Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14].[CH2:53]([N:55]=[C:56]=[O:57])[CH3:54].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:53]([NH:55][C:56](=[O:57])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14])[CH3:54]
Reactant: CCN=C=O
Reactant: NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (3-amino-propyl)-amide trifluoroacetate (Example 63) (10 mg, 0.027 mmol) is dissolved in dry DMF (0.25 ml). Ethyl isocyanate (0.92 mg, 0.013 mmol) is dissolved in dry DMF (0.25 ml). The two solutions were combined and triethylamine (>1 eq) is added. The reaction mixture is allowed to stand at room temperature over night. The solvent is removed in vacuo. Purification is carried out using mass directed preparative LC-MS eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)C=CC1C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1(/[CH:7]=[CH:27]/[CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Agent: O=CC=Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(/C=C/c1ccccc1)NC(=O)Cc1ccccc1
Yield: 88 %

Procedure:
Compound 46 was prepared from 2-phenylacetamide and cinnamaldehyde using the procedure for compound 44. Yield: 88%. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=7.6 Hz, 2H), 7.21-7.37 (m, 15H), 6.41-6.45 (m, 1H), 6.27-6.32 (m, 1H), 6.04-6.09 (m, 1H), 3.44-3.52 (m, 4H). LC-MS (ESI): m/z 385.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:12]1=[O:13]>>[OH:11][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:15][CH2:14][C:12]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:13]
Reactant: NCCCN1CCOCC1
Reactant: O=C1CCc2ccccc2O1
Product: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 116.5 %

Procedure:
N-(3-Aminopropyl)morpholine (1.77 g) was added to 3,4-dihydrocoumarine (1.81 g) and stirred for 1 hours at 70° C., thereby yielding the entitled compound (4.16 g) as pale yellow syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH:17]3[CH2:18][CH2:19]3)=[CH:23][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(OCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(OCC3CC3)cc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.6 g (10.4 mmol) 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester, 1.7 g (10.4 mmol) 4-cyclopropylmethoxy-phenol and 6.7 g (20.7 mmol) Cs2CO3 in 60 mL DMF is stirred for 12 h at 80° C. Water is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with NaHCO3 solution and are dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; PE/ethyl acetate; gradient 9:1→8:2) to yield the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20](O)(=[O:30])[CH2:21][CH2:22][CH2:23]CCCCCC.[CH2:32]([O:36][CH2:37][CH:38]=[CH:39][CH3:40])[CH2:33][CH2:34][CH3:35].C(O)CCC>>[CH2:37]([O:36][CH:32]([O:30][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:33][CH2:34][CH3:35])[CH2:38][CH2:39][CH3:40].[CH2:37]([O:36][CH:32]=[CH:33][CH2:34][CH3:35])[CH2:38][CH2:39][CH3:40]
Reactant: CC=CCOCCCC
Reactant: CCCCCCCCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CCC=COCCCC
Product: CCCCOC(CCC)OCCCC

Procedure:
A glass autoclave was filled with 0.022 g of the catalyst HRuCl(CO)(PPh3)3, 0.031 g of triphenylphosphine, 0.005 g of decanoic acid, 3.18 g (24.8 mmol) of 1-butoxybut-2-ene and 1.83 g (24.8 mmol) of n-butanol. After a reaction time of 16 hours at 160° C. under autogenous pressure, the reaction mixture was analyzed by means of calibrated gas chromatography. At a conversion rate of 85%, 1,1-dibutoxybutane was formed with a selectivity of 85.1% and 1-butoxybut-1-ene with a selectivity of 10.1%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][CH2:29][CH:30]([Mg]Br)[CH2:31][CH3:32]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH:30]([CH2:31][CH3:32])[CH2:29][CH3:28])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CCC(CC)[Mg]Br
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C(CC)CC)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Pentan-3-ylmagnesium bromide (2.0 M, 0.21 mL, 0.41 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-ethyl-1-(pyridin-2-yl)butan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated to afford the desired product as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C(O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19]/[C:12](=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([NH:1][C:31]([NH2:32])=[O:30])[CH:10]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:24]=1)=[O:27]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(N)ccc32)c2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(NC(N)=O)ccc32)c2ccccc2)cc1

Procedure:
560 mg of 6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone, 236 mg of potassium cyanate and 3.8 ml of glacial acetic acid are dissolved in 20 ml of ethanol and refluxed for 1 hour. After this time the solvent is evaporated, the residue is taken up in methylene chloride, washed with water and dried over sodium sulphate. After evaporation, the product is dried in the desiccator.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C(Cl)Cl.CO>[ClH:26].[ClH:32].[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:16]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Reaction time: 0.5 h

Procedure:
Dissolve 4-(4-(3-chloro-4-fluorophenyl)-1-(2-(dimethylamino)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (194 mg; 0.43 mmol) in DCM (5 mL) and methanol (3 mL) and add 4 M hydrogen chloride in dioxane (5 mL; 20 mmol). Stir 30 min and evaporate; add DCM/MeOH and evaporate under vacuum to provide the title compound (245 mg) as a white solid. MS (ES): m/z=351 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[C:14]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Product: CCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
In 5 ml of DMF, 330 mg (1.4 mol) of 2,4-dichloro-7-etylthieno[3,2-d]pyrimidine was dissolved, and then 228 mg (3.1 mmol) of t-butylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 312 mg (yield: 81.7%) of the title compound.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[Cl:33])=O>>[Cl:33][C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:25]1[N:10]=[C:11]([C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[S:22][CH:24]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1cnccc1Cl
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3cnccc3Cl)cs2)c(C)s1
Yield: 80.4 %

Procedure:
Methyl 4-4-(4-chloro(3-pyridyl))(3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 240 mg (0.970 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in a manner similar to Example 22, step (a) to afford 286 mg (77% yield) of methyl 4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.N1C=NN=N1.C(N(CC)[P:35]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)C.C([O:58]O)(C)(C)C.OS([O-])=O.[Na+]>C(#N)C.C(Cl)Cl>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][P:35](=[O:58])([O:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[O:44][CH2:45][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OO
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(OP(=O)(OCc5ccccc5)OCc5ccccc5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (180 mg, 0.5 mmol) was dissolved in a mixture of 1H-tetrazole (350 mg, 5 mmol) in 10 ml of dry acetonitrile and 10 ml of dry methylene chloride. At room temperature dibenzyl diethylphosphoramidite (476 mg, 1.5 mmol) was added under nitrogen and the mixture was stirred for 2 h. Then 70% tert-butyl hydroperoxide solution (1 ml) was added and the mixture was stirred for 1 h. At 0° C. 15 ml of 10% NaHSO3 was added and the mixture was stirred for another 15 minutes. The mixture was then extracted three times with CH2Cl2, and the organic layer was washed water. Evaporation of solvent yielded Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester as a yellow oil, which was purified by column chromatography. Fractions contained Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo [2.2.2]oct-1-yl ester was combined and concentrated in vacuum to get 280 mg product. MS (M+1) 621.
Reaction SMILES: [CH3:1][CH:2]([SH:6])[C:3]([O-:5])=[O:4].[Cl:7][C:8]1[C:9](F)=[C:10]([CH:13]=[CH:14][CH:15]=1)C=O.[CH3:17]N(C)C=O>>[Cl:7][C:8]1[C:9]2[S:6][C:2]([C:3]([O:5][CH3:17])=[O:4])=[CH:1][C:10]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CC(S)C(=O)[O-]
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(Cl)c1F
Product: COC(=O)c1cc2cccc(Cl)c2s1

Procedure:
In a similar manner to Example 18, methylthioglycolate (13 g) was reacted with 3-chloro-2-fluorobenzaldehyde (19.57 g) in dimethylformamide to give methyl 7-chlorobenzo[b]thiophene-2-carboxylate, which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 7-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide, which was reacted with ethylmagnesium bromide to give 1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one. This ketone (1.17 g) was reacted with phenyltrimethylammonium tribromide (2.15 g) to give 2-bromo-1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one (2.32 g) which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[O:2].[CH2:13]([Mg]Br)[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[Mg]Br
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)nc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a −10° C. solution of methyl 6-formylnicotinate (800 mg, 4.8 mmol) in tetrahydrofuran was added isobutylmagnesium bromide (3.6 mL, 7.2 mmol, 2.0M in THF). The resulting mixture was stirred at −10° C. After 2 hours, additional isobutylmagnesium bromide (2.4 mL, 4.8 mmol) was added and the reaction was stirred at −10° C. for another 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to a brown oil. Purification by column chromatography (0-15% ethyl acetate in petroleum ether) gave methyl 6-(1-hydroxy-3-methylbutyl)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 9.14 (s, 1H), 8.29-8.27 (d, 1H), 7.36-7.34 (d, 1H), 4.85-4.83 (m, 1H), 3.78 (s, 3H), 1.95-1.91 (m, 1H), 1.65-1.51 (m, 2H), 1.03-1.01 (d, 3H), 0.96-0.95 (d, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:18](OC(OCC)OCC)C.[ClH:28]>C(O)=O>[Cl-:28].[CH:1]([N+:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=1)([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CCOC(OCC)OCC
Reactant: CC(C)Nc1cccnc1Nc1ccccc1
Solvent: O=CO
Product: CC(C)[n+]1cn(-c2ccccc2)c2ncccc21
Product: [Cl-]
Temperature: 25 °C
Yield: 67.2 %

Procedure:
N3-isopropyl-N2-phenylpyridine-2,3-diamine (10 g, 44.0 mmol), triethoxymethane (293 mL, 1760 mmol), formic acid (0.017 mL, 0.440 mmol) and hydrogen chloride (4.24 mL, 44.0 mmol) were mixed together and heated to reflux overnight. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The solid product was collected and washed with hexanes. 1-isopropyl-3-phenyl-3H-imidazo[4,5-b]pyridin-1-ium chloride (8.1 g, 67% yield) was isolated as white crystalline solid after recrystallization from boiling ethanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1.[Cl:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[Cl:47].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOCC.CCO>[Cl:31][C:32]1[N:37]=[C:36]([C:44]2[CH:43]=[CH:42][C:41]([Cl:40])=[C:46]([Cl:47])[CH:45]=2)[C:35]([Cl:39])=[CH:34][N:33]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ncc(Cl)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.19 g (0.5 mmol) of bis(benzo-nitril) dichloro-palladium (II) and 0.2 g 1,4-bis(di-phenylphosphino)butane in 10 mL of toluene was heated at reflux with stirring for 1 h under nitrogen. The suspension was cooled to room temperature. One gram (6.6 mmol) of 3A, 1.57 g of 3,4-dichlorobenzene boronic acid (8.2 mmol), 2.5 mL EtOH and 5 mL of 1 M Na2CO3 were added and the mixture heated to reflux for 20 h. The reaction mixture was cooled and diluted with 100 mL Et2O. The suspension was filtered through a plug of silica gel and the cake washed with an additional 100 mL of Et2O. The ether was evaporated and the residue chromatographed over silica gel (10% EtOAc/hexane). A fraction containing 0.72 g (32%) of 2,5-dichloro-4-(3,4-dichlorophenyl)pyrimidine was isolated as a white solid. (m.p. 125-126° C.)
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])=O)[CH:9]=[CH:10][CH:11]=1>C(O)C.C(O)(=O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[N:2][NH2:3])[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)C(=NN)c2cccc(OC)c2)c1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
To a solution of 1.0 g hydrazine hydrate in 25 ml ethanol is added a warm solution of 3,3'-dimethoxybenzil, 7.0 g in 125 ml ethanol. The solution is heated to 65° C for 48 hours. Three drops of acetic acid are added and heating is continued for 48 hours. The solution is concentrated, diluted with 100 ml water and extracted with methylene chloride. The organic layer is removed, dried over magnesium sulfate and the solvent removed. The oily residue is chromatographed on 200 g of BioSil-A using chloroform-benzene mixtures. Elution of product is completed with methylene chloride. The product from chromatography is recrystallized from chloroform-hexane yielding 2.8 g of pale yellow needles. M.P. 109°-110.5°.
Reaction SMILES: FC1C=C[C:5]([CH:8]2[O:13]C(=O)CC(=O)[O:9]2)=CC=1.[CH:16](=O)[C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(O)=O>C(N(CC)CC)C>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:5][C:8]([OH:13])=[O:9])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: O=C1CC(=O)OC(c2ccc(F)cc2)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
5.26 g (0.025 mol) of 2-(4-fluorophenyl)-1,3-dioxane-4,6-dione (m.p.: 166°-167° C.) and 4.15 g (0.025 mol) of veratraldehyde were added to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction was carried out according to Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12][N:13]([CH3:28])[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:43]CCCl>>[ClH:43].[ClH:43].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][CH2:20][CH:17]2[CH2:16][CH2:15][C:14]([N:13]([CH3:12])[CH3:28])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18]2)=[CH:2]1
Reactant: NCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)C1(c2ccccc2)CCC(CNCc2c[nH]c3ccccc23)CC1
Product: Cl
Reaction time: 24 h

Procedure:
C-(1H-Indol-3-yl)-methylamine (292 mg, 2 mmol.) and 4-dimethylamino-4-phenylcyclohexanecarbaldehyde (463 mg, 2 mmol.) were dissolved, under argon, in abs. 1,2-dichloroethane (20 ml). Sodium triacetoxyborohydride (600 mg, 2.8 mmol.) was added to this mixture, and stirring was carried out for 24 h at RT. For working up, the mixture was concentrated and 1M HCl (20 ml) and ether (40 ml) were added thereto. The aqueous phase was washed with ether (2×20 ml), adjusted to pH 11 with 5M NaOH, diluted with water (10 ml) and extracted with EE (3×20 ml). The combined EE extracts were dried, filtered and concentrated. The resulting crude product, a mixture of the two diastereoisomeric target compounds, was purified by chromatography on silica gel with methanol/conc. ammonia solution (500:1) and separated. The non-polar diastereoisomer of (4-{[(1H-indol-3-ylmethyl)amino]methyl}-1-phenylcyclohexyl)dimethylamine dihydrochloride could be obtained in the form of a brown oil in a yield of 83 mg. The oil was dissolved in 2-butanone (5 ml); chlorotrimethylsilane (72 μl, 0.56 mmol.) was added thereto, and stirring was carried out for 2 h at RT. The resulting solid was filtered off with suction. The dihydrochloride of the non-polar diastereoisomer of (4-{[(1H-indol-3-ylmethyl)amino]methyl}-1-phenylcyclohexyl)dimethylamine could thus be obtained in a yield of 48 mg (white solid, m.p. 181–183° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.C(OC(C1N=NC(OCC2C(C3C=CC(F)=CN=3)=NOC=2C)=CC=1)=O)C>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccn1
Agent: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)nn1
Product: O=C(O)c1conc1-c1ccccn1
Yield: 77.7 %

Procedure:
As described for example 112a, 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (9.6 g, 44 mmol), instead of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester, was converted to the title compound (6.5 g, 79%) which was obtained as an off-white solid. MS: m/e=189.3 [M−H]−.