Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@H:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43](CCN)[CH2:42][CH2:41]1>C(N(CC)CC)C>[ClH:31].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@@H:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]4)=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: COCCN1CCN(CCN)CC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccccc2Cl)C3)cc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3[C@@H](c3ccccc3Cl)C4)cc2)CC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=143-145° C. 1H NMR (DMSO) 400 MHz δ 9.67 (s, 1H), 8.36-8.32 (m, 1H), 8.30 (s, 1H), 7.82-7.78 (m, 2H), 7.54-7.43 (m, 3H), 7.27-7.22 (m, 3H), 7.18-7.13 (m, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.79-6.75 (m, 1H), 4.78 (t, J=6.0 Hz, 1H), 3.86-3.70 (m, 5H), 3.69-3.24 (m, 12H), 3.22-3.09 (m, 2H), 3.07-2.98 (m, 2H). LCMS 554 [M+H]. Calc. for C33H36ClON5.3.07 Hydrochloric acid.0.34 Ethyl Acetate.0.04 Water: C, 59.23; H, 6.06; N, 10.05. Found C, 59.17; H, 6.05; N, 10.05.
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:19])[CH3:18].O>C1COCC1>[C:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27])=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ex-33A: To a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.74 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) in 25 ml THF, 4-acetylbenzenesulfonyl chloride(1.1 g, 5 mmol) was added at 0° C. The mixture was stirred overnight and then poured into H2O. The precipitate was filtered, dried, and recrystallized from EtOAc/Hexene to give 1.3 g (76.8%) of 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.11 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 6.59 (b, 1H), 2.67 (s, 3H), 0.89 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:35]>O1CCOCC1>[ClH:35].[NH:22]1[CH2:23][CH2:24][CH:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:18])[CH2:20][CH2:21]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Solvent: CO
Solvent: C1COCCO1
Product: Cl
Product: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCNCC2)CC1
Yield: 46 %

Procedure:
General procedure B was subsequently followed using benzyl-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate (330 mg), MeOH (10 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) to furnish the title compound 12 as a white solid (120 mg, 46%), umax (CHCl3)/cm−1 3016, 2949, 1699, 1639, 1431, 1250, 1227, 1125, 1019; m/z (ESI) C18H26N3O3 requires 332.1969, found [M+H]+ 332.1968.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH3:31])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH3:31])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: CSCCCCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCCCCCn1c(C)nc2c(N)nc(C)c(C)c21
Temperature: 160 °C
Yield: 50 %

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.75 g, 7.45 mmol) were combined and heated at 160° C. overnight. The reaction mixture was cooled to 0° C. and then diluted with water (50 mL). The pH was adjusted to >13 with 15% sodium hydroxide and then the mixture was extracted with chloroform (2×100 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified on deactivated silica gel (triethylamine) eluting with 2% methanol in chloroform and then recrystallized from ethyl acetate/hexanes to provide 1.089 g of 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white solid, m.p. 121-122° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]1[C:15]([O:17]CC)=[O:16].[Li+].[OH-].O.C1COCC1>CO>[C:11]([O:10][C:8]([N:6]1[CH2:7][C@@H:3]([C:2]([F:21])([F:1])[F:20])[C@H:4]([C:15]([OH:17])=[O:16])[CH2:5]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(F)(F)F)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of trans-1-tert-butyl 3-ethyl 4-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (61.2 g, 0.19 mol), LiOH (39.9 g, 0.95 mol) in a mixed solvent of water (300 mL), THF (300 mL) and MeOH (150 mL) was stirred at rt overnight. The reaction mixture was concentrated in vacuum, then acidified with 1N HCl to pH=1, and extracted with EtOAc (three×300 mL). The combined organics were dried over Na2SO4 and concentrated to give the title compound (47 g, 87% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(O)c(Cl)c1

Procedure:
46.2 g (0.273 mol) of 3-chloro-4-hydroxy-benzaldehyde, 104 g (1 mol) of malonic acid, 140 ml of pyridine and 4 ml of piperidine are heated to 100° C. for 2 hours, whilst stirring. The volatile constituents are distilled off under reduced pressure at 80° C. and the residue is stirred with 800 ml of water. The resulting crystals are filtered off and recrystallised from methanol-water. 3-Chloro-4-hydroxy-cinnamic acid of melting point 180°-182° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.O[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: OC1CCOC1
Reactant: Cc1nc(O)ccc1Br
Product: Cc1nc(OC2CCOC2)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13](Cl)=[O:14].C(N(CC)CC)C>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccs1)c1cc(Cl)cc(Cl)c1
Yield: 92.9 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 3,5-dichlorobenzoyl chloride (120 mg, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 3,5-dichloro-N-(2-thiophen-2-yl-ethyl)-benzamide (118 mg, 0.39 mmol, 92% yield) as a white powder after purification by chromatography on silica gel (eluent: EtOAc/hexane 2/8).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](Cc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A mixture of 1A (1.61 g, 4.0 mmol) and sodium azide (0.78 g, 12.0 mmol) in DMF (27 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with H2O (120 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, step-wise gradient from 2-40% EtOAc in Hexanes) to give 2A (1.46 g, 100%) as a clear oil. 1H NMR (600 MHz, CDCl3): δ 7.05 (2H, d, J=8.4 Hz), 6.85 (2H, d, J=8.4 Hz), 4.97 (1H, d, J=7.8 Hz), 4.51-4.58 (1H, m), 4.13 (2H, t, J=5.4 Hz), 3.71 (3H, s), 3.58 (2H, t, J=5.4 Hz), 3.06 (1H, dd, J=13.8, 5.4 Hz), 3.00 (1H, dd, J=13.8, 5.4 Hz), 1.42 (9H, s); 13C NMR (150 MHz, CDCl3): δ 172.3, 157.3, 155.1, 130.4, 128.7, 114.6, 79.9, 66.9, 54.5, 52.2, 50.2, 37.5, 28.3; MS (ESI, m/z): 387 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:17]2[CH2:16][O:15][CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 3-(methylamino)methylazetidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol), oxetan-3-one (135 mg, 1.88 mmol), in dichloromethane (10 mL) was stirred at RT for 1.5 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with water, the phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (330 mg, 69%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2 H, t, J=6.58 Hz), 4.57 (2 H, t, J=6.26 Hz), 4.01 (2 H, t, J=8.40 Hz), 3.57-3.55 (3 H, m), 2.71-2.61 (1 H, m), 2.41 (2 H, d, J=7.57 Hz), 2.08 (3 H, s), 1.44 (9 H, s).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:8]2[NH:9][C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH2:6][C:5]2[NH:18][C:19]4[C:24]([C:25](=[O:26])[C:4]1=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+]>CO>[CH:22]1[CH:23]=[C:24]2[C:25]([C:4]3[C:5]([NH:18][C:19]2=[CH:20][CH:21]=1)=[CH:6][C:7]1[C:16]([C:15]2[C:10]([NH:9][C:8]=1[CH:3]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])=[O:26]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 40 °C

Procedure:
79 Parts of methanol and 12 parts of a 50% NaOH aqueous solution were fully stirred in a stainless steel flask having a refluxing device. 10 Parts of the 6,13-dihydroquinacridone obtained in Example 1 and 10 parts of sodium m-nitrobenzenesulfonate were gradually mixed with the above-prepared solution, and the mixture was refluxed at 70° to 75° C. for 3 to 5 hours. The reaction mixture was cooled to 40° C. and filtered, and the resultant cake was cleaned with hot water until a wash liquid became colorless and transparent, to give 9.77 parts (98.3% of a theoretical value) of a nonsubstituted quinacridone. The so-obtained quinacridone was measured by IR and absorbance to show 99.2% of quinacridone and 0.8% of 6,13-dihydroquinacridone. The quinacridone had a specific surface area of 22.1 m2 /g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[S:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[O:26]([CH2:25][C:23]1[CH:22]=[CH:21][C:20]([S:33][C:34]2[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=2)=[C:19]([NH:18][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 2g as a 4.1M solution in ethanol (0.050 mL, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 2g (0.025 mL, 0.102 mmol) and continued heating at 80° C. (12 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0269 g, 21.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.54 Hz, 3 H) 1.76-1.99 (m, 2H) 3.00 (t, J=7.35 Hz, 2 H) 5.12 (s, 2 H) 6.31 (d, J=6.99 Hz, 1 H) 6.79 (d, J=8.82 Hz, 2 H) 6.91-7.07 (m, 4 H) 7.17-7.37 (m, 4 H) 7.43-7.55 (m, 2 H) 7.84 (d, J=8.82 Hz, 1 H) 8.47 (d, J=7.35 Hz, 1 H) 9.04 (d, J=8.46 Hz, 1 H) 9.97 (s, 1 H); MS (ESI+) m/z 494.2 (M+H)+; (ESI−) m/z 492.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[Br:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].N1CCOCC1>CO>[Br:12][C:13]1[CH:14]=[C:15]([CH:23]2[C:10]3[C:2](=[C:3]4[CH:4]=[CH:5][N:6]([CH3:11])[C:7]4=[CH:8][CH:9]=3)[O:1][CH:25]([OH:26])[CH2:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Solvent: C1COCCN1
Solvent: CO
Product: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 4-hydroxy-N-methyl indole (11 mg, 0.075 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (20 mg, 0.074 mmol) in methanol (0.6 ml) containing morpholine (7 μl, 0.08 mmol) was held under reflux for 2 h and the mixture was allowed to stir at room temperature overnight. The solvent was evaporated to dryness. The residue was dissolved in acetic acid (0.8 ml) and water was added until the mixture became turbid. It was held at 50° C. for 10 minutes. It was cooled and added slowly to saturated sodium bicarbonate solution. The product was extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent was evaporated and the crude product was passed through a bond-elute (hexane:ethyl acetate=9:1 and 8:2 as eluents), giving the title compound (16 mg, 52%). 1H NMR (acetone-d6): 7.09 and 7.08 (d each, J=2.9 Hz; 1H), 7.00 and 6.98 (d each, J=1.7 Hz; 1H), 6.95 and 6.93 (d each, J=1.7 Hz; 1H), 6.85 and 6.83 (d each, J=8.6 Hz; 1H), 6.55 and 6.50 (d each, J=8.5 Hz; 1H), 6.42 and 6.41 (d each, J=3.3 Hz; 1H), 6.15 (fine split doublet, J=6.8 Hz) and 6.08 (d, J=4.9 HZ) (1H), 5.67-5.70 and 5.54-5.58 (m each, 1H), 4.34 (overlapping dd, J=5.8, 10.1 Hz; 1H), 3.84, 3.81, 3.78 and 3.75 (s each, 9H), 2.38-2.43 and 2.09-2.25 (m each, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([NH:18][NH2:19])=[O:17].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:19][NH:18][C:16](=[O:17])[C:15]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:13]([OH:12])[CH:14]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NN)cc1O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)Cc2ccc(Cl)cc2)cc1O
Temperature: 85 °C

Procedure:
A mixture of 4-chlorophenylacetyl chloride (1.36 g, 7.22 mmol) (Aldrich), 3-hydroxy-4-methyl-benzoic acid hydrazide (1.0 g, 6.02 mmol) (from Example 6 supra) and triethylamine (1.36 mL) in tetrahydrofuran (20 mL) was heated at 85° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue washed with ethyl acetate and dichloromethane and dried to give 3-hydroxy-4-methyl-benzoic acid N′-[2-(4-chloro-phenyl)-acetyl]-hydrazide. (Yield 0.91 g, 95%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].C(=O)([O-])OC.[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH2:31])=[C:29]([F:35])[CH:28]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH:31][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:16]#[N:17])=[C:29]([F:35])[CH:28]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: COC(=O)[O-]
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl

Procedure:
By using the above method, starting with 3 g of 7-(3-chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 2.35 g of the methyl carbonate of 4chloro-2-fluoro-5-hydroxy-aniline, and 1.1 g of pyridine hydrochloride in 30 ml of 2-ethoxyethanol, 1.7 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m/e) M+H 435.8, 437.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][O:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].[OH-].[Li+].Cl.C(OCC)(=O)C>CO.C1COCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][O:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The compound of Example 4 (25 mg, 47.7 μmol) along with 1.0 ml of 4:I methanol/THF, and 0.09 ml of 1 N lithium hydroxide were stirred at 0° C. for thirty minutes. An additional 0.09 ml of 1 N lithium hydroxide was added and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into 0.5 N hydrochloric acid/ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated under Vacuum to give the product; melting point 136-139° C. High resolution mass spectrum m/e 510.2471 (calculated for C29H36NO7 (M+H), 510.2492).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[NH:10][CH2:11][CH2:12][CH2:13][NH2:14].[Br:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[S:19][C:20]=1[Br:21]>>[Br:15][C:16]1[C:17]([CH3:24])=[C:18]([CH2:22][NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]2[NH:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[S:19][C:20]=1[Br:21]
Reactant: NCCCNc1nc2ccncc2[nH]1
Reactant: Cc1c(C=O)sc(Br)c1Br
Product: Cc1c(CNCCCNc2nc3cnccc3[nH]2)sc(Br)c1Br
Yield: 39 %

Procedure:
Using the general method for reductive amination a mixture of N-(3H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine (0.037 g, 0.19 mmol) and 4,5-dibromo-3-methylthiophene-2-carbaldehyde (0.054 g, 0.19 mmol) gave the title compound as a white solid (0.034 g, 49%). m/z (ES+) 459 (100% M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18]C)=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1.Cl>[OH-].[Na+].C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1
Reactant: COC(=O)C1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(C2CCCC(C(=O)O)C2)cc(-c2ccccc2O)nc1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A suspension of methyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclo-hexanecarboxylate (151 mg, 0.43 mmol) in 2N NaOH (1 mL) and THF (2 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was neutralized with 1N HCl (2 mL), and then diluted with water. The resulting precipitates were collected by filtration, washed with EtOH, and dried (60° C., 2 hrs, under reduced pressure) to give 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclohexanecarboxylic acid as a yellow solid (105 mg, yield; 72%).
Reaction SMILES: C(N1CCN(CC2C=CC(N[C:17]3[N:22]=[C:21]([C:23]4[CH:35]=[C:34]([F:36])[C:26]5[N:27]=[C:28]([CH3:33])[N:29]([CH:30]([CH3:32])[CH3:31])[C:25]=5[CH:24]=4)[C:20]([F:37])=[CH:19][N:18]=3)=NC=2)CC1)C.[Cl:38]C1N=CC=CN=1>>[Cl:38][C:17]1[N:22]=[C:21]([C:23]2[CH:35]=[C:34]([F:36])[C:26]3[N:27]=[C:28]([CH3:33])[N:29]([CH:30]([CH3:32])[CH3:31])[C:25]=3[CH:24]=2)[C:20]([F:37])=[CH:19][N:18]=1
Reactant: Clc1ncccn1
Reactant: CCN1CCN(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc(C)n(C(C)C)c5c4)n3)nc2)CC1
Product: Cc1nc2c(F)cc(-c3nc(Cl)ncc3F)cc2n1C(C)C

Procedure:
Prepare the following intermediates essentially as described for [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine below using the corresponding amine and chloro-pyrimidine derivatives:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[OH:12]>C(Cl)Cl.CCOCC.[Cr]>[CH3:7][O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)=[O:12]
Reactant: COC(=O)C(c1ccc(F)cc1)C(O)c1ccnc(SC)n1
Agent: [Cr]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of CrO3 in CH2Cl2 (300 mL) is added pyridine. The mixture is stirred vigorously for 1 hour at room temp. A solution of the crude 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl ester, 2, prepared above in CH2Cl2 (50 mL) is added dropwise to the chromium suspension. The reaction mixture is stirred at room temperature for 16 hours, diluted with ether (1 L) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (25% EtOAc/hexanes) to afford 3.7 g (43% yield) of the desired product as a yellow solid.