Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:12](=[O:24])[N:11]([CH3:25])[C:10]=3[S:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:24])[N:11]([CH3:25])[C:10]=3[S:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)sc21
Temperature: 50 °C
Yield: 18.8 %

Procedure:
To a solution of ethyl 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (51 mg, 0.09 mmol) in EtOH (2 mL) was added NaBH4 (10.2 mg, 0.27 mmol). The reaction was heated at 50° C. for 18 h, cooled to RT, quenched with aq. HCl (0.1N, 2 mL) then concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (8.9 mg, 29.7% yield) as a white solid. 1H NMR (CD3OD) δ: 7.54-7.50 (m, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 4.34 (s, 2H), 4.04 (t, J=6.8 Hz, 2H), 3.58-3.55 (m, 5H), 1.84-1.80 (m, 2H). LCMS: MH+ 525 and TR=3.382 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:11]([O:12][CH3:13])=[CH:10][S:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:24](=[O:25])[CH2:23][Cl:22])=[C:8]([CH3:14])[S:9][CH:10]=1
Reactant: CCOCCNc1c(OC)csc1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOCCN(C(=O)CCl)c1c(OC)csc1C

Procedure:
To a well stirred mixture of 6,05 g (0.03 mol) N-(2-ethoxyethyl)-4-methoxy-2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of CH2Cl2 is added dropwise without cooling the solution of 3.4 g (0.03 mol) of chloroacetyl chloride in 10 ml of CH2Cl2. After the exothermic reaction (27°) has subsided, stirring is continued for a further hour at ambient temperature.
Reaction SMILES: [N:1]1([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCCc4ccccc43)nc2c1
Yield: 68.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.25 mmol, 1.00 equiv), sodium hydroxide (20 mg, 0.5 mmol, 2.00 equiv), and methanol/H2O (20/5 mL). The resulting solution was heated to reflux for 4 hrs and then concentrated to dryness. The residue was diluted with 15 mL water and acidified to pH=5 with 3N aq. HCl. The resulting solid was collected by filtration, washed with water, and dried to afford 65 mg (65%) of 3-(3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylic acid as an orange solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH3+:14])[C:7]2=[O:15].C(N(C(C)C)CC)(C)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH:14][C:25](=[O:27])[O:28][CH2:29][CH3:30])[C:7]2=[O:15]
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)C(=O)C([NH3+])CO2
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.82 g (12.3 mmol) of 6-methoxy-4-oxochroman-3-aminium chloride were dissolved in tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. with an ice bath. Diisopropylethylamine and ethyl carbononochloridate were added. The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution (2×) and water (1×). The organic phase was washed dried over MgSO4, and concentrated in vacuo to give 3.5 g (13.2 mmol, quant.) of crude material.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])C(O)=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Yield: 53.3 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 300 mg (0.543 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-N-isobutyl-2-methylhexanamide [prepared as described in Example 17(a)] and 170 mg (0.543 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 216 mg of the title compound as a colorless powder, melting at 118°-120° C.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]([C:21]3[C:30]([OH:31])=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[C:9]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:39]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:33]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]3([C:21]4[C:30](=[CH:29][C:24]5[O:25][CH2:26][CH2:27][O:28][C:23]=5[CH:22]=4)[O:31][CH2:39]3)[C:9]2=[O:32])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2c1cc2c(cc1O)OCCO2
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C21COc2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (96%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.41-7.24 (m, 10H), 6.97 (s, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 6.04 (d, J=1.8 Hz, 1H), 5.69 (d, J=1.8 Hz, 1H), 4.81 (ABq, 2H), 4.21-4.06 (m, 4H), 3.62 (s, 3H), 3.47 (s, 3H); MS (ES+) m/z 522.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1)=[O:4].O>O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>[OH:9][CH2:8][C:5]1([C:3]([NH:2][CH3:1])=[O:4])[CH2:7][CH2:6]1
Reactant: CNC(=O)C1(C(=O)OC)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C1(CO)CC1
Reaction time: 1 h

Procedure:
Methyl 1-(methylcarbamoyl)cyclopropanecarboxylate 5b (942 mg, 6 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice-acetone bath, by addition of a solution of diisobutylaluminum hydride in tetrahydrofuran (1 M, 18 mL), then the reaction solution was stirred for 1 h, followed by addition of 3 mL of water. After removing the dry ice-acetone bath, the reaction solution was continuously stirred at room temperature for 1 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(hydroxymethyl)-N-methyl cyclopropanecarboxamide 5c (800 mg, a yellow solid), which was used directly in the next step.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Cl)[C:10](=[CH2:12])[CH3:11]>>[CH3:11][C:10](=[CH2:9])[CH2:12][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: C=C(C)CCl
Product: C=C(C)CSc1ccccc1O
Yield: 65 %

Procedure:
This compound was prepared in 65% yield from 2-mercaptophenol and methallyl chloride according to the procedure for 16b in Example VII. Brown Oil; 1H NMR (CDCl3): δ 1.86 (s, 3H), 3.26 (s, 2H), 4.52 (s, 1H), 4.73 (s, 1H), 6.68 (s, 1H), 6.85 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.97 (dd, J=1.1, J=8.0 Hz, 1H), 7.25 (dt, J=1.4, J=7.7, 1H), 7.39 (dd, J=1.7 Hz, J=7.7 Hz, 1H); 13C NMR (CDCl3): δ 20.91, 44.49, 114.74, 114.92, 118.84, 120.67, 131.25, 136.31, 140.32, 157.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:29]#[C:30][CH2:31][CH3:32]>C1COCC1.[Cu]I>[C:29]([C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)#[C:30][CH2:31][CH3:32]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Reactant: C#CCC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 27.6 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (65 mg, 0.134 mmol), Palladium dichlorobistriphenylphosphine(II) (7.01 mg, 0.013 mmol), copper(I)iodide (25.6 mg, 0.134 mmol) and TEA (0.019 ml, 0.134 mmol) in THF (5 ml) was bubbled 1-butyne (7.26 mg, 0.134 mmol) for 5 minutes and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give N-[(3-{[3-(1-butyn-1-yl)-5-cyanophenyl]oxy}-4-chloro-2-fluorophenyl)methyl]-4-chloro-1H-imidazole-5-carboxamide (17 mg, 0.037 mmol, 28% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (br. s., 1H), 7.40 (s, 1H), 7.28-7.39 (m, 3H), 7.17 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 2.38 (q, 2H), 1.17 (t, 3H). LC-MS (ES+) m/z 457.14, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29].C(Cl)Cl>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CC2CNCCN2)n1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100-mL round-bottomed flask were added 2-((6-methoxy-2-pyridinyl)methyl)piperazine (373 mg, 1.80 mmol), triethylamine (0.375 mL, 2.70 mmol), 2-thiophenesulfonyl chloride (0.328 mL, 1.80 mmol, Aldrich, St. Louis, Mo., and DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((6-methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (135 mg) as viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][N:18](S(C)(=O)=O)[CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([N:18]1[CH2:19][CH2:20][C:14]2([CH2:15][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13]2)[CH2:16][CH2:17]1)=[O:33]
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: COC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methanesulfonyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using methyl chloroformate in place of methanesulfonyl chloride. The title compound was obtained as a colourless oil (20 mg, 28%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])=[O:4]
Reactant: Nc1cccc(Br)c1O
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Br)C(=O)Nc1cccc(Br)c1O
Yield: 99.9 %

Procedure:
2-Bromopropionyl chloride (1.47 ml, 14.6 mmol) was added dropwise to a vigorously stirred and ice-cooling mixture of 2-amino-6-bromophenol (2.74 g, 14.6 mmol) and sodium bicarbonate (3.06 g, 36.4 mmol) in ethyl acetate (50 ml)/water (15 ml). The mixture was stirred at 0° C. for 3 h and diluted with water. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue used for the following step without further purification to afford 4.71 g (99%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](Cl)=[N:15][OH:16].O>O1CCCC1>[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](=[N:15][OH:16])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cc1ccc(C(Cl)=NO)c(F)c1I
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(=NO)c2ccc(C)c(I)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
4-Methoxybenzylamine (2.00 mL, 15.2 mmol) was added dropwise to a solution of 2-fluoro-N-hydroxy-3-iodo-4-methylbenzimidoyl chloride (WO2006094187, 1.46 g, 4.7 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give a semi-solid. The solid was triturated with a hexanes/diethyl ether mixture and the solid was filtered and dried to give the title compound (1.66 g, 86%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
A mixture of 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (2.95 g, 9.46 mmol), piperazine (10.60 g, 123 mmol) in dioxane (50 mL) is heated overnight at 110° C. Water is added and the reaction mixture is extracted with ethyl acetate. The combined ethyl acetate layers are washed with brine, dried and concentrated. The crude material is purified by chromatography eluting with dichloromethane-5% methanol. Fractions containing product are combined and concentrated to afford 1-(4-tert-butylphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (2.4 g, 70% yield) as a light cream solid. TLC (silica gel, dichloromethane-10% methanol) Rf=0.27; ESI/MS 362 (M+H), RT 3.27 min; NMR 10.14 (1H, s); 8.12 (1H, d, J=3Hz); 8.09 (2H, d); 7.68 (2H, d); 7.47 (2H, m); 6.91 (1H, d, J=6 Hz); 3.20 (4H, m); 2.53 (4H, m); 2.25 (1H, br s); 1.36 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:22][CH2:23][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccccc1)N1CC[C@@](CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1

Procedure:
Prepare by the method of Example 1.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:30])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[N:11]([N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[N:15]=2)[CH:12]=1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[NH:41][NH2:42])[C:36]#[N:37]>>[C:36]([C:35]1[CH:38]=[CH:39][C:40]([N:41]2[C:5]([C:7]3[C:8]([CH3:30])=[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[C:10]4[N:11]([N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[N:15]=4)[CH:12]=3)=[CH:4][CH:3]=[N:42]2)=[C:33]([F:32])[CH:34]=1)#[N:37]
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Reactant: N#Cc1ccc(NN)c(F)c1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3F)cn2n1

Procedure:
The title compound was prepared from N-[6-(3-dimethylamino-acryloyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 25, 85 mg, 0.197 mmol) and 3-fluoro-4-hydrazino-benzonitrile (45 mg, 0.298 mmol) using similar methods to those employed in Example 40, Step 4 and Example 26, Step 1 (22 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[CH:16]=[CH:17][NH:18]3)=[CH:13][C:12]=2[O:22][CH3:23])=[C:9]([CH3:24])[O:8][N:7]=1>C(O)(=O)CC>[CH3:5][C:6]1[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([OH:21])=[C:16]([N+:1]([O-:4])=[O:2])[CH:17]=[N:18]3)=[CH:13][C:12]=2[O:22][CH3:23])=[C:9]([CH3:24])[O:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc2c(=O)cc[nH]c2cc1-c1c(C)noc1C
Solvent: CCC(=O)O
Product: COc1cc2c(O)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Nitric acid (1.86 g, 1.32 ml, 29.5 mmol) was added dropwise to a stirred solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4(1H)-quinolinone (for a preparation see Intermediate 6) (6.9 g, 25.6 mmol) in propionic acid (70 ml). After complete addition the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, the solid was filtered off, washed with diethyl ether and dried to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitro-4-quinolinol (5.0 g, 15.86 mmol, 62.1% yield) as a bright yellow solid. LCMS (formate) Rt 1.15 min, MH+ 316
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:15])[NH:1][C@@H:2]([CH3:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of L-alaninol (2.00 g, 26.6 mmol) in methylene chloride (60 ml) were added chloroformic acid benzyl ester (4.57 ml, 32.0 mmol) and triethylamine (4.48 ml, 32.0 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford [(1S)-2-hydroxy-1-methylethyl]carbamic acid benzyl ester (4.61 g, yield 83%) as white crystals.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+]([O-])=O)[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:25]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[O:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc(F)c([N+](=O)[O-])c1)OCc1ccccc1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A mixture of spray-dried KF (80 mg, 1.39 mmol), intermediate 3 (100 mg, 0.27 mmol) and catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 110-120° C. for 10 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale yellow color solid (51 mg, 55%), mp 84-86° C. 1H NMR (400 MHz, CDCl3): δ 8.50 (1H, dd, J=6.8, 1.6 Hz), 8.10-8.13 (1H, m), 7.34-7.39 (6H, m), 6.90 (1H, br s), 5.23 (2H, s), 4.28 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 331 (M−H)−.