Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:20])[F:21])[CH:12]=2)=[O:19])=[N:6][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromopyridin-2-yl amine (1.190 g, 6.88 mmol, 1.0 eq.) in THF (20 mL), add 3-trifluoromethylphenyl isocyanate (0.96 mL, 6.88 mmol, 1.0 eq.) in a drop-wise manner at room temperature. Stir the reaction mixture at room temperature for 30 minutes. Filter the solid and wash with MeOH (2×10 mL). Dry the solid to afford 1.81 g (5.0 mmol, 73%) of the title compound. MS (ES), m/z 360, 362 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:23])[NH:14][O:15]CC1C=CC=CC=1)=[O:11].[ClH:24].[H][H]>[Pd].[C].C(O)C>[ClH:24].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:23])[NH:14][OH:15])=[O:11]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1NC(=O)NC(=N)NOCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)NC(=N)NO

Procedure:
To a solution of 6.0 g. (0.017 moles) of 1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea in 160 ml. of absolute ethanol there is added 1.0 g. of 5% Pd/carbon and then 1 ml. of saturated ethanolic hydrogen chloride. The mixture is hydrogenated at room temperature and atmospheric pressure until one equivalent of hydrogen is taken up (1 hour). The suspension is filtered through a bed of celite and the filtrate evaporated to an off-white solid. The solid is recrystallized from 150 ml. of 7:1 acetonitrile:methanol to give 1-(2,6-dimethylphenyl)-3-hydroxyamidinourea hydrochloride, m.p. 191°-2° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:11]=2)=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(C)C)cc1
Yield: 83.9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(4-isopropylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.074 g; 0.184 mmol), sodium hydroxide 10N (0.184 mL; 1.84 mmol) in methanol (2 mL) to afford 0.060 g (83%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1.[CH3:21][NH2:22].[I-].[Na+]>C(#N)C.O>[CH3:21][NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1
Reactant: CN
Reactant: O=c1c2ccccc2sc2ccc(OCCCCl)cc12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNCCCOc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
26 g (85 mmol) 2-(3-chloropropoxy)-9H-thioxanthen-9-one is suspended in 140 mL acetonitrile. 66 g (73.2 mL, 0.85 mol) of a 40% solution of methyl amine in water was added and the mixture was heated to 60° C. After four hours, 1.3 g (8.5 mmol) sodium iodide and 20 mL of a 40% solution of methyl amine in water were added and the reaction was allowed to continue for 16 hours at 60° C. The precipitated compounds were isolated by filtration and washed three times with 100 mL acetonitrile. The pooled acetonitrile fractions were evaporated under reduced pressure. The crude 2-(3-methylaminopropoxy)thioxanthen-9-one was crystallized from 200 mL hexane, isolated by filtration and dried. 19 g of 2-(3-methylaminopropoxy)thioxanthen-9-one was isolated. 2-(3-methylaminopropoxy)thioxanthen-9-one was further purified by preparative column chromatography on a Prochrom LC80 column, using Kromasil C18 100A 10 mm as silica and methanol/1M ammonium acetate 68/32 as eluent at a flow rate of 150 mL per minute.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]([O:15][CH2:16][CH:17]=[CH2:18])[CH:12]1[O:14][CH2:13]1>>[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:12]1[O:14][CH2:13]1
Reactant: C=CCOCC1CO1
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCOCC1CO1)(OCC)OCC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
140 g (0.85 mol) of hydridotriethoxysilane were mixed with 100 g (0.88 mol) of allyl glycidyl ether, and 10 g of this mixture were initially introduced into a reaction vessel at 95° C. under normal pressure with 100 mg (9.5×10-5 mol) of tetrakis(1-phenyl-3-n-hexyl-1-triazenido) platinum complex. The remainder of the above mentioned was added dropwise to the mixture in the course of 80 minutes, the temperature rose to 160° C. When the addition was complete, the reaction mixture was stirred at 150° C. for an additional 30 minutes. After distillation, 3-glycidoxypropyltriethoxysilane was obtained as a colorless, liquid product in a 62.6% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:13]=[C:12]([NH:14][C:15]([CH:17]5[CH2:19][CH2:18]5)=[O:16])[NH:11][C:10]=4[CH:20]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)[nH]c5c4)c3)c2)CC1
Yield: 43.5 %

Procedure:
Using N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (159 mg, 515 μmol) produced in Example C1(vi), 3-(1-cyanocyclopropyl)benzoic acid (210 mg, 1.12 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (307 mg, 1.60 mmol) and N,N-dimethylpyridine-4-amine (58.1 mg, 47.6 μmol) as starting materials, and in the same manner as in Example C1(vii), the title compound (107 mg, 43%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>CO>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15]([O:21][CH3:20])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (6.38 g, 21.69 mmol) in anhydrous methanol (100 mL), was added 4.67 N sodium methoxide (5.57 mL, 26 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then at rt for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with brine, dried over Na2SO4, filtered, and concentrated to give 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine which was used without the need for purification. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.31-7.40 (m, 4 H), 7.23-7.31 (m, 1 H), 3.95 (s, 3 H), 3.72 (br. s., 2 H), 3.43 (br. s., 2 H), 2.84 (d, J=4.5 Hz, 2 H), 2.78 (d, J=4.0 Hz, 2 H). MS (ESI+) m/z 290.4 (M+H)+.
Reaction SMILES: C[CH:2]([CH:6]([C:26]1[CH:30]=[CH:29][N:28]([CH:31]([CH3:33])[CH3:32])[N:27]=1)[N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([O:24][CH3:25])=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].C1COCC1.[OH-].[Na+].Cl>CO>[CH:31]([N:28]1[CH:29]=[CH:30][C:26]([CH:6]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[C:15]([O:24][CH3:25])=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:2][C:3]([OH:5])=[O:4])=[N:27]1)([CH3:32])[CH3:33]
Reactant: COc1ccc2cccnc2c1N1CCCN(C(c2ccn(C(C)C)n2)C(C)C(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
A 35 mL scintillation vial equipped with a magnetic stirrer was charged with (±)-methyl 3-(1-isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (450 mg, 1.0 mmol), THF (5 mL), MeOH (5 mL) and 1 N NaOH solution (6 mL, 6.0 mmol). The resulting suspension was stirred at 40° C. overnight (18 h). 2 N HCl (ca. 3 mL) was added to bring the pH to 7 and the mixture extracted with 10% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH (3×50 mL). The combined organic layer was concentrated and dried in vacuo to afford the title compound (360 mg, 82%) as a light yellow foam. MS (ES) m/z 438.4 (M+Hf).
Reaction SMILES: [CH:1](OC(Cl)(Cl)Cl)=[O:2].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([NH:29][NH2:30])=[O:28])[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>O1CCOCC1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[C:26]([C:27]4[O:28][C:1](=[O:2])[NH:30][N:29]=4)[CH:25]=3)[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=COC(Cl)(Cl)Cl
Reactant: NNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)o1

Procedure:
7.2 A solution of 131 mg (0.65 mmol) of trichloromethyl formate in 3 ml of dioxane is added to a suspension of 178 mg (0.50 mmol) of 3-[3-(3,5-di-fluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzohydrazide in 1 ml of dioxane, and the mixture is heated at the boil for 4 hours. The reaction mixture is allowed to cool, and water is added. The resultant precipitate is filtered off with suction, washed with water and dried. The residue is chromatographed on a silica gel column with dichloromethane/methanol, giving 6-(3,5-difluorophenyl)-2-[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl]-2H-pyridazin-3-one (“A15”) as colourless crystals; ESI 383;
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C1COCC1>[NH2:1][C:2]1[C:3]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1-c1ccco1
Temperature: 90 °C
Reaction time: 14 h
Yield: 0.1 %

Procedure:
3-Amino-6-chloro-2-iodopyridine (1.78 g), 2-furanboronic acid (1.17 g), and sodium carbonate (1.11 g) were suspended in a solvent mixture consistent of toluene (23 mL), THF (23 mL) and water (7 mL). The mixture was degassed using subsequent evaporation and flushing with nitrogen (5×) and tetrakis(triphenylphosphine)palladium(0) (808 mg) was added. The reaction mixture was stirred at 90° C. for 7 hours and 14 hours at room temperature. After addition of 2-furanboronic acid (783 mg), the mixture was stirred again for 4 hours at 90° C., then another portion of 2-furanboronic acid (390 mg) was added and the reaction mixture was stirred for 5.5 hours at 90° C. After 15 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.25) to afford 1.26 mg of the title compound of the formula
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]1[CH:58]=[CH:59][C:60]([CH2:64][CH3:65])=[C:61]([OH:63])[CH:62]=1>C(Cl)(Cl)Cl>[Br:1][C:58]1[C:57]([O:56][CH3:55])=[CH:62][C:61]([OH:63])=[C:60]([CH2:64][CH3:65])[CH:59]=1
Reactant: [Br-]
Reactant: CCc1ccc(OC)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1O
Reaction time: 4 h
Yield: 104.1 %

Procedure:
A solution of tetrabutyl ammonium tribromide (38.10 g, 79 mmol) in CHCl3 (100 mL) was added to a stirred solution of 5-methoxy-2-ethyl-phenol (12.0 g, 79 mmol) dissolved in CHCl3 (90 mL). The reaction mixture was stirred for 4 hrs and then quenched with 5% solution of sodium thiosulfate (90 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as an oil (19 g). LCMS: APCI−VE=230 M/E.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of (2R)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazine (1.67 g) and 1N aqueous sodium hydroxide (9.53 ml) in dioxane (16 ml) was stirred for 2 hours at ambient temperature. The mixture was adjusted to pH 5 with 1N HCl on an ice bath. To the mixture was added sodium carbonate (1.35 g), and then methanesulfonyl chloride (873 mg) dropwise on an ice bath. After stirring at the same temperature for 2 hours, the resulting mixture was acidified with 4N HCl, and extracted with AcOEt. The extract was dried over sodium sulfate and concentrated in vacuo to give 1.95 g of (2R)-1-tert-butoxycarbonyl-4-methanesulfonylpiperazine-2-carboxylic acid as an amorphous powder.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 868.7 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), N-ethyl-p-toluenesulfonamide (240 mg, 1.20 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (112 μL, 1.00 mmol) and toluene (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting pale brown suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 4:1, 15 mL fractions). Fractions 10-17 provided 244 mg (89% yield) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:6]([CH3:19])=[C:5]2[CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22].C1COCC1.[OH-].[Na+].Cl>O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)[C:6]([CH3:19])=[C:5]2[CH:20]([CH3:26])[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(C)C(=O)O)c2cc(Br)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step 3 (11.59 g, 24.2 mmol), THF (125 mL), MeOH (60 mL), H2O (30 mL) and 10 N NaOH (10 mL) was stirred at r.t. overnight. The mixture was then acidified with 2N HCl and the product was extracted in EtOAc, the extracts were dried over Na2SO4, and the product was purified by flash chromatography on silica with EtOAc:toluene:AcOH 5:95: 1. It was then swished in ether:hexane 1:2 to yield 10.29 g, 94%, of the title product. 1H NMR (CD3COCD3) 1.50 (3H, d), 2.38 (3H, s), 4.05 (1H, q), 5.44 (2H, s), 6.95 (2H, d), 7.16 (1H, dd), 9.28 (1H, d), 7.47 (2H, d), 7.80 (1H d).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[C:19]3[CH2:25][CH:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[O:23][C:20]3=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH:24]2[O:23][C:20]3=[CH:21][N:22]=[C:17]([N:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)[CH:18]=[C:19]3[CH2:25]2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(C(=O)OCc5ccccc5)CC4)ncc3O2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1

Procedure:
The title compound is prepared by catalytic hydrogenation of 4-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-5-yl]-piperazine-1-carboxylic acid benzyl ester in methanol in the presence of 10% Pd/C. LC (method 10): tR=1.28 min; Mass spectrum (ESI+): m/z=389 [M+H]+.
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc(Br)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC(c2ccc(Br)cc2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed methanol (5 L), methyl 3-(4-bromophenyl)cyclobutane-1-carboxylate (2175 g, 8.08 mol, 1.00 equiv), followed by the addition of a solution of sodium hydroxide (1623 g, 40.58 mol, 5.02 equiv, 5 M) in water (5 L). The resulting solution was stirred at 80° C. for 3 h, cooled to 30° C. and concentrated under vacuum. The resulting solution was diluted with 10 L of H2O and 8 L of DCM, and then extracted with 2×2 L of dichloromethane. The pH value of the combined aqueous layers was adjusted to 5-6 with hydrogen chloride (6 mol/L). The resulting solution was extracted with 3×4 L of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with 1.5 L of hexane and 300 mL of EA. The solids were collected by filtration. The filtrate was concentrated under vacuum and combined with the previous solids to afford 1312 g (crude) of 3-(4-bromophenyl)cyclobutane-1-carboxylic acid as a dark red solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@H:37]2[O:17][C:18]1[CH:31]=[CH:30][C:21]2[C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert.-butyl azodicarboxylate (18 g) in tetrahydrofuran (80 mL) is added dropwise over 45 minutes to a solution of (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (11 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (11.95 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 minutes and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 10.35 g; LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[C@:9]12([CH3:19])[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH2:12][C:10]2=O>>[CH3:19][C@:9]12[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH:12]=[C:10]2[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Reactant: C#Cc1ccccn1
Product: CC1(C)C2C=C(C#Cc3ccccn3)[C@]1(C)CC2

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), (1R)-(+)-camphor (6.0 mmol, 912 mg); yields 2-{[(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-e-n-2-yl]ethynyl}pyridine as a transparent yellow oil (125 mg, 9% overall yield). 1H NMR (CDCl3, 300 MHz) Δ8.57 (, 1H), 7.64 (m, 1H), 4,43 (m, 1H), 7.17 (m, 1H), 6.49 (d, J=3 Hz, 1H), 2.41 (t, J=3 Hz, 1H), 1.92 (br m, 1H), 1.65 (m, 1H), 1.18 (m, 1H), 1.17 (s, 3H), 1.09 (br m, 1H), 0.84 (s, 3H), 0.82 (s, 3H). MS (EI ionization) 237 (M+).
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[Si:8]([O:16][CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1nc2ccccc2[nH]1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
At room temperature, triethylamine (2.27 ml, 16.3 mmol) and TBDMS chloride (1.65 g, 10.95 mmol) were added to a solution of 2-hydroxymethylbenzimidazole (1.48 g, 9.95 mmol) in DMF-(30 ml). After 3.5 h, the reaction-was terminated by addition of water, the mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1, Rf=0.35) gave 2.52 g of 2-tert-butyldimethylsilyloxymethyl-benzimidazole (97% of theory) as a brownish powder. MS (DCI, NH3)=263 (M+H+). 1H-NMR (DMSO-d6): 0.00 (6H, s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15 (1H, br s).