Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[C:30]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[C:30]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:24]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=3[CH:17]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)Nc4ccccc4-c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
In a 1 dram vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), biphenyl-2-amine (17 mg, 0.10 mmol), and HATU (40 mg, 0.105 mmol). DMF (0.4 mL) and DIPEA (50 μL, 0.29 mmol) were added, and the vial was capped and stirred at r.t. for overnight, then diluted with MeOH, filtered, and purified directly by prep HPLC. Concentration afforded the title compound (17 mg, 41% yield) as a fluffy white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.96 (s, 1 H) 8.53 (q, J=4.58 Hz, 1 H) 7.96-8.06 (m, 3 H) 7.85-7.91 (m, 2 H) 7.80 (d, J=8.55 Hz, 1 H) 7.77 (d, J=7.32 Hz, 1H) 7.70 (dd, J=8.55, 1.83 Hz, 1 H) 7.57-7.61 (m, 1 H) 7.56 (d, J=6.10 Hz, 1 H) 7.48 (d, J=7.32 Hz, 2 H) 7.36-7.46 (m, 7 H) 7.31 (t, J=7.48 Hz, 1 H) 2.87 (d, J=4.88 Hz, 3 H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=2.02 min, (ES+) m/z (MH+)=541. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=15.37 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=13.75 min, purity=100%.
Reaction SMILES: C1CC[N:9]2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)CC1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[O:32][C:31]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[CH:25]=3)[O:21][N:20]=2)[CH2:14][CH2:13]1.BrC1N=CC=CN=1>O1CCOCC1>[N:9]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[O:32][C:31]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[CH:25]=3)[O:21][N:20]=2)[CH2:14][CH2:13]1
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: C1CCC2=NCCCN2CC1
Agent: Brc1ncccn1
Solvent: C1COCCO1
Product: c1cnc(N2CCC(Cc3noc(-c4cc5cnccc5o4)n3)CC2)nc1
Reaction time: 48 h

Procedure:
DBU (53 ΔL, 352 Amos) was added to a stirred solution of 2-(3-piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 50 mg, 176 μmol) and 2-bromopyrimidine (31 mg, 193 μmol) in dioxane (1 mL) at 20° C. After 2 d, the solvent was removed in vacuo, then the residue was purified by chromatography (MeOH—CH2Cl2, 1:19) to yield the title compound: RT=2.64 min; m/z (ES+)=363.1 [M+H]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH:5]([NH:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]3[N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=23)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([NH:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[C:18]3[C:23](=[CH:22][N:21]=[C:20]4[C:19]=3[CH:27]=[CH:26][N:25]4[S:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:30])[N:24]=[N:1]2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6]
Reactant: O=N[O-]
Reactant: CC(C)NC(=O)[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)NC(=O)[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Reaction time: 0.75 h

Procedure:
Sodium nitrite (12 mg, 0.17 mmol) was added to a solution of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarboxylic acid isopropylamide (70 mg, 0.15 mmol) in acetic acid (1 mL) and stirred for 45 minutes. The mixture was concentrated under vacuum affording trans 4-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanecarboxylic acid isopropylamide which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.58 min, m+H=467.35.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]([CH3:15])[N:13](O)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.C[OH:21]>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:14]([CH2:15][OH:21])[N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: CN1C(c2cccc([N+](=O)[O-])c2)=NNN1O
Agent: Cl[Sn]Cl
Product: Nc1cccc(-c2nnnn2CO)c1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of (3-nitrophenyl)(hydroxy)acetonitrile (3.5 g, 19.6 mmol) in 100 mL toluene was added sodium azide (8 g, 123 mmol) and Bu3SnCl (26 ml, 98 mmol). The mixture solution was heated at reflux for 10 hours. The solvent was removed in vacuo, the residue was dissolved in water, acidified with 1N HCl, and extracted with 3×100 mL ethyl acetate. The crude product was purified by flash chromatography on silica gel to afford 5-(3-nitrophenyl)(hydroxy)methyltetrazole (2.0 g, 9 mmol, 46%) as yellow solid. To a solution of 5-(3-nitrophenyl)(hydroxy)-methyltetrazole (1.3 g, 5.9 mmol) in 50 mL methanol was added SnCl2 (8 g, 35.4 mmol). The resulting reaction mixture was heated at 60° C. for 20 minutes. The reaction mixture was dried in vacuo, then purified directly over an ion-exchange column to afford 5-(3-aminophenyl)(hydroxy)methyltetrazole (1.0 g, 5.2 mmol, 88%), which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH2:13]([O:12][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1)[CH3:14]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodium ethoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 5.3 gram (98% yield). Mp: 133.8˜134.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.CCOC(C)=O.CO.CCN(CC)CC>CN(C=O)C>[NH2:13][C:12]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:9][C:8](=[O:10])[CH2:7][O:6][C:5]=2[CH:11]=1
Reactant: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc2c(cc1Cl)NC(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Stannous chloride dihydrate (30 g, 0.13 mol) was added in portion to a solution of 6-chloro-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (6.7 g, 0.026 mol) in DMF (100 mL) with ice bath cooling. The mixture was allowed to warm to room temperature and was then stirred overnight. EtOAc (300 mL) and MeOH (300 mL) were added to the reaction mixture, Et3N was added until pH >8 and the resulting suspension was filtered through Celite®. The solvent was removed under vacuum and the residue was suspended in water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with ether to give the product (2.5 g, 45%) as a yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:31])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reaction time: 16 h

Procedure:
A solution of 4-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (2.3 g, 5.4 mmol) in methanol (75 mL) is purged with nitrogen and 10% Pd on carbon (0.3 g) is added, and the reaction is again purged with nitrogen. The reaction is placed on a Parr shaker under hydrogen for 16 h. After the system is purged of hydrogen, the catalyst is filtered and washed with methanol. The filtrate is concentrated to provide 4-(2-oxo-piperazin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester which is used without further purification. MS (EI) 298 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:20])=[O:19]
Reactant: OCCN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCOCC1

Procedure:
A solution of 4-(2-hydroxylethyl)-morpholine (Aldrich, 5.1 mL, 42 mmol), triethylamine (17 mL, 124 mmol), and methanesulfonyl chloride (4.8 mL, 62 mmol) in 100 mL THF were processed as described in Example 1C to give the crude material which was used directly in the next reaction.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[C:30]([C:35]([O:37]C)=[O:36])[N:31]=[CH:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[C:30]([C:35]([OH:37])=[O:36])[N:31]=[CH:32]4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Temperature: 120 °C
Yield: 68.4 %

Procedure:
To a solution of methyl 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (54 mg, 0.099 mmol) in 2:1 tetrahydrofuran:methanol (1.5 ml) was added 1 N sodium hydroxide (0.15 mL, 0.15 mmol). The solution was heated in a microwave reactor to 120° C. for 500 seconds. The solution was concentrated under a nitrogen stream and 1 N hydrochloric acid (0.15 mL, 0.15 mmol) was added. The solution was further concentrated under a nitrogen stream. Water and ethyl acetate were added and a solid precipitated that would not dissolve. The water layer was removed and the resulting mixture was washed twice with water. The organic solvents were removed under vacuum and the resulting solid was dried at 45° C. under a nitrogen stream to afford 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (36 mg, 68%). 1H-NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.22-8.13 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.61-7.51 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.94 (s, 2H), 2.51-2.45 (m, 1H), 1.12-1.13 (m, 4H). HRMS (ESI) C29H20Cl2N2O4 calculated: 531.0880 (M+H)+, found: 531.0872 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].ClCCl.C(OC)(C)(C)C>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCO
Product: OC1(c2cccc(F)c2F)CCNC1
Yield: 50.8 %

Procedure:
Preparation according to preparation 4: (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (2.86 g, 9.88 mmol), ammonium formiate (1.25 g, 19.76 mmol), ethanol (50 mL) and palladium on carbon (130 mg). Refluxed for 90 min. Dichloromethane/methyl tert-butyl ether (1:1, 50 mL) was added and the mixture was filtrated through celite, the filtrate was evaporated and purified by flash column chromatography on silica gel (triethylamine/methanol, 0:1 to 1:4) to give the title compound (1.0 g). MS m/z (relative intensity, 70 eV) 199 (M+, bp), 141 (84), 113 (65), 127 (64), 63 (48).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.CCOCC.O>[CH2:1]([O:8][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1noc(-c2cccnc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1noc(-c2cccnc2OCc2ccccc2)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl alcohol (1.5 eq) in DMF (0.4M) was added NaH (1.5 eq, 60%) followed by 2-chloro-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine (1 eq) in DMF (0.5M) after 30 min.). The reaction was stirred at 20° C. for 1 h, diluted with Et2O and water. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 80:20) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[N:17]=[C:16]([NH2:28])[N:15]=1>CN(C=O)C>[NH2:28][C:16]1[N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[N:17]=1
Reactant: COc1ccccc1-c1cc(Cl)nc(N)n1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)nc(N)n1
Temperature: 85 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.16 g, 0.85 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidin-2-ylamine (0.2 g, 0.85 mmol) in DMF (5 mL) was stirred at 80-90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding {3-[2-amino-6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:28]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (1.0 g, 3.3 mmol) in N,N-dimethylformamide (10 mL) was added 3-bromobenzoic acid (0.72 g, 3.6 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (1.4 g, 3.6 mmol) and triethylamine (1.0 mL, 7.2 mmol). After stirring for 18 hours the solution was diluted with ethyl acetate (100 mL) and washed with 0.1 N HCl (2×100 mL) and saturated sodium bicarbonate solution (100 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (1.2 g) as a white solid. 1H NMR (CDCl3): δ9.94(s, 1H), 9.05 (d, J=7.2 Hz, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.43 (dd, J=8.0, 7.8 Hz, 1H), 7.19 (s, 2H), 5.29 (dd, J=7.2, 7.0 Hz, 1H), 3.75 (s, 6H), 3.61 (s, 3H), 1.59 (d, J=7.0 Hz, 3H). MS m/z 488, 500 (M+1, M+3).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl-].[CH3:14][NH3+:15].C(=O)(O)[O-].[Na+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:14][NH:15][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: C[NH3+]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CNC(C(=O)OC)c1ccccc1
Yield: 71.2 %

Procedure:
In this example a mixture containing 30.7 g of methyl bromo-phenylacetate, 36.2 g of methyl ammonium chloride (i.e. CH3NH3Cl); 3.0 g of benzyltriethylammonium chloride and 67.5 g of sodium bicarbonate in about 300 ml of methylene chloride (and about 25 ml of water) was warmed to refluxed and refluxed for about 18 hours. The mixture was then cooled and washed three times with water, dried over magnesium sulfate and concentrated by vacuum evaporation affording 17.1 g of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][CH3:16])=[O:8].[OH-].[Na+].Cl>CO>[C:21]([O:20][C:18]([NH:17][CH:4]([CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][CH3:16])=[O:8])[C:3]([OH:25])=[O:2])=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
To a stirred solution of 2-tert-butoxycarbonylamino-5-((S)-2-methoxymethyl-pyrrolidin-1-yl)-5-oxo-pentanoic acid methyl ester (0.72 g, 2 mmol) in CH3OH (20 mL) was added 2 N aqueous sodium hydroxide (20 mL). After stirred at room temperature for 12 h, the mixture was acidified by the addition of 6 N aqueous hydrochloric acid at 0° C. to pH=4. Most of methanol was removed under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and H2O (20 mL). The aqueous layer was further extracted with CH2Cl2 (20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (0.54 g, 79%) as a foamy solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[CH3:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])=[O:9])[CH:16]=2)=[C:19]([CH3:27])[CH:20]=1
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1
Temperature: 90 °C
Yield: 15 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea (794 mg) in ethanol (50 ml) were added electrolytic iron powder (442 mg), ammonium chloride (847 mg) and water (10 ml), followed by stirring to heat at 90° C. for 1 hr. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion. The filtrate was concentrated under a reduced pressure to give a residue, which was then supplied with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, and then ethyl acetate:methanol=20:1 to 10:1) to provide the titled compound (110 mg, 15%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(C)([O-])C.[K+].Cl[CH2:18][C:19]#[N:20]>O1CCCC1>[C:19]([CH2:18][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)#[N:20]
Reactant: N#CCCl
Reactant: Sc1nc2ccccc2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1 liter flask were combined 33.4 g. (0.2 mole) of 2-mercaptobenzothiazole and 22.4 g. (0.2 mole) of potassium t-butoxide with 300 ml. of tetrahydrofuran. The reaction mass was stirred at room temperature for 15 minutes. Chloroacetonitrile, 16 g. (0.2 mole) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then poured into 400 ml. of benzene and was washed with three 250 ml. portions of water. The benzene phase was dried with anhydrous magnesium sulfate. The solvent was evaporated. There was obtained a yield of 37.2 g. of the title compound, m.p. 75°-77°C.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C1C=CC=CC=1)C=C2)C(O)=O)(C)(C)C.[C:37]([O:41][C@@H:42]([C:48]1[C:49]([C:64]2[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59](=[O:63])[N:60]([CH3:62])[CH3:61])[CH:52]=[CH:51]2)[C:43]([O:45]CC)=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C@@H:42]([C:48]1[C:49]([C:64]2[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59](=[O:63])[N:60]([CH3:62])[CH3:61])[CH:52]=[CH:51]2)[C:43]([OH:45])=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)C)ccc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(C(=O)N(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)acetate. 1H-NMR 300 MHz, (CD3OD) δ 7.91 (s, 1H), 7.87 (d, 1H), 7.65-7.58 (m, 3H), 7.50 (d, 1H), 7.40-7.32 (m, 1H), 5.23 (s, 1H), 3.18 (s, 3H), 3.05 (s, 3H), 2.69 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C25H28ClN2O4: 455.9. Found: 455.2, 457.2.