Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[CH:18][C:17]=1[CH3:35].Cl.[OH-].[Na+]>O1CCCC1>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:35])[CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(F)cccc4F)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(F)cccc4F)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2,6-difluorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:31]([NH:38][C:39](=[O:40])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NC(=O)NCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (100 mg, 0.234 mmol) in THF (5 ml) was added dropwise benzylisocyanate (32 μl, 0.257 mmol). The reaction mixture was stirred at room temperature for 2 hours and the solvent was concentrated in vacuo. The residue was purified by silica gel (4.5 g) column chromatography eluting with chloroform/methanol (30:1) to give 1-[(R)-4-(6-(3-benzylureido)indol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (101 mg, 77%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:16]([O:18]C)=[O:17])=[C:12]([CH3:15])[CH:13]=2)[CH:8]=[N:7]1)(=O)C.[OH-].[Li+]>O1CCCC1.O>[CH3:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][NH:6]2)=[CH:10][C:11]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cc2cnn(C(C)=O)c2cc1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2[nH]ncc2cc1C(=O)O
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A 2N-aqueous sodium hydroxide solution (0.63 ml, 1.3 mmol) was added to a solution of methyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate (0.0731 g, 0.315 mmol) in tetrahydrofuran (1 ml), and the resulting mixture was stirred for 3 hours with heating under reflux. Then, a 2N-aqueous lithium hydroxide solution (0.63 ml, 1.3 mmol) was added thereto and stirred for another 3 hours. The resulting solution was diluted with water and washed with diethyl ether, and the aqueous layer was adjusted to pH 1 to 2 with 1N-hydrochloric acid to precipitate a solid. The solid precipitated was collected by filtration and the precipitate on a filter was washed with water and dried under reduced pressure to obtain 6-methyl-1H-indazole-5-carboxylic acid (0.0514 g, 93%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:15]=1[C:16](O)=[O:17].C[Si](Cl)(C)C>C1COCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:15]=1[C:16]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: Brc1ccccn1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1C(=O)c1ccccn1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a −40° C. solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2-bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at −40° C., and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0° C. and stirred for 2 h then quenched with TMSCl (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0° C. and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[O:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2]([C:30]#[N:31])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: CN(C)C=O
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)oc2c1
Temperature: 130 °C
Reaction time: 6 h
Yield: 35.7 %

Procedure:
A mixture of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (126 mg, 0.29 mmol), Zn(CN)2 (134 mg, 1.14 mmol), Pd2(dba)3 (53 mg, 0.06 mmol) and dppf (63 mg, 0.12 mmol) in DMF (4 mL) was stirred at 130° C. for 6 h. The reaction mixture was cooled to rt, poured into water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile as a white solid (40 mg, 35.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.20 (s, 1H), 7.83-7.78 (m, 2H), 7.61 (d, J=6.9 Hz, 1H), 7.41 (s, 1H), 7.14 (s, 1H), 5.54 (s, 2H), 4.68 (d, 1H), 3.32 (br s, 2H), 1.91 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 388 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[CH2:29].C(O)CC.C(=O)([O-])[O-].[K+].[K+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:33]5[CH:34]=[CH:35][C:30]([CH:28]=[CH2:29])=[CH:31][CH:32]=5)[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C=Cc1ccc(-c2cn3c(-c4ccc(C(=O)NC5CC5)cc4)cnc3c(NCC(C)C)n2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A mixture of 0.5 g (1.17 mmol) 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide (intermediate example 6-1), 345 mg (4-ethenylphenyl)boronic acid, 17 mL n-propanol, 1.75 mL of an aqueous 2M potassium carbonate solution, 15 mg triphenylphosphine, and 82 mg bis(triphenylphosphine)palladium was stirred at 120° C. for 2 hours. The solution was cooled, water added and extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was subjected to a column chromatography on silica gel to give 509 mg (97%) of the title compound. 1H-NMR (CDCl3): δ=0.67 (2H), 0.92 (2H), 1.06 (3H), 1.08 (3H), 2.09 (1H), 2.95 (1H), 3.58 (2H), 5.28 (1H), 5.80 (1H), 6.13 (1H), 6.34 (1H), 6.75 (1H), 7.47 (2H), 7.59 (1H), 7.65 (2H), 7.87 (2H), 7.92 (2H), 7.95 (1H) ppm.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[C:3]#[CH:4].C([Mg]Cl)#C.COC1C=CC=CC=1C=O.Br[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2>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.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[C:3]#[C:4][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1C(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-hydroxy-3-(2-methoxyphenyl)-1-propyne (150 mg, 0.92 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 2-methoxybenzaldehyde (Aldrich) according to Method A above), was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (70 mg) (Aldrich) and CuI (40 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(2-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yi)methylene]-2H-indol-2-one. (Yield 71 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]
Reactant: Cc1csc(C(=O)CBr)n1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nc(C)cs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]([OH:11])[C:5]2=[C:4]([Br:16])[C:3]=1N.N([O-])=O.[Na+].[ClH:22]>>[Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]([OH:11])[C:5]2=[C:4]([Br:16])[C:3]=1[Cl:22]
Reactant: Nc1c(Br)nc2nc(C(F)(F)F)n(O)c2c1Br
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21

Procedure:
5,7-Dibromo-6-amino-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (1.2 grams) in 7 milliliters of concentrated HCl was cooled to o°-10°C. Thereafter, sodium nitrite (0.35 gram) was added as a solid. The addition was carried out portionwise to maintain the temperature below 10°C. Five minutes after completion of the addition of the sodium nitrite, cuprous chloride (0.45 grams) was added portionwise and the resulting reaction mixture stirred for thirty minutes and filtered to separate the desired 5,7-dibromo-6-chloro-1-hydroxy-2-(trifluoromethyl)-1-H-imidazo(4,5-b)pyridine product, m.p. 215°C.
Reaction SMILES: ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:15]([O:22][C:23]([NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To 1000 ml of dichloromethane suspension containing 25.9 g of pyridinium chlorochromate (PCC) was added dropwise under ice-cooling a mixture of 15 g of N-benzyloxycarbonyl-trans-4-aminocyclohexanol and 1000 ml of dichloromethane. The resulting mixture was stirred at room temperature for 4 hours. Then, diethyl ether was added to the reaction mixture and insoluble materials were removed by filtration from the mixture. The filtrate was condensed and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give 10.562 g of N-benzyloxycarbonyl-4-aminocyclohexanone (yield: 71%, melting point: 65°-69° C.).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C(=O)C>[CH2:6]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:5])=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCCSCCCCCC(=O)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCSCCCCCC(N)=O
Temperature: 25 °C

Procedure:
19.3 Grams of ammonium acetate and 100 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred at room temperature. Thereto was slowly added dropwise 21.0 g of 6-(octadecylthio) hexanoic acid chloride, followed by continuing the stirring for 20 hours and, then, stirring with heating at 60° C. by a water bath for 2 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with acetone. The precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.0 g of the desired product as a white crystal. m.p. 105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:40])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.023 ml benzoylchloride (0.2 mmol). After 1.5 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 84 mg residue which was purified by column chromatography (9 g silicagel, ethylacetate/heptane 2:1). 69 mg product as a light yellow solid (98%) was obtained. MS (ISP) 555.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH2:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15]C=3)=[N:9][C:8]=2[CH:21]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[N:31]1C=CC=C[CH:32]=1>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:20][C:19]([C:32]#[N:31])=[C:16]([CH3:15])[CH:17]=3)=[N:9][C:8]=2[CH:21]=1
Reactant: c1ccncc1
Reactant: N#Cc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3s2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(-c2nc3cc(N)ccc3s2)ccc1C#N
Temperature: 95 °C

Procedure:
8.8 g (29.8 mmol) of 4-(5-nitro-benzothiazol-2-ylmethyl)-benzonitrile are dissolved in 300 ml pyridine, combined with 15.4 g sodium dithionite and 60 ml water at 50° C. and heated to 95° C. for 1 hour. The pyridine is distilled off, the residue is combined with ice water, the precipitated product is suction filtered and dried.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[OH:23])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: C[Si](C)(C)CCOCOc1cnccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cnccc1C(O)c1ccc(C2CC2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-cyclopropylbromobenzene (synthesized as described in WO0268439; 2.5 g, 0.0127 mol) in tetrahydrofuran (20 ml), a 1.58 mol/L n-butyllithium/n-hexane solution (8.4 ml, 0.0133 mol) was added dropwise at −70° C. over 8 minutes. After stirring at −70° C. for 1 hour, a tetrahydrofuran solution of 4-formyl-3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (4.2 g, 0.0165 mol) was added over 5 minutes and stirred at −70° C. for 2.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give (4-cyclopropylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (2.5 g, 53%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[N+:23]([O-])=O)[CH2:19][CH2:18][CH2:17]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(O)(=O)C.O>[NH2:23][C:22]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][C:14]=1[O:13][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc(COc2cc3c(cc2[N+](=O)[O-])CCC3)cc1F
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2cc3c(cc2N)CCC3)cc1F
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 60.3 %

Procedure:
11.0 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate was dissolved in 120 mL of acetic acid and 12.0 mL of water, and 8.89 g of reduced iron was added thereto at 60° C., followed by stirring at 60° C. for 4.5 hours. The reaction liquid was cooled to room temperature, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in water and ethyl acetate, neutralized by the addition of sodium hydrogen carbonate, and then filtered through Celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=95:5 to 90:10) to obtain 6.06 g of methyl 4-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2-fluorobenzoate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(C1C=CC=CN=1)=C.CC(C=CC)=C>N1C=CC=CC=1>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC1CCC(c2ccccn2)C(C)C1
Agent: C=C(C)C=CC
Agent: C=Cc1ccccn1
Solvent: c1ccncc1
Product: CC1=CC(C)C(c2ccccn2)CC1

Procedure:
The pyridine of the invention, that is 2-(2,4-dimethylcyclohexyl)pyridine, may be synthesised by a Diels-Alder reaction between 2-vinylpyridine and 2-methyl-1,3-pentadiene to produce 2-(2,4-dimethylcyclohex-3-en-1-yl)pyridine, which is then subjected to a hydrogenation reaction to give 2-(2,4-dimethylcyclohexyl)pyridine. The reaction may be shown schematically as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([CH:21]([OH:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Temperature: 25 °C

Procedure:
To 300 mg of 9,9-bis(4-pyridinylmethyl)-2-acetylfluorene was dissolved in 5 ml of ethanol cooled to 0° was added 100 mg of sodium borohydride. The reaction mixture was warmed to room temperature overnight, quenched with water and methanol and the solvents evaporated. The residue was partitioned between ethyl acetate and 1N NaOH, washed with water, brine, dried (MgSO4) and evaporated. Recrystallization from ethanol yielded product. NMR (CDCl3, 200 MHz) δ: 1.50(d,J=6.5 Hz, 3H), 3.39(s,4H), 4.92(q,J=6.4 Hz, 1H), 6.43(2d,4H), 7.08-7.58(m, arom.), 7.87(d,2H), 7.97(d,2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH2:12][OH:13].CN(C)C1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>CN(C=O)C.O>[C:30]([O:13][CH2:12][C:11]([S:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])(=[O:32])[CH3:31]
Reactant: CC(CO)(Sc1cc2ccccc2[nH]1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CC(=O)OCC(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution (20 ml) of 2-(1H-indol-2-yl)thio-2-phenylpropanol (2.81 g) and N,N-dimethylaniline (1.23 g) in anhydrous DMF, was a solution (2 ml) of acetyl chloride (0.86 g) in anhydrous DMF was added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was diluted with water, and was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (diluting solvent: n-hexane/ethyl acetate =9:1), and further recrystallized from ethanol to give 1.35 g (yield: 42 %) of the product compound as a pale yellow prism crystal. The melting point was 105°-106° C.