Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13]([NH2:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]-4,4-difluoro-L-proline, pyridine (0.6 eq.) and di-t-butyl dicarbonate (1.3 eq) in dioxane, ammonium bicarbonate (1.26 eq) was added and the mixture was stirred at room temperature for 20 hours. Dioxane was concentrated and the residue dissolved in ethyl acetate and washed with HCl 1 N, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated in vacuo to obtain a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[C:30]([CH3:39])=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][CH:38]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:30]=1[CH3:39]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cccc(O)c1C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1C

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 3-hydroxy-2-methylbenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (9%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(Br)s1
Yield: 49 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 1, 5-bromo-thiophene-2-carbaldehyde (5 g, 26.17 mmol) in ethanol (100 mL) was reacted with nitro methane (1.4 mL, 26.17 mmol) and 10N NaOH (1.4 mL, 27.47 mmol) to afford 3 g of the product (48.99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:33]([CH3:35])([CH3:34])[C:32]([OH:44])=[O:31])=[CH:41][CH:40]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)C(C)(C)c1ccc(C=O)cc1
Product: CC(C)(C(=O)O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl ester according to the procedure of Example 66. MS m/z 569; MS m/z 567.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.C(=O)(O)[O-].[K+].[CH2:35]([OH:37])[CH3:36]>>[CH2:35]([O:37][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:36]
Reactant: CCO
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C

Procedure:
2α, 3α-Epoxy-5α-pregn-16-ene-11,20-dione (3 g.) was dissolved with warming in dry ethanol (80 ml.). The solution was stirred and allowed to cool to room temperature. Concentrated sulphuric acid (0.7 ml.) was added and the solution was stirred at room temperature for 30 minutes. Potassium bicarbonate solution (10%, 35 ml.) was added and the mixture poured into ice-cold water (1 liter) and extracted with chlorform (2 × 200 ml.). The extract was dried over sodium sulphate and evaporated to a colourless oil (2.73 g.) which was purified by preparative TLC in ethyl acetate/petrol 1/1, the plates being run 3 times and the main UV-absorbing, band separated and recrystallised from ethyl acetate/ petrol to give title compound (950 mg.) as fine white crystals, m.p. 89-91° [α]D ± 77° c 0.3).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH3:29])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25]N>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH3:29])[CH3:21])=[N:7][C:6]=2[N:8]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN(C)CC(C)(C)CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
The title compound was prepared as described above in Example 20 by reacting 2.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 15 mL of N,N,2,2-tetramethyl-1,3-propanediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[S:17])=[CH:11][CH:10]=1.[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:27][S:28]([O:31][CH2:32][CH3:33])(=[O:30])=[O:29]>C(O)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH2:32]([S:17][C:16](=[NH:18])[NH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=2)=[CH:14][CH:13]=1)[CH3:33]
Reactant: NC(=S)Nc1ccc(CCNCc2cccc(Cl)c2)cc1
Reactant: CCOS(C)(=O)=O
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCSC(=N)Nc1ccc(CCNCc2cccc(Cl)c2)cc1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a stirred mixture of the product of step (e) (272.5 mg, 0.852 mmol) and ethanol (2.6 ml) was added methanesulfonic acid (81.88 mg, 0.852 mmol). After stirring for a few minutes, ethyl methanesulfonate (211.6 mg, 1.70 mmol) was added. The reaction mixture was refluxed, with stirring, for 3 hours. Additional ethyl methanesulfonate (117 mg) was added and refluxing continued for 2 hours to complete the reaction. On cooling, the product crystallized to a thick mass. Ether was added and the product was isolated by filtration and then recrystallized from ethanol-ether to yield 407.3 mg of N-(4-(2-(3-chlorobenzylamino)ethyl)phenyl)carbamimidothioic acid ethyl ester dimethanesulfonate, m.p. 173°-5° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].[Zn]>[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([OH:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
Zinc (15.0 g, 0.23 mol) and tetrahydrofuran (THF) (180 ml) was added to the reaction vessel and cooled to −10° C. Titan tetrachloride was added dropwise to the mixture (21.6 g, 0.114 mol) at about −10° C. After the addition was completed the mixture was refluxed for two hours. Then the mixture was cooled to 40° C. and 4-hydroxybenzophenone (7.68 g, 0.039 mol) and 3-chloropropiophenone (6.48 g, 0.039 mol) dissolved in THF (75 ml) were added to the mixture. Refluxing was continued for additional 3.5 hours. The cooled reaction mixture was poured in aqueous potassium carbonate solution (21 g K2CO3+210 ml water) and allowed to stand overnight at the ambient temperature. The mixture was filtered and the precipitate was washed with THF. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. Ethyl acetate phase was evaporated to dryness and the residue was crystallized first from methanol-water (8:2) and then from methanol-water (9:1). Yield 5.4 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.Cl>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: NCCN1CCOCC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(NCCN3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
A glass microwave reaction vessel was charged with cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (200 mg, 0.587 mmol) and 2-morpholinoethanamine (0.092 mL, 0.704 mmol) in 2-propanol. A drop of HCl (2N in ether) was added, and the reaction mixture was stirred and irradiated in a microwave at 175° C. for 2 hours. Additional 2-morpholinoethanamine (0.030 mL, 0.24 mmol) was added, and the mixture was heated an additional 20 minutes. The mixture was evaporated and the residue diluted with 10% IPA/DCM, washed with water, brine, and the organic layer dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. Intermediate cis-N-isopropyl-4-(2-(2-morpholinoethylamino)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was isolated as a yellow film (128 mg).
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC=CC=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([NH:23][C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(CC1CCCCC1)NC1CCCCC1

Procedure:
The N-cyclohexylcyclohexaneacetamide is prepared from cyclohexylacetyl chloride (from 10 gm. of cyclohexylacetic acid and 50 ml. of thionyl chloride, 45 minutes at reflux) in 50 ml. of dry benzene added to 14 gm. of cyclohexylamine in 100 ml. of benzene over ten minutes. The reaction is stirred at reflux for one hour, cooled and diluted with methylene chloride. The organic layer is washed with dilute hydrochloric acid, then water and sodium bicarbonate solution, dried and concentrated. Product is recrystallized from alcohol water: 11.8 gm. (76%), m.p. 164°-165°.
Reaction SMILES: [F:1][C:2]1[C:3]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)=[C:6]([C:8]#[N:9])[CH:7]=1.CO>C(Cl)(Cl)Cl.B(Br)(Br)Br>[C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)#[N:9]
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 57 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]cyanobenzene in 0.6 ml of chloroform, 48 μl of boron tribromide was added dropwise at 0° C. After the addition, the temperature of the reaction mixture was raised to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and 1 ml of methanol was added thereto. The solvent was removed under reduced pressure, the resultant was diluted with ethyl acetate, and then, saturated aqueous sodium bicarbonate solution was added thereto to be pH 4. The resultant was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 36 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:25]([N+:28]([O-])=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1>C(O)(=O)C.C(OC(=O)C)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 82.8 %

Procedure:
353 mg of iron dissolved in aqueous 5% acetic acid solution was activated at 100° C. 450 mg of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[7 (3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine (see, Journal of Medicinal Chemistry 2000, 43, 1380) dissolved in a mixture of ethylacetate and acetic acid (1:1) was added thereto dropwise, and refluxed. The hot reacted solution was filtered under a reduced pressure through celite pad, and the pad was washed with ethylacetate. The washed solvent was washed with saturated sodium bicarbonate solution several times. The organic layer was dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (353 mg, 83%).
Reaction SMILES: O.[Cl:2][C:3]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].B.O1CCCC1>C1COCC1>[Cl:2][C:3]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.2 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid hydrate (5.0 g, 26.2 mmol, Acros) in THF (80 ml) was added dropwise 1 M borane-tetrahydrofuran complex (50 ml, 50 mmol, Aldrich) at ambient temperature under nitrogen. The resulting suspension was stirred at ambient temperature for 20 min and then heated to 80° C. for 1.5 h. To the reaction at ambient temperature was added a further amount of 1 M borane-tetrahydrofuran (20 ml, 20 mmol) and the suspension heated to 80° C. for 1 h. The solution was allowed to cool to ambient temperature and then carefully quenched by dropwise addition of methanol (40 ml). The solution was heated to 80° C. for 40 min. The solvent was removed in vacuo and the residue applied to a 50 g aminopropyl cartridge (pre-washed with methanol). The cartridge was eluted with methanol and the combined methanol fractions concentrated in vacuo to leave a white solid (4.58 g). A portion of the semi-crude material (1.5 g) was pre-absorbed on florosil and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.92 g); LCMS: (System 4) (M-H)−=157, tRET=1.29 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[OH-].[K+].[I-].[K+].[CH3:20]Cl>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:20])[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:3]1=[O:15]
Reactant: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Reactant: CCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 100.1 %

Procedure:
106 g of 2-methyl-5-(4-chlorobenzylidene)-cyclopentanone, 49.5 g of 85% strength aqueous potassium hydroxide solution, 8.3 g of potassium iodide and 400 g of tert-butanol were weighed in succession into a 700 ml stainless steel autoclave, and 50.5 g of methyl chloride were injected at 20° C. The mixture was stirred at room temperature for 23 hours and then 300 ml of tert-butanol were distilled off at 20 mbar up to an overhead temperature of max. 50° C. 400 ml of water were added to the residue, and the mixture was stirred thoroughly. The resulting suspension was filtered off over a suction filter, and the filter cake was washed twice with 200 ml of water each time and dried. 112.8 g of a pale beige solid were thus obtained with a purity of 89.5%. The yield of the crude product was 90.2% of theory.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:12][CH:11]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(-c2cccn3ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3cccn4ccnc34)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a solution of 4-(imidazo[1,2-a]pyridin-8-yl)phenol (0.68 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.13 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.53 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.53 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:17](Br)([CH3:19])[CH3:18].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH:17]([CH3:19])[CH3:18])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: CC(C)Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Sc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, isopropyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 270 (M+, 30), 269 ([M—H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1>>[C:13]([C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][C:11]=1[NH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:14]
Reactant: Nc1cccnn1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccccc1Nc1cccnn1

Procedure:
Starting compounds: 3-aminopyridazine and 4-fluorobenzonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([O:20][CH3:32])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)O)cc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)OC)cc(F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of the alcohol of Step 1 (105 mg, 0.25 mmol) in DMF (5 mL) at 0° C. was added NaH (11 mg, 0.3 mmol). The reaction mixture was stirred at 0° C. for 20 minutes and MeI (51 mg, 0.4 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 30% EtOAc in Hexanes to provide 90 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C:3]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=[CH2:16])[CH:11]=2)[CH:6]=1)[OH:4]>C1COCC1.CO.[C].[Pd]>[CH2:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:4])[CH:2]([CH3:41])[CH3:1])[CH:14]=[CH:13]2)[CH3:16]
Reactant: C=Cc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 171 %

Procedure:
2-Methyl-1-(1-trityl-1H-imidazol-4-yl)-1-(6-vinylnaphthalen-2-yl)-1-propanol (1.20 g) was dissolved in THF (5 ml)-methanol (10 ml). To the solution was added 10% palladium carbon (120 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered off and washed with THF. The filtrate was concentrated and the residue was recrystallized from isopropyl ether-hexane (1:1) to give the titled compound (1.13 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Oc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
Equimolar portions (0.106 moles) of 3-hydroxypyridine, sodium hydroxide and p-toluenesulfonyl chloride were combined in 100 ml of water and stirred at 50° C. for 2.5 hours. The aqueous solution was extracted with chloroform, dried over sodium sulfate and distilled to yield an oil which crystallized on standing. Recrystallization from cyclohexane yielded a white solid, mp 76°-78° C., lit. mp 79° C.