Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([F:11])[C:5]=1[F:12])[CH3:2].C(O[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1F)C.C([Li])(CC)C.II.OB(O)C1C=CC=C(F)C=1.FC1C=C(Br)C=CC=1.[Mg].COB(OC)OC.Cl.C([O-])([O-])=O.[K+].[K+]>[Pd].CCCCCCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:6]([F:11])[C:5]=1[F:12])[CH3:2]
Reactant: CCOc1ccc(I)c(F)c1F
Reactant: CCOc1cccc(F)c1F
Agent: [Pd]
Agent: COB(OC)OC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOc1ccc(-c2cccc(F)c2)c(F)c1F
Yield: 86.2 %

Procedure:
Mixture of 20.0 g (79.3 mmol) of 4-ethoxy-2,3-difluoroiodobenzene [obtained by lithiating 4-ethoxy-2,3-difluorobenzene with sec-butyl lithium and then reacting with iodine], 18.9 g (118.9 mmol) of dihydroxy(3-fluorophenyl)borane [obtained by reacting a Grignard reagent, which was prepared from 3-fluorobromobenzene and magnesium, with trimethoxyborane and then hydrolyzing with hydrochloric acid], 21.9 g (158.6 mmol) of K2CO3, 2.0 g of 5% Pd—C, and 100 ml of mixed solvent of toluene/ethanol/ water (1/1/1) was heated to reflux for 13 hours. Subsequently, after the catalyst was filtered off, the mixture was subjected to extraction with toluene, and the organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/toluene=8/2) to obtain 17.3 g of a crude 4-ethoxy-2,3,3′-trifluorobiphenyl. (Yield: 86.2%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[CH:27]=[C:26]([CH3:28])[N+:25]([O-:29])=[N:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[C:26]([CH3:28])[N+:25]([O-:29])=[N:24][CH:23]=1
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Br)cn[n+]1[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1cn[n+]([O-])c(C)c1
Temperature: 110 °C
Yield: 48.7 %

Procedure:
Step L (2): A high pressure bottle was charged with 2-(2-methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.1 g, 13.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1 complex with dichloromethane, 1.0 g, 1.1 mmol), 4-bromo-6-methylpyridazine 1-oxide (2.0 g, 11 mmol, B. Buettelmann et. al US Patent Application Publication 2004/0254179 A1), cesium carbonate (in 5 mL of water, 8.0 g, 21 mmol), and 1,4-dioxane (80 mL). The mixture was degassed by bubbling nitrogen through the solution. The bottle was capped and heated at 110° C. for 2 h. The resulting mixture was filtered through diatomaceous earth (Celite®). The filtrated was concentrated in vacuo. The crude product was purified using silica gel column chromatography (EtOAc/hexane) to afford 4-(2-methoxy-4-nitrophenyl)-6-methylpyridazine 1-oxide (1.4 g, 49% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(Oc3ccccc3)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Yield: 102.2 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((3-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (877 mg, 2.41 mmol) in ethanol (10 ml) was added 8N aqueous sodium hydroxide solution (1.51 ml, 12.1 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (10.0 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (831 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CCc1cc(OC)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccnc(CCC(=O)O)c1
Temperature: 25 °C

Procedure:
41.95 g of methyl 3-(4-methoxypyridin-2-yl)propionate (starting material C1) are dissolved in 700 ml of tetrahydrofuran, and 217 ml of 1N sodium hydroxide solution are added. The mixture is stirred at RT until no more starting material is detectable (TLC). The mixture is neutralized using 217 ml of 1N hydrochloric add solution, evaporated to dryness and dried under high vacuum. The colorless residue is ground and extracted four times with dichloromethane/methanol (9:1). The combined extracts are evaporated to dryness. This gives 33.2 g of the title compound as a colorless powder of m.p. 131-132° C. The mass spectrum shows the molecular peak MH+ at 182 Da.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23]CC)=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:26])[N:8]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=1[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:2][CH2:3][CH3:4].C(O)C.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:26])[N:8]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:7]=1[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)OCC)cs3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (5 ml) was added 1N sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.97 g, 92.4%) as crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:39][OH:40].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([NH:39][OH:40])=[NH:24])=[C:21]([F:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Yield: 69.5 %

Procedure:
To a stirred solution of 0.84 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile in 5 mL of tetrahydrofuran and 5.6 mL of methanol were added 1.14 g of hydroxylamine hydrochloride followed by 1.8 mL of triethylamine. The reaction mixture was stirred at reflux temperature for 2 h and then at room temperature overnight. The reaction mixture was refluxed for an additional 2 h and then concentrated under reduced pressure. The residue was taken up into dichloromethane then water was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.840 g of crude product as a yellow gum. Precipitation in heptane afforded 620 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine as a beige powder.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][C:10]1[N:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][CH:11]=1.C(OC(=O)C)C>CN(C=O)C.O>[CH3:1][O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[N:15][C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(C)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
Potassium carbonate (4.15 g) and methyl iodide (2.80 ml) were added to a solution of 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) in DMF (120 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was distributed between ethylacetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the title compound (3.94 g) as needle crystals.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([CH:12]=[C:13]1[C:19]2=[CH:20][S:21][CH:22]=[C:18]2[C:17](=O)[NH:16][C:15]2=[CH:24][S:25][CH:26]=[C:14]12)#[N:11].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:17]1[C:18]2[C:19](=[CH:20][S:21][CH:22]=2)[C:13](=[CH:12][C:10]#[N:11])[C:14]2[C:15](=[CH:24][S:25][CH:26]=2)[N:16]=1
Reactant: N#CC=C1c2cscc2NC(=O)c2cscc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: N#CC=C1c2cscc2N=C(Cl)c2cscc21
Yield: 96 %

Procedure:
140 ml of phosphorus oxychloride and 1.5 ml of N,N-dimethylaniline are added to 14.0 g (54 mmoles) of 9-cyanomethylene-4,5-dihydro-dithieno[3,4-b:4',3'-e]azepin-5-one (cis/trans-isomer mixture) and the mixture is refluxed under nitrogen for 1 hour. After all the excess phosphorus oxychloride and dimethylaniline have been distilled off under reduced pressure from an oil pump, the residue is partitioned between methylene chloride and water, the aqueous phase is extracted twice more with methylene chloride and the combined organic phases are washed thoroughly with dilute HCl and water. Drying and concentrating the organic phase gives 14.4 g (96%) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine, which is sufficiently pure for the further reaction.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([O:26]CC)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (2.24 mmol) of ethyl 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in a mixture of 15.5 ml of dioxane and 7.7 ml of water, 215 mg (8.97 mmol) of lithium hydroxide were added and the mixture was stirred at RT overnight. For workup, the reaction solution was concentrated under reduced pressure, then water was added and the mixture was acidified with 1N hydrochloric acid. The precipitate formed was filtered off, washed and dried under reduced pressure. The filtrate was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The two solids gave a total yield of 764 mg (95% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C.C>COCCOC.CCOC(C)=O.O>[NH:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:19]=[C:9]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=1
Reactant: Nc1ccccc1N
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(Br)nc1-c1nc2ccccc2[nH]1
Temperature: 170 °C
Yield: 60.4 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10 g, 45.87 mmol), benzene-1,2-diamine (5.45 g, 50.46 mmol), diethoxyphosphorylformonitrile (8.23 g, 50.46 mmol) and triethylamine (12.79 mL, 91.74 mmol) in DME (30 mL) was heated in the microwave at 170° C. for 40 minutes. The mixture was allowed to cool and water was added. The resultant dark-coloured precipitate was dissolved in EtOAc and stirred with charcoal for 30 minutes. After filtering through celite, the filtrate was concentrated in vacuo to give the product as a yellow solid (8.04 g, 60% Yield). 1H NMR (400 MHz, DMSO) 7.22-7.32 (2H, m), 7.55 (1H, d), 7.75 (1H, d), 7.8 (1h, br s), 8.8 (1H, br s), 13.1 (1H, s); MS (ES+) 291
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccc(Br)cc1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(Br)cc1

Procedure:
ninhydrin, 4-(4-bromophenyl)-semicarbazide hydrochloride
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=O.Cl.[OH-].[NH4+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>O.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[N:22]=[C:26]2[C:25]([OH:24])([CH3:30])[CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ccc(Cl)cc2N)CC1
Reactant: CC(C)(O)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(n2c(C(C)(C)O)nc3cc(Cl)ccc32)CC1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
To a mixture of cis-[4-(2-amino-4-chloro-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.25 g, 3.67 mmol, prepared from 1-chloro-4-fluoro-3-nitrobenzene and tert-butyl cis-4-aminocyclohexanecarbamate) and 2-hydroxyisobutyric acid (2.7 g, 25.9 mmol) in water (5 mL) was added concentrated hydrochloric acid (3.25 mL, 40 mmol). The mixture was stirred and heated at 110° C. for 2 days. The dark colored solution was treated with ammonium hydroxide (15 mL, 225 mmol) and extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate. After the evaporation of solvents, a red colored solid was obtained (1.1 g). This material was dissolved in THF (20 mL) and treated with di-tert-butyl-dicarbonate (950 mg, 4.3 mmol). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified through flash column chromatography using ethyl acetate and hexanes (1:4) to give [4-(5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl)-cyclohexyl]-carbamic acid tert-butyl ester (600 mg). This compound was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 1 hr. Solvents were evaporated and the residue was extracted with methylene chloride and sodium hydroxide solution (1N). The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was dissolved in methylene chloride and treated with hydrogen chloride in dioxane (4M). Solvents were evaporated and the residue was triturated with ether. The purple solid was filtered to give a hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol. 1H-NMR (CD3OD) □ 7.96 (d, 1H), 7.57 (s, 1H), 7.21 (d, 1H), 5.34 (m, 1H), 2.61 (m, 2H), 1.72-1.89 (m, 13H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.Br[C:29]1[CH:30]=[C:31]([NH:35][C@H:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[C:31]([NH:35][CH:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)OC1(C)C
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: O
Solvent: COCCOC
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Yield: 73.8 %

Procedure:
To a nitrogen gas purged mixture of 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (231 mg, 0.565 mmol), (R)-2-(5-bromopyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (200 mg, 0.565 mmol), and Na2CO3 (847 μl, 1.694 mmol) in DME (3765 μl) was added Tetrakis (131 mg, 0.113 mmol). The reaction mixture was heated at 100° C. in a sealed microwave vessel for 1 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, and concentrated under reduced pressure. Purification of the residue on silica (0-5% methanol/ethyl acetate, 25 gm silica) to give 232 mg foam, (2-1a).
Reaction SMILES: BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Br[C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[CH3:38].C(OC(=O)C(C)C(OCC)=O)C.[Na].C(OC(=O)C(C)C(OCC)=O)C.CC[O-].[Na+].BrC1C=C(C(C)(C)C)C=CC=1CBr.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.O.C(O)C>[C:34]([C:32]1[CH:31]=[CH:30][C:29]([CH3:38])=[CH:28][CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(C(C)(C)C)cc1Br
Agent: CC(C)(C)c1ccc(CBr)c(Br)c1
Agent: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)(C)C)cc1
Temperature: 20 °C
Yield: 60 %

Procedure:
N-Bromosuccinimide (98 g, 0.55 mol) and 0.5 g benzoyl peroxide were added to solution of 2-bromo-4-tert-butyl-1-methylbenzene (113.5 g, 0.5 mol) in CCl4 (500 ml). The resulting mixture was refluxed for 6 h, cooled to 20° C. and filtered. The resulting filtrate was evaporated and used without further purification. A solution of sodium diethylmethylmalonate, prepared from 104.5 g (0.6 mol) diethylmethylmalonate and 40.8 g of sodium ethylate in 500 ml abs. ethanol was treated dropwise with 2-bromo-1-(bromomethyl)-4-tert-butylbenzene (0.5 mol). The resulting mixture was refluxed for 4 h, treated with a solution of NaOH (50 g, 1.25 mol) in water (60 ml) and refluxed for 2 h, then poured into water (11), and finally washed with toluene (2×100 ml). The aqueous solution was treated with 130 ml of 35% HCl. The resulting mixture was extracted with chloroform (4×250 ml), the organic phase was dried over MgSO4 and evaporated. The residue was heated to 160-170° C. for 15 min yielding the product (92 g, total yield from 1-tert-butyl-4-methylbenzene 60%).
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38])[CH2:15][CH2:14][CH2:13]2)[CH3:20])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To 54 mg (0.2 mmol) Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine in 2 ml CH2Cl2 3 drops of Huenig's base and 527 mg (0.25 mmol) 4-chlorobenzene sulfonylchloride were added. The solution was stirred at RT for 2 h, concentrated and purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 to yield 70 mg (78%) Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amine as yellow oil, MS: 447 (MH+, 1Cl).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2>CCO.C(Cl)Cl>[O:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[C:2]1=2
Reactant: OCc1cc2ccc3ccc4ccccc4c3c2o1
Solvent: CCO
Solvent: ClCCl
Product: O=Cc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91.2 %

Procedure:
Using the procedure outlined in Example 14B, phenanthro[4,3-b]furan-2-methanol (18A) gave a 91.2% yield of phenanthro[4,3-b]furan-2-carbaldehyde, mp 169°, (C,H), (95% EtOH/CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[CH:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: OC1CCCC1
Agent: [Rh]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (489 mg, 1.69 mmol) in dichloromethane (10 mL) at 25° C. was treated with cyclopentanol (0.38 mL, 4.23 mmol) followed by rhodium (II) acetate dimer (15 mg, 0.034 mmol). After the resulting solution was stirred at 25° C. for 1 h, it was diluted with dichloromethane (10 mL), poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) to afford rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid methyl ester (395 mg, 67% yield) as a colorless oil: EI-HRMS m/e calcd for C15H19ClSO5 (M+) 346.0642, found 346.0643.