Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 84.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (intermediate 66G) (100 mg, 0.148 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (67 mg, 0.223 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.007 mmol) and sodium carbonate (40 mg, 0.372 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 90 mg (84.1% yield) of the titled compound after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=659.8 (M+1) (de t-butyl).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:43])([CH:33]([O:37]C(=O)C(C)=C)[CH:34](C)C)[C:15]([O:17][CH2:18]CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=[O:16].C(=O)([O-])O.[Na+]>CO>[F:43][C:14]([F:13])([C:33]([OH:37])([CH3:34])[CH3:2])[C:15]([O:17][CH3:18])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)C(=O)OC(C(C)C)C(F)(F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>C1COCC1.O.CO>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(N4CCCC4)c(C(F)(F)F)c3)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(N4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 2-(7-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (17.8 mg, 0.037 mmol) in 5 mL (THF/water/MeOH 3:1:1), LiOH hydrate (7.68 mg, 0.183 mmol) was added. After stirring at room temperature for 2 h, the mixture was partially concentrated and the residue was extracted with 0.5 M citric acid and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated to give the title compound as a brownish sticky solid (16.3 mg). LCMS m/z=459.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.95 (m, 4H), 2.09-2.16 (m, 1H), 2.57-2.64 (m, 1H), 2.73-2.90 (m, 4H), 3.27-3.35 (m, 4H), 3.53-3.59 (m, 1H), 4.99 (s, 2H), 6.82 (dd, J=8.8, 2.4 Hz, 1H), 6.96-7.01 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.45 (dd, J=8.6 Hz, 2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1)C(OCC)=O.[CH3:17][Mg]Br.C([O:22][CH2:23][CH3:24])C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([OH:22])([CH3:24])[CH3:17])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:12]=1
Reactant: CCOCC
Reactant: CCOC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)nc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.200 g, 0.789 mmol, Anichem) in tetrahydrofuran (5 mL) at 0° C. was added 3.0M methylmagnesium bromide in diethyl ether (0.66 mL, 2.0 mmol). After 30 minutes, the reaction was quenched by the addition of saturated ammonium chloride solution and extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. Used without further purification in Step B. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=1.4 Hz, 1H), 7.66-7.59 (m, 1H), 1.59 (s, 6H); 19F NMR (282 MHz, CDCl3) 5-68.30 (s); LCMS (M+H)+: 240.1.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C:39]([OH:41])=[O:40]
Reactant: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1ccccn1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](N)C(=O)O)Cc1ccccn1
Yield: 69.6 %

Procedure:
A solution of PAMA-K (0.600 g, 1.047 mmol) and piperidine (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for 3 hrs. Solvent was evaporated under reduced pressure to give a residue, which was purified by Amberchrom (CG-161C) eluting with MeOH/H2O to give (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.256 g, 70%). MS (ESI), 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:15][CH2:14]3)=[CH:11][C:10]([C:16]([O:18][CH2:19]C)=O)=[N:9]2)=[N:6][CH:7]=1.C1(C(=O)CC(=O)C(OCC)=[O:28])CC1.BrC1C=C[C:38]([NH:41][NH2:42])=NC=1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:14][CH2:15]3)=[CH:11][C:10]([C:16]3[O:18][C:19](=[O:28])[N:41]([CH3:38])[N:42]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: CCOC(=O)c1cc(C2CC2)n(-c2ccc(Br)cn2)n1
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(C3CC3)n(-c3ccc(Br)cn3)n2)oc1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
Step-1: Ethyl 1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxylate: To a stirred solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (0.378 g, 2.05 mmol) in acetic acid (5 mL) was added 5-bromo-2-hydrazinylpyridine (386 mg, 2.05 mmol) at room temperature and the resulting mixture was refluxed for 2 h. The reaction was then cooled to room temperature and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexane system as eluent) to afford 300 mg (43%) of the title compound as pale yellow syrup. 1HNMR (400 MHz, CDCl3) δ 8.55 (d, J=2.0 Hz, 1H), 7.98 (dd, J=2.0 & 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 6.50 (s, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.70-2.64 (m, 1H), 1.40 (t, J=7.0 Hz, 3H), 1.05-1.00 (m, 2H), 0.75-0.71 (m, 2H); ESI-MS (m/z) 336, 338 [(MH)+Br79,81].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.Cl[C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16]>CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COC(=O)C(=O)Cl
Reactant: COc1ccc2ccn(C)c2c1
Solvent: CCOCC
Product: COC(=O)C(=O)c1cn(C)c2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
6-Methoxy-1-methyl-1H-indole (1.0 g, 6.19 mmol) was dissolved in ether (10 mL) and cooled to 0° C. Methyl chlorooxoacetate (1.17 mL, 12.4 mmol) was added dropwise. Stirring was continued at 0° C. for 6 h. The mixture was filtered and washed well with ether to give methyl (6-methoxy-1-methyl-1H-indol-3-yl)glyoxylate (621 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2F)nc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 0 °C
Yield: 73 %

Procedure:
2-(2-Fluoro-phenyl)-3H-quinazolin-4-one from Step B (0.86 g, 3.5 mmol) was suspended in chloroform in a 50 ml round bottomed flask equipped with magnetic stirrer. The flask was cooled to 0° C. and to it was added thionyl chloride (1.2 ml) drop wise followed by N,N-dimethylformamide (0.01 ml) and the mixture heated to 80° C. for 4 hrs. The solvent was removed by evaporation in a rotary evaporator to leave a title compound as a solid (0.68 g, 73%). MS (ES) 259.1 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH:6]=[CH:7][CH:8]=1>C(O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(-c2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: CSc1cccc(-c2ccccc2N)c1

Procedure:
3'-Methylthio-2-nitrobiphenyl (8 g) was heated at 90°-95° C. for 5 hours with hydrated sodium sulphide (15.6 g) and ethanol (200 ml) to give 2-amino-3'-methylthiobiphenyl (m.p. 114°-115° C.) as a brown oil which was converted into its hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH:29][NH2:30].N1C=CC=CC=1>O>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([N:29]([CH3:28])[NH2:30])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: CNN
Solvent: O
Solvent: c1ccncc1
Product: CN(N)c1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a mixed liquid of methylhydrazine (32 mg) and pyridine (0.5 ml), and the mixture was stirred at room temperature for 3 hours. Water (5 ml) was added. At this time, the pH of the reaction mixture was about 5. Solids formed were collected by filtration and subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the resultant residue to conduct filtration, thereby obtaining the title compound (60 mg) as a brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl[CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[N:15]([CH2:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCOc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OCC
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCOc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OCC

Procedure:
Prepared from compound 7 and 4-chloromethylbenzoic acid as described for compound 83. Purified by chromatography (dichloromethane). Crystallized from diethyl ether. M.p. 152°-154° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8]C(=O)C(F)(F)F)=[CH:6][C:5]([CH2:15][C:16](=[O:22])[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4]1)[CH3:2].Cl>CO>[CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:15][C:16](=[O:22])[N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(CC(=O)N2CCCC2)cc1NC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: CCn1nc(CC(=O)N2CCCC2)cc1N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-{1-ethyl-3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-5-yl}-2,2,2-trifluoroacetamide (120 mg, 0.377 mmol) in methanol (1.5 mL) was added 2M HCl (1 mL, 0.377 mmol), and the reaction mixture was stirred at 50° C. for 2 h and concentrated. The residue was neutralized using saturated NaHCO3 solution and concentrated. The residue was dried under high vacuum to give 79 mg and used for next reaction without further purification. MS: (M+H)+=222.8. 1H NMR (400 MHz, DMSO-d6) ppm 1.18 (t, J=7.2 Hz, 3H), 1.70-1.85 (m, 4 H), 3.24 (t, J=6.8 Hz, 2H), 3.31 (s, 2 H), 3.43 (t, J=6.8 Hz, 2H), 3.78 (q, J=7.2 Hz, 2H), 5.11 (s, 1H).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([C:20](=[NH:24])OCC)[CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1N>CO>[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:20]1[C:16]1[CH:15]=[C:14]([C:10]2([CH3:13])[CH:9]3[CH:11]2[CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]3=[O:25])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Reactant: Nc1ccccc1N
Solvent: CO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nc3ccccc3[nH]2)c1
Yield: 46.3 %

Procedure:
To ethyl 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate (Preparation 42, 0.13 g, 0.34 mmol) in methanol (4 ml) at room temperature was added 1,2-diaminobenzene (37 mg, 0.34 mmol) and the mixture was heated under reflux for 1 h and then cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and washed with 10% aqueous potassium carbonate solution (10 ml). The aqueous layer was then reextracted with dichloromethane (2×8 ml). The combined organic layers were dried (MgSO4) and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with hexane:ethyl acetate (1:1 and then 1:2) to give the title compound as a white foam (61 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]2[CH2:12][CH2:11]2)[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Brc1cccc(OC2CC2)c1
Temperature: 180 °C
Yield: 83.1 %

Procedure:
A mixture of 3-bromophenol (4.80 mmol, 0.83 g), bromocyclopropane (27.71 mmol, 2.22 ml), K2CO3 (23.15 mmol, 3.2 g) in DMF (18 ml) was heated at 180° C. for 8 hours in a microwave oven. Water and diethyl ether were added and the organic phase was evaporated affording 0.85 g of the expected product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:27](COCC[Si](C)(C)C)[C:26]2[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=2[N:24]=1>CN1C(=O)CCC1>[NH:24]1[C:25]2[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=2[N:27]=[C:23]1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3ccccc3[nH]2)c2ncccc21
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one obtained from example 13e) and 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (108 mg) in NMP (2.0 ml) was stirred at 120° C. for 12 h, treated with sat.NaHCO3aq. and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC and crystallized from AcOEt/Hexane to give 3-[1-(1H-benzimidazol-2-yl)-2,3-dihydro-1H-indol-5-yl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]Cl)=[CH:10][CH:11]=2)[N:6]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(CCCCCl)s2)cs1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4ccccc4)CC3)s2)cs1
Reaction time: 15 h

Procedure:
A mixture of 5.43 g of 2-amino-4-[5-(4-chlorobutyl)-2-thienyl]thiazole, 4.0 g of 4-phenylpiperazine, 3.2 g of potassium carbonate, 0.1 g of potassium iodide and 50 ml of dimethylformamide is stirred at 70°-80° C. for 15 hours. The resultant mixture is poured into water and extracted with water. The extract is washed with water and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol to give 2-amino-4-[5-(4-(4-phenyl-1-piperazinyl) butyl)-2-thienyl]thiazole, melting at 165°-167° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccncc1
Product: c1ccc(CN2CCC(Oc3ccncc3)CC2)cc1
Yield: 52 %

Procedure:
The title compound was prepared from 1-benzyl-4-hydroxypiperidine and 4-chloropyridine (979 mg, 8.62 mmol), using the same method as that described for preparation 25, as an oil in 52% yield. 1H NMR (CDCl3, 400 MHz): 1.81-1.96 (m, 2H), 1.98-2.18 (m, 2H), 2.30-2.48 (m, 2H), 2.70-2.83 (m, 2H), 3.52-3.70 (m, 2H), 4.40-4.50 (m, 1H), 6.72-6.80 (m, 2H), 7.22-7.39 (m, 5H), 8.40 (m, 2H); LRMS APCI m/z 269 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[N:3]=[C:2]([NH:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC1CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cncc(NC2CC2)n1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A glass microwave reaction vessel was charged with 2,6-dichloropyrazine (1.0 g, 6.71 mmol) and cyclopropanamine (0.383 g, 6.71 mmol) in DMF (4 mL) followed by cesium carbonate (2.187 g, 6.71 mmol). The reaction was stirred and heated in an oil bath at 100° C. for 15 h, then cooled to RT. The mixture was diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-10% EtOAc in Hex) to give 6-chloro-N-cyclopropylpyrazin-2-amine (0.87 g, 5.13 mmol, 76%) as a yellow solid. MS (ESI, pos. ion) m/z: 170 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH2:16])([CH2:14][NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:21]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CN)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(N)(CNC(=O)c2ccc(F)cc2F)CC1

Procedure:
To a solution of 4-Amino-4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (250 mg; 1.1 mmol; 1.0 eq.) in pyridine (12 ml) at room temperature, a 0.1 M DCM solution of 2,4-difluoro-benzoyl chloride (182.8 mg; 1.04 mmol; 0.95 eq.) was added slowly. The reaction mixture was quenched by adding 0.5 mL of methanol when LC-MS showing no starting material remaining. The reaction mixture and concentrated to dryness to afford 4-Amino-4-[(2,4-difluoro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([CH2:9][NH:10][CH2:11][C:12]([O:14]CC)=[O:13])([OH:8])=[O:7])#[N:2]>O>[C:1]([CH2:3][CH2:4][O:5][P:6]([CH2:9][NH:10][CH2:11][C:12]([OH:14])=[O:13])([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)CNCP(=O)(O)OCCC#N
Solvent: O
Product: N#CCCOP(=O)(O)CNCC(=O)O

Procedure:
25 g (0.1 mols) of ethyl N-[O-(β-cyanoethyl)-phosphonomethyl]-aminoacetate in 200 ml of water are heated under reflux for 16 hours. The water is then evaporated off in vacuo in a rotary evaporator and the residue is dried at 50° under high vacuum. Thereafter the residue is warmed with 300 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][O:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 33 %

Procedure:
A solution of ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate (3.8 g.) in ethanol (140 ml.) and water (5 ml.) containing sodium hydroxide (5 g.) was heated under reflux for 16 hours. The mixture was then evaporated and the residue was diluted with water (100 ml.) and ether (50 ml.). The ether layer was separated and discarded. The aqueous layer was acidified to pH 2-3 by addition of 20% v/v hydrochloric acid and the solid (3.0 g.) which formed was separated and crystallised from ethyl acetate to give di-(4-chlorophenyl)methyleneamino-oxyacetic acid, m.p. 147°-148° C., in 33% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](N(OC)C)=[O:9])=[N:6][CH:7]=1.[CH3:14][CH2:15][Mg+].[Br-]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc(O)cn1
Agent: [Br-]
Product: CCC(=O)c1ccc(O)cn1
Yield: 48 %

Procedure:
Following the same procedure as described in example 11, step B, 5-hydroxy-N-methoxy-N-methylpicolinamide (0.5 g, 1.0 eq) was reacted with EtMgBr (6.0 mL, 4.0 eq) to get the desired product (0.2 g, 48% yield).