Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:25])[CH2:23][CH3:24])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([CH2:26][N:27]([C:28]1[CH:29]=[CH:30][C:31]([Br:34])=[CH:32][CH:33]=1)[C:11]([C@@H:9]1[CH2:10][C@H:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)=[O:13])[C@@H:22]([CH3:25])[CH2:23][CH3:24])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC[C@H](C)[C@@H](CNc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1cccc(F)n1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid (120 mg, 0.55 mmol) in thionyl chloride (2 mL) was heated at reflux for over night. The mixture was concentrated and dried under high vacuum for 3 h. Then the residue was dissolved in DCM (3 mL) and added dropwise to a solution of {(1S,2S)1-[(4-Bromo-phenylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (205 mg, 0.55 mmol) and triethyl amine (153 uL, 1.1 mmol) in DCM (3 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated and the residue was subjected to ISCO (12 g column, 0-40% EtOAc in hexane over 25 min.) to give the desired product (235 mg, 80%). MS (MH+ 534 and 536).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([CH2:37][NH2:38])[OH:36].O>CN(C=O)C>[OH:36][CH2:35][CH2:37][NH:38][C:20]([C:18]1[N:19]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[NH:16][CH:17]=1)=[O:21]
Reactant: COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1OC1CCCC1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(=O)NCCO)c[nH]2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 2-(3-Cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid (500 mg, 1.65 mmol) in DMF (15 ml) at room temperature was added carbonyldiimidazole (295 mg, 1.8 mmol). The resultant solution was stirred for 30 minutes and then ethanolamine (180 μl, 1.8 mmol) was added and the reaction mixture stirred at room temperature overnight. Water (75 ml) was added and the mixture extracted with ethyl acetate (2×75 ml). The combined organics were washed with brine (40 ml), dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2 ; CH2Cl2 :EtOH (95:5) (1% NH3)) afforded 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid, N-(2-hydroxyethyl) amide (247 mg, 43%) as a white solid, mp 206-208° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1/[CH:37]=[CH:38]/[CH2:39]O.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][C:26]1[NH:27][CH:28]=[CH:29][N:25]=1)=[O:9]
Reactant: OC/C=C/c1ccccc1Cc1ncc[nH]1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccccc2Cc2ncc[nH]2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-{2-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 528 mg (100%).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:18]([O:19][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Estradiol (2 g, 0.0073 mol) was added to nicotinoyl chloride hydrochloride (5.3 g, 0.029 mol) in dry pyridine (30 ml) at 0° C. The mixture was refluxed for 1 hour and then poured over 100 ml of ice water, filtered and dried over P2O5 under vacuum. Yield 90% (3.18 g), m.p. 148°-150° C. Anal. calculated for C30H31N2O4 : C, 74.50; H, 6.47; N, 5.79. Found: C, 74.40; H, 6.32; N, 5.75. The product has the formula: ##STR91##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([CH3:19])[N:9]2[CH3:20])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:33][CH2:19][C:10]1[N:9]([CH3:20])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12](=[O:13])[C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)n(C)n(-c2ccc(F)cc2)c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(CBr)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.2 g, 4.3 mmol) and azobisisobutyronitrile (AIBN) (0.09 g, 0.06 mmol) in DCM is added N-bromosuccinimide (NBS) (0.9 g, 4.3 mmol) in three portions at RT. The resulting reaction mixture is stirred at RT overnight. The mixture is concentrated and the residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the product as a white solid (1.3 g, 84% yield). MS (m/z) 357.0 (M+H).
Reaction SMILES: [H-].[Na+].CO[N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl.C1C[O:38][CH2:37]C1>>[CH3:37][O:38][CH2:30][NH:5][C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1CCOC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Product: COCNC(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF was added a mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methyl ether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 2.70 grams of the title compound as a white solid. (M+H)+ expect 502.0, found 502.0.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(C(C)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)N1C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-2-acetyl-6-benzoylamino-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 11, (70 mg, 0.14 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 36 mg of the desired product as a white solid. 1H NMR (CD3OD) δ 7.90 (d, J=6.9 Hz, 2H), 7.52 (m, 3H), 5.2–4.2 (series of m, 7H), 3.40 (m, 1H), 3.18 (m, 1H), 2.8–1.2 (series of m, 12H), 2.35 (s, 3H); MS 487 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH:11](C)[CH2:12][CH:13]=O)[O:8][N:7]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:31][CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(CC=O)c1cc(-c2cccs2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 38.3 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)butanal (21 mg, 0.095 mmol) and 1-benzylpiperazine (16.5, 0.095 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (60.4 mg, 0.285 mmol), cold acetic acid (6.5, 0.114 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.2 hr and followed the same processes as in Example 1 to obtain 13.9 mg (81.0%) of the target compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][Cl:20])[N:14]=1.[CH2:21]([O:23]CC)[CH3:22]>CN(C=O)C>[Cl:20][CH2:19][C:15]1[N:14]=[C:13]([CH3:12])[C:18]([O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: O=C(O)c1ccccc1O
Reactant: ClCc1cccc(CCl)n1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h

Procedure:
To a solution of salicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at reduced pressure. The reaction crude product is purified by chromatography on silica gel by eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product as yellow oil are obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])#[N:25]>N1CCCCC1.CO>[C:18]1([CH2:17][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:10]=[CH:11][C:12]([CH:13]=[C:26]([C:24]#[N:25])[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CC#N
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A mixture of 4-(bis(phenylmethyl)amino]benzaldehyde (60.2 g, 0.20 mol), methyl cyanoacetate (21.8 g, 0.22 mol), methanol (300 mL), and piperidine (10 drops) is heated at reflux for 1.5 hours. After cooling, the yellow product is collected by filtration, washed with methanol, and dried in air. The yellow colorant, methyl 3-[4-[bis(phenylmethyl)amino]phenyl]-2-cyano-propenoate, is obtained in a yield of 53.5 g (70.0% of theory).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]3([C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]3)[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]5([C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]5)[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)C1(c2cn3nc(Cl)ccc3n2)CC1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(=O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CC1
Product: Cl
Yield: 49.1 %

Procedure:
2.72 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.27 g of isopropyl 1-(6-chloroimidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxylate were stirred at 165° C. for 4.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.72 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration again. The residue was crystallized by the addition of ethyl acetate-acetone (2:1), collected by filtration, washed with ethyl acetate and dried to yield 714 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[Si]([C:14]#[N:15])(C)C.[F:16][C:17]1[C:24]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:23][C:22]([O:36][CH3:37])=[CH:21][C:18]=1[CH:19]=O>C1COCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>[C:14]([CH:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:18]1[CH:21]=[C:22]([O:36][CH3:37])[CH:23]=[C:24]([O:25][Si:26]([CH:27]([CH3:28])[CH3:29])([CH:33]([CH3:34])[CH3:35])[CH:30]([CH3:31])[CH3:32])[C:17]=1[F:16])#[N:15]
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1cc(C=O)c(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(C#N)Nc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After adding 18 g of 4-aminobenzonitrile, 50 g of MS3A, 6.65 g of Yb(OTf)3 and 28.6 ml of trimethylsilyl cyanide to a solution of 50.04 g of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde (Example 3b) in 300 ml of THF under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was suspended in ethyl acetate-heptane (1:2) and the solid was filtered to give 4-{[cyano-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)methyl]amino}benzonitrile (59.32 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12e and thiazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH3:18].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Yield: 89.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-methyl-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine (9.4 g, 34.06 mmol) and dimethylformamide dimethyl acetal (9.0, 68.12 mmol) in dimethylformamide (70 mL) was heated to 140° C. for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure (50° C. bath temperature). The residue was slurried in methanol and concentrated at reduced pressure. This methanol slurry/concentration procedure was repeated twice. The residue was triturated with methanol and the light yellow crystalline solid which formed was collected and dried to give 10.1 g (85%) of 3-(2-chloro-phenyl)-2-(dimethylamino-vinyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine which had: 1H NMR δ 7.83 (d, J=12.5 Hz, 1 H), 7.68 (d, J=5 Hz, 1 H), 7.57 (m, 1 H), 7.41 (m, 2 H), 7.31 (m, 1 H), 7.14 (d, J=5 Hz, 1 H), 4.06 (d, J=12.5 Hz, 1 H), 2.77 (br s, 6 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[CH3:15])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dissolve 2,4,6-trichloropyrimidine (23.5 g, o.13 mol) in anhydrous MeOH (220 mL), and add solid sodium bicarbonate (28.3 g, 0.33 mol). Cool to 0° C. and add 2-methylpyrrolidine (12 g, 0.14 mol) dropwise. Let stir at room temperature for 16 h. Filter off the excess sodium bicarbonate, and evaporate under reduced pressure. Purify by SiO2 liquid chromatography, using 50:1 hexanes:EtOAc, increasing to 30:1 hexanes:EtOAc, to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([CH:18]=C)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].CSC.C[OH:25]>ClCCl>[NH2:20][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[C:14]([CH:18]=[O:25])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CO
Reactant: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Solvent: ClCCl
Solvent: CSC
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Temperature: 25 °C

Procedure:
A solution of 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) in dichloromethane (30 mL) and methanol (5 mL) was cooled to −78° C. Ozone was bubbled through the solution for 10 minutes. While still cold, the reaction was purged with oxygen for 15 minutes and dimethyl sulfide (0.7 mL, 9.4 mmol) was added. The reaction was warmed to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous fractions were extracted with chloroform (3×20 mL) and sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-6% methanol in dichloromethane) to provide 237 mg of 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde as an off-white solid. MS (ESI) m/z 269 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1>[Pd]>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CC1CNCc2[nH]c3ccccc3c21
Agent: [Pd]
Product: Cc1cncc2[nH]c3ccccc3c12
Temperature: 160 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
4-methyl-2,3,4,9-tetrahydro-1H-β-carboline (214 mg, 1.17 mmol) was suspended in xylenes (10 ml). Pd (10% wt. on carbon, 21 mg) catalyst was added thereto and the reaction mixture was stirred at 160° C. for 24 hours, then cooled to RT and filtered through celite. The filtrate was concentrated to dryness to give 4-methyl-9H-β-carboline (210 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([F:11])[CH:3]=1.BrC1C=CC(C[C:20](N)=[O:21])=C(F)C=1.S(=O)(=O)(O)[OH:25]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:21][CH3:20])=[O:25])=[C:4]([F:11])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(Br)cc1F
Reactant: NC(=O)Cc1ccc(Br)cc1F
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of a crude (72% purity) mixture of 2-(4-bromo-2-fluorophenyl)acetonitrile and 2-(4-bromo-2-fluorophenyl)acetamide (1.4:1 ratio, 2.0 g) in methanol (6 mL) was treated dropwise with conc. sulfuric acid (4 mL, 75 mmol). The vessel was then sealed, heated in an oil bath at 80° C., and stirred for three days. At this point the reaction was cooled to room temperature and was diluted slowly with water (50 mL). The mixture was then extracted twice with dichloromethane. The organic layers were combined and washed with saturated aq sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound as a clear oil. The crude oil was used directly in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (s, 3 H) 3.74 (s, 2 H) 7.34 (t, J=8.08 Hz, 1 H) 7.38-7.43 (m, 1 H) 7.55 (dd, J=9.60, 2.02 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:21]([OH:22])[OH:20]
Reactant: COCCc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-bromophenyl)ethyl methyl ether (V.2; 1 eq.) in THF (0.16M) at −78° C. was added n-butyllithium (2.5M; 1.1 eq.). The reaction mixture was stirred for 1 h at −78° C. then tri-iso-propylborate (1.2 eq.) was added and the final mixture was allowed to warm slowly to room temperature and stirred for 1 h. The reaction was quenched with the addition of aqueous HCl (1N) and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated to afford the desired material as a foam which was used as such.