Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])=[O:4]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 82.6 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (68 mg, 0.23 mmol) and 3-amino-2,2-dimethyl-propionic acid (81 mg, 0.69 mmol) (ChemBridge) in 0.5 N NaOMe in MeOH solution (0.92 mL, 0.46 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water and dried in vacuo to provide the title compound (71 mg, 0.19 mmol) as an off-white solid in 81% yield. LC-MS ESI−: 379.04 (M−1)−.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([O:23][CH3:24])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:25][C:26]1[C:29]([CH3:31])([CH3:30])[C:28](=O)[CH:27]=1>C(Cl)Cl>[CH3:30][C:29]1([CH3:31])[C:28]([NH:1][C@@H:2]([CH2:8][C:9]2[CH:10]=[C:11]([O:23][CH3:24])[C:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([O:15][CH3:16])[CH:14]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:27][C:26]1=[O:25]
Reactant: CCOC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Reactant: CC1(C)C(=O)C=C1O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C1(C)C

Procedure:
The title compound was prepared in a similar manner to that of the compound of Example 41 from ethyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (1.5 g, 4.5 mol), and 3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.5 g, 4.5 mmol) in DCM (15 ml) as a white foam (1.8 g, 93%). δH (300 MHz, DMSO d6) 8.68 (1H, d, J 8.6 Hz), 7.22–7.37 (3H, m), 7.18 (2H, d, J 8.3 Hz), 6.78 (2H, d, J 8.4 Hz), 4.46 (1H, s), 4.32 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.69 (6H, s), 3.24 (1H, dd, J 13.8, 5.9 Hz), 3.09 (1H, dd, J 13.8, 9.1 Hz), 1.24 (3H, t, J 7.1 Hz), 1.16 (3H, s), 1.08 (3H, s); m/z (ES+, 70V) 424 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](OCC)=[O:15])[N:2]=1.[Li+].[BH4-].O>C1COCC1>[OH:15][CH2:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 81.4 %

Procedure:
Compound 10 (7.0 g, 31 mmol) was dissolved in anhydrous THF (900 ml) followed by the addition of LiBH4 (3.4 g, 155 mmol). The mixture was stirred at room temperature for 9 h and then cooled. Water (100 ml) was added into the mixture and stirred overnight. Then the solvent was removed in reduced pressure. With the addition of water (500 ml), extraction was conducted with dichloromethane (1 L) and then with ethyl acetate. The organic phases were combined, concentrated in vacuum and purified by silica gel column chromatography with ethyl acetate/methane (3:1) as the eluent to afford white solids (5.0 g, 82%), and mp 228-230° C. (reference[2]: 225-228° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]([CH3:15])[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:9]#[N:10]>CO>[CH3:4][N:5]([CH3:15])[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:9]([NH:2][OH:3])=[NH:10]
Reactant: NO
Reactant: Cc1cc(C#N)cc(N(C)C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(N(C)C)n1
Temperature: 0 °C
Yield: 33.7 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (1.71 g, 15.2 mmol) in methanol (50 mL), hydroxylamine hydrochloride (905 mg, 13.02 mmol) is added. The suspension is stirred for 30 min before 2-dimethylamino-6-methyl-isonicotinonitrile (699 mg, 4.34 mmol) is added. The mixture is refluxed for 2 h before it is evaporated. The residue is dissolved in a small amount of water and separated by MPLC on RP-C18-silica gel to give 2-dimethylamino-N-hydroxy-6-methyl-isonicotinamidine (284 mg) as a brownish resin; LC-MS: tR=0.60 min, [M+1]+=195.42.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[CH:22]=[CH:23][C:24](O)=[O:25].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)[CH3:3])=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](N)c1cccc(NCc2cccnc2)c1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C=Cc1cccc(Cl)c1)c1cccc(NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
A mixture of (s)-[3-(1-amino-ethyl)-phenyl]-pyridin-3-ylmethyl-amine (0.2 mmol), 3-chlorocinnamic acid (0.2 mmol), EDACeHCl (0.4 mmol), DMAP (0.2 mmol), triethylamine (0.6 mmol) in dichloromethane (4 mL) was stirred at 5 room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the desired title compound (51 mg) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH2:7][CH2:6]1.C(=O)([O-])O.[Na+]>C(O)C>[N:11]1([CH:8]2[CH2:9][CH2:10][N:5]([CH2:2][CH2:3][OH:4])[CH2:6][CH2:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: OCCBr
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCCN1CCC(n2ccc3ccccc32)CC1
Yield: 65.6 %

Procedure:
A mixture of 2-bromoethanol (3.75 g), 1-(4-piperidinyl)-1H-indole (5 g) and sodium hydrogen carbonate (4.2 g) in ethanol (100 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was stirred in water and this mixture was extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE and the solvent was evaporated, yielding 4 g (64%) of 4-(1H-indol-1-yl)-1-piperidineethanol (intermediate 8).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18][C:19](=O)/[C:20](/[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:21](\O)/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C[O-].[Na+]>CO.ClCCl>[C:25]([O:24][C:22]([C:21]1[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([OH:18])[N:16]=[C:14]([CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:15]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: N=C(N)CC1(c2ccccc2)CCCCC1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a mixture of HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.0 g, 7.91 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (9) (3.66 g, 11.86 mmol) in methanol (50.0 mL) was added sodium methoxide (1.28 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm up to room temperature and was stirred for 16 h. After completion of the reaction, the solvent was reduced and the crude product was dissolved in dichloromethane and the resultant mixture extracted with dichloromethane. The organic layer was washed with 1N HCl and with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 10% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (255) (3.2 g, 85.0%) as a yellowish thick liquid which turned into a solid after storing at room temperature.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].ClC(OC)=O.N1CCCC1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([N:18]3[CH2:19][CH2:20][CH2:17][CH2:16]3)=[O:14])=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)N3CCCC3)c(=O)n12
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
A mixture containing 20.4 g (0.1 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 15.5 ml (0.11 mol) of triethylamine in 600 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 10 ml (0.1 mol) of methyl chloroformate dissolved in 50 ml of chloroform is dropped to the above mixture at -10° C. during 30 to 35 minutes. After stirring for 20 minutes, 9 g (0.11 mol) of pyrrolidine dissolved in 100 ml of chloroform are dropped to the above solution at a temperature between -5° C. and -8° C. during 1 hour. The reaction mixture is stirred at the same temperature for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 400 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 400 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. After suspending the oily residue in petroleum ether, 8.3 g (32.3%) of the named compound are obtained, which forms yellow crystals after recrystallization from ethanol, m.p.: 132°-134° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[CH:11]=[CH:12][C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH2:40])=[CH:36]1)[CH3:34]>C(Cl)Cl>[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH:40][C:13](=[O:15])[CH:12]=[CH:11][C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[F:8])=[CH:36]1)[CH3:34]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
Triethylamine (1.5 mL), 2-fluorocinnamic acid (1.8 g) and WSC.HCl (2.1 g) were at 0° C. added to methylene chloride (70 mL) suspension of the compound obtained in Example 143 (2.8 g). The mixture was stirred for 4 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (chloroform), to give the captioned compound (2.7 g, 70%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(Cl)Cl.O.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[Cl:18][C:15]1[CH:14]=[C:13]([F:19])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[S:25]([Cl:24])(=[O:27])=[O:26]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-chloro-3-(4-chloro-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-Pyrazole in 20 mL of chlorosulfonic acid was heated in a 120° C. oil bath for four hours and allowed to cool to room temperature. Methylene chloride was added and the solution added dropwise to a stirring mixture of ice and water (caution, extremely reactive). The layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried with MgSO4, filtered and concentrated and the resultant solid residue washed with a very small amount of ether and recrystallized from hexanes to afford 1.65 g (63%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenesulfonyl chloride as a white solid; mp 116°-117° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[CH:44]=[CH2:45]>CCOCC>[CH2:45]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH:44]=[CH2:43]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C=CCBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. allyl bromide (1.5 eq.) was added and the mixture stirred at RT for 2 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as yellow solid (67%).
Reaction SMILES: C(OC([C:6]1[C:7]([NH:9][C:10](=[O:12])[CH:11]=1)=[O:8])=O)C.N[CH2:14][CH2:15][P:16](=[O:19])([OH:18])[OH:17].C(=O)([O-])[O-].[Na+].[Na+].S(=O)(=O)(O)O>O>[C:10]1(=[O:12])[N:9]([CH:15]([P:16]([OH:19])(=[O:17])[OH:18])[CH3:14])[C:7](=[O:8])[CH:6]=[CH:11]1
Reactant: NCCP(=O)(O)O
Reactant: CCOC(=O)C1=CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(N1C(=O)C=CC1=O)P(=O)(O)O
Reaction time: 0.33 h

Procedure:
Ethoxy carbonyl maleimide, 169 mg, was added to 2-aminoethyl phosphonic acid, 125 mg, and sodium carbonate, 106 mg, in 1 ml of water at 0° C. The mixture was stirred for 20 minutes, then 4 ml of water was added and the mixture was stirred at room temperature for 1 hr. The solution was acidified to pH 5.5 with dilute sulfuric acid and concentrated in vacuo to 1 ml. The product was isolated by chromatography on three 1000μ reverse-phase TLC plates developed in water. Four bands were noted on examination of the developed plates under U.V. light. The third band at 15-16.7 cm from the origin was isolated; 100 mg of maleimidoethane phosphonic acid-sodium salt was recovered as an amorphous powder. The 200 MHZ NMR spectrum in D2O showed the maleimide hydrogens as a singlet at 7,2 ppm and the ethylene hydrogens as multiplets at 4.0 and 2.2 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[N:18]([O:19][CH3:20])[CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.00 g, 13.93 mmol), N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.94 g, 15.32 mmol) and 1-hydroxybenzotriazole (2.07 g, 15.32 mmol) were placed in a 100 mL round bottomed flask and dissolved in DMF (30 mL). Diisopropylethylamine (6.1 mL, 34.82 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 2.60 g (72% yield) of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]([NH:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]2C2CCCCO2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][CH2:11][CH3:12]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]=2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Yield: 103.3 %

Procedure:
Trifluoroacetic acid (1 ml, 1.48 g, 7.08 mmol) was added to a stirred solution of N2-[(1R)-1-methylbutyl]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (0.613 g, 1.833 mmol) in methanol (10 ml). The resultant mixture was stirred for 66 hours under an atmosphere of nitrogen and then evaporated to give the title compound as an off-white solid (0.690 g).
Reaction SMILES: [ClH:1].[O:2]([NH2:4])[CH3:3].[C:5]1([C:11]#[C:12][C:13]2[CH:14]=[C:15]([C:19](=O)[CH3:20])[CH:16]=[N:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[CH3:3][O:2][N:4]=[C:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:12]#[C:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:14]=1)[CH3:20]
Reactant: CC(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=C(C)c1cncc(C#Cc2ccccc2)c1
Yield: 38.2 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using methoxylamine hydrochloride (700 mg, 8.4 mmol), 1-(5-phenylethynylpyridin-3-yl)-ethanone, (prepared as described in EXAMPLE 84), (230 mg, 1.05 mmol) and potassium carbonate (720 mg, 5.24 mmol) to give the title compound (115 mg, 38%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8 g of 2-tert-Butyl-4-methyl-phenol (49 mmol) and 16.36 g of potassium carbonate (58 mmol) were stirred in 120 ml DMF until a suspension was formed. 6.74 ml of benzylchloride were then added dropwise and the reaction mixture was stirred for 24 h at RT. After two hours heating at 60° C., the reaction mixture was cooled to RT, filtered off, diluted with ethyl acetate, and washed with water followed by brine. The organic phase was dried over magnesium sulphate, filtered off and concentrated under vacuo. The residue was purified by flash column chromatography (heptane/AcOEt 98/2) to give 8.647 g of a colorless liquid. MS (ISP) 255.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].CN(C=O)C.OOS([O-])=O.[K+].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>O>[CH3:8][NH:7][C:5]([C:4]1[C:3]2[N:12]([CH3:13])[C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:1][C:2]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CNC(=O)c1cccc(N)c1NC
Reactant: O=Cc1cccnc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cccc2nc(-c3cccnc3)n(C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-amino-N-methyl-2-(methyl-amino) benzamide (18; 0.2 g, 0.0011 mol) in the mixture of DMF (5 ml) and water (1 ml) was added OXONE® (0.81 g, 0.0013 mol) and followed by nicotinaldehyde (0.13 g, 0.00122 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated on a high vacuo pump and purified by column chromatography on silica gel to afford the desired product N,1-dimethyl-2-(pyridin-3-yl)-1H-benzimidazole-7-carboxamide as brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.0 (s, 1H), 8.76-8.75 (d, J=4.0 Hz, 1H), 8.59 (bs, 1H), 8.25-8.23 (d, J=7.6 Hz, 1H), 7.81-7.8 (d, J=7.6 Hz, 1H), 7.64-7.61 (m, 1H), 7.35-7.27 (m, 2H), 3.79 (s, 3H), 2.85-2.84 (d, J=4.4 Hz, 3H). LCMS (ES) m/e MS (M+1-267) Purity: 98.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>C(O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C#N)cc3[N+](=O)[O-])cc12
Yield: 80 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4 hours. Column chromatography afforded the title compound (80%) as a red solid: mp, 170.0°-171.0° C.; 13C NMR (CDCl3) δ 147.3,137.1, 135.4, 132.0, 131.4, 128.6, 128.0, 125.3, 120.6, 117.9, 117.1, 116.3, 113.1, 111.9, 99.1, 68.1, 57.3, 40.6, 31.2, 28.1, 21.9. Anal. calcd for C21H21N5O2.0.05 CH2Cl2 : C, 66.59; H, 5.60; N, 18.44. Found: C, 66.56; H, 5.26; N, 18.42.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[C:26]([C:28]([NH:30][C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=4[F:38])=[O:29])[CH:25]=[CH:24][C:23]=3[F:39])[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O>O1CCCC1>[F:39][C:23]1[CH:24]=[CH:25][C:26]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:29])=[CH:27][C:22]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=2)[CH:20]=1
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (250 mg, 0.43 mmol) in 10 ml of tetrahydrofuran was added 1 ml of 1M HCl (1.0 mmol). The mixture was stirred at room temperature for 60 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 205 mg, 94%.