol), potassium phosphate (559 mg, 2.63 mmol), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium (II) (32 mg, 0.05 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (10 mg, 0.02 mmol). The reaction was stirred at 160° C. for 1 hour in a microwave reactor. The reaction was cooled to rt and filtered through Celite© and rinsed with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified via chromatography on silica gel (0-25% ethyl acetatehexanes) to provide the desired product (298 mg, 79%). MS (ESI) mass calcd. C23H35N3O3Si 429.7. m/z found, 430.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixed liquid of 1.00 g of tert-butyl piperidin-4-ylcarbamate and 20 ml of pyridine was added 0.77 ml of methanesulfonyl chloride, followed by stirring at room temperature for 18 hours. After evaporating the pyridine under reduced pressure, ethyl acetate was added thereto, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained solid was washed with diethyl ether to obtain 1.19 g of t-butyl[1-(methylsulfonyl)piperidin-4-yl]carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([NH:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([N:11]([C:31](=[S:32])[NH:30][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a mixture of tert-butyl-6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (1.5 g, 5.2 mmol) in tetrahydrofuran (34 mL) is added benzoyl isothiocyanate (0.84 g, 5.17 mmol). The reaction is stirred for 1 hour at room temperature, concentrated under reduced pressure, and triturated with hexane/ethyl acetate (1:1) to give title compound (1.84 g). The collected solute is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound, which is combined with the triturated material (2.12 g, 90%). ES/MS (m/e): 454 (M+H).