Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.O>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:16]([C:3]2[C:2](=[O:1])[N:7]3[C:8]4[C:13]([N:14]=[CH:15][C:6]3=[N:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:18])=[N:36][N:35]=[N:34]1
Reactant: O=C(O)c1cnc2cnc3ccccc3n2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cnc2cnc3ccccc3n2c1=O
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of 250 mg of 1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxylic acid and 200 mg of carbonyldiimidazole in 5 ml of dry dimethylformamide was heated over a steam bath for 15 minutes and then 100 mg of 5-aminotetrazole were added thereto. The mixture obtained was heated over a steam bath for another 30 minutes and was then poured into water and left at room temperature for 1 hour. The solid obtained was filtered off, was washed with water and ether and dried to obtain 240 mg (61% yield) of N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxamide melting above 300°.
Reaction SMILES: [CH:1]1([CH2:7][C:8](=[O:21])[CH:9]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[C:10](F)(F)F)[CH2:6][CH2:5][CH2:4][CH2:3]C1.C1(CC(=O)C(C2C=CC(N)=CC=2)C(F)(F)[F:31])CCCC1>>[CH:1]1([CH2:7][C:8](=[O:21])[C:9]([F:31])([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C(C(=O)CC2CCCC2)C(F)(F)F)cc1
Reactant: Nc1ccc(C(C(=O)CC2CCCCC2)C(F)(F)F)cc1
Product: CC(F)(C(=O)CC1CCCC1)c1ccc(N)cc1

Procedure:
1-cyclohexyl-3-(4'-aminophenyl)-4,4,4-trifluoro-2-butanone, and 1-cyclopentyl-3-(4'-aminophenyl)-4,4,4-trifluoro-2-butanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]#[CH:25])[C:16]([CH3:26])=[C:15]([CH3:27])[N:14]=1.C(N(CC)CC)C>ClCCl>[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:25]=2)[C:16]([CH3:26])=[C:15]([CH3:27])[N:14]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C#CCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2cc(-c3ccc(F)cc3)no2)c1C
Temperature: 40 °C
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (52.0 g, 225 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine (26.92 g, 112.3 mmol) in anhydrous dichloromethane (1 L) at room temperature. Triethylamine (25 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16 hours, diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to a suspension. The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether and dried under vacuum to provide 32.45 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13][NH2:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)Cl
Reactant: CN
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C(=O)NC
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoyl chloride (1.00 g, 4.04 mmol) in CH2Cl2 (20 mL) was added methylamine (0.70 mL, 40% solution in water, 8.08 mmol). The mixture was stirred for 3 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a brown oil (0.857 g, 88%). 1H NMR (300 MHz, CDCl3): δ 1.21 (t, J=7.4 Hz, 3H), 2.75 (q, J=7.5 Hz, 2H), 2.97 (d, J=4.9 Hz, 3H), 5.74 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.39 (s, 1H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]4[CH:31]=[CH:30][C:25]5[NH:26][C:27](=[O:29])[NH:28][C:24]=5[CH:23]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (54 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 43 mg (44%) of tan powder. LC/MS: 374 (M+H); HPLC: 97% pure, RT=2.20 min; 1H NMR: (DMSO, δ) 10.49 (s, 1H), 10.39 (s, 1H), 9.20 (s, 1H), 8.88 (s, 1H), 8.83 (s, 1H), 8.47 (dd, J=8.4, 2.5, 1H), 7.25 (d, J=8.4, 1H), 7.21 (s, 1H), 7.10 (d, J=4.8, 1H), 6.95 (d, J=8.8, 1H), 6.87 (d, J=4.8, 1H), 6.79 (d, J=8.4, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[CH3:15][S:16]([O:10][CH2:9][CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(CO)CC1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(COS(C)(=O)=O)CC1CCCCC1

Procedure:
A solution of 2-(cyclohexylmethyl)hexan-1-ol (1.3 g) in 10 ml of dry pyridine under nitrogen was cooled to 0° C. and treated dropwise with stirring with 1.0 g of methanesulfonyl chloride. After 1 hour the mixture was poured into water and extracted with ethyl acetate. The extracts were washed twice with dilute hydrochloric acid, once with brine and dried (MgSO4). Evaporation of the solvent gave an oil, 2-(cyclohexylmethyl)hex-1-yl methanesulfonate, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:41]([O:43][CH2:44][CH2:45][NH2:46])[CH3:42]>>[CH2:41]([O:43][CH2:44][CH2:45][NH:46][C:35]([C:14]1[C:15](=[O:34])[N:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:17]2[C:12]([C:13]=1[OH:40])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:36])[CH3:42]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 591 (M+H+).
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=1>O1CCCC1>[CH2:33]([O:32][C:30]([C:29]([CH3:35])=[CH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:24]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)C(C)=Cc1ccc(CCl)cc1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(Cc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0° is added dropwise over 20 minutes a solution of 2-(3-pyridyl)indole (1.9 g) in 12 ml of tetrahydrofuran. After complete addition the mixture is stirred at 0° for 0.5 hour and is then treated dropwise with a solution of 2.39 g of ethyl 3-(p-chloromethylphenyl)-2-methylacrylate in 5 ml of tetrahydrofuran. The resulting mixture is stirred at 0° for 1 hour, then at room temperature for 1 hour, and poured in 100 ml of ice-water. The resulting mixture is extracted with ether (2×50 ml) and the organic layer is washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 3-[p-(2-ethoxycarbonylpropen-1-yl)benzyl]-2-(3-pyridyl)indole.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:18][C:15]([CH3:16])([CH2:14][CH2:13][O:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH3:17])(=[O:24])[CH3:23]
Reactant: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 4 (0.500 g, 1.6 mmol), ZrOCl28.H2O (0.0025 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.251 g, 3.2 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3) δ1.56 (d, J=8.0, 6H), 1.60 (d, J=8.0, 5H), 2.14 (t, J=6.8, 2H), 4.33 (t, J=6.8, 2H), 7.82 (d, J=8.1, 2H), 8.04 (d, J=8.0, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1.I[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:10]([N:11]([CH2:31][CH2:32][CH3:33])[C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1
Reactant: CCCI
Reactant: CCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(=O)CC)c1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
60% NaH (23 mg, 0.58 mmol) is added to a solution of N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide (0.15 g, 0.39 mmol) in DMF (1 ml) at room temperature. After stirring at room temperature for 20 minutes, iodo propane (0.058 ml, 0.58 mmol) is added. The mixture is stirred at room temperature for 3 days. 20 ml of water is added and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography to give N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide. Rf (hexane/EtOAc=2:1)=0.42.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>C1COCC1.CN(C=O)C>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][NH:33][C:13]([C:6]1[C:5]([NH:4][C:3]2[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:2]=2[F:1])=[CH:10][C:9](=[O:11])[N:8]([CH3:12])[CH:7]=1)=[O:15]
Reactant: NCC(O)CO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCC(O)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 33 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 3-amino-1,2-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (33%) as a pale cream solid; m.p. (EtOAc/Hexane) 96-101° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.17 (s, 1H), 7.61 (dd, J=9.9, 1.9 Hz, 1H), 7.59-7.55 (m, 1H), 7.22 (t, J=8.4, 1H), 5.78 (s, 1H), 3.85-3.79 (m, 1H), 3.56 (dd, J=5.4, 2.3 Hz, 2H), 3.51 (s, 3H), 3.53-3.50 (m, 1H), 3.39-3.33 (m, 1H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0332. HPLC 84.8% (254 nm).
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[C:36]1[O:40][C:39]([CH3:41])=[N:38][CH:37]=1)[C:29]([NH:31][NH2:32])=O.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:29]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:32][N:31]=2)[CH:33]=[CH:34][C:35]=1[C:36]1[O:40][C:39]([CH3:41])=[N:38][CH:37]=1
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 3-methoxy-4-(2-methyl-1, 3-oxazol-5-yl)benzohydrazide (500 mg) was added acetic acid (3 mL), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (933 mg).
Reaction SMILES: Cl[CH:2]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:18][CH3:19])[C:8]([O:16][CH3:17])=[N:9]2)[CH3:3].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:13]1[C:4]([CH:2]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH3:3])=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:15])[N:9]=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[N:6]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C(C)Cl)c2nc1OC
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)c(Cl)c(C(C)n3ccnc3)c2nc1OC
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-(1-chloroethyl)-6,7dichloro-2,3-dimethoxyquinoxaline (95 mg, 0.295 mmol), imidazole (22 mg, 0.325 mmol), anhydrous potassium carbonate (45 mg, 0.325 mmol) in dry dimethylformamide (10 mL) was heated under nitrogen at 100° C. for 6 hours, cooled, and partitioned between brine and three portions of ethyl acetate. The combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with dichloromethane:mehanol) to give 6,7dichloro-2,3-dimethoxy-5-(1-imidazol-1-ylethyl)quinoxaline (60 mg, 58%); as a yellow solid.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.[F:29][CH:30]([F:62])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([OH:53])=O)=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:45]2=[N:46][CH:47]=1>CN(C=O)C>[F:62][CH:30]([F:29])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([NH:16][CH:11]([CH3:12])[CH3:10])=[O:53])=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:59])([CH3:60])[CH3:61])[C:45]2=[N:46][CH:47]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) and DMF (2 mL). The reaction mixture was stirred at 25° C. for 15 h. Propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) and HATU (28.0 mg, 73.5 μmol) were added. After 3 h the solvents were evaporated and the residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 50% EtOAc in hexanes over 30 min) to yield 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32.5 mg, 61.3 μmol, 100%) as a light yellow solid. MS (M+Na)+=553.1; 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.45-7.53 (m, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.53 (t, J=74.0 Hz, 1H), 5.73 (s, 2H), 4.38-4.59 (m, 1H), 4.21 (s, 3H), 3.55-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.88-1.03 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.O[N:22]1[C:26]2C=CC=CC=2N=N1.O>CN(C)C=O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:22][CH3:26])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), I-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform: methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.58 mmol) produced in Example 12(v) was dissolved in pyridine (3.0 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.88 mmol) was added, and the mixture was stirred at 70° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=10/90→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 39%) as a colorless powder.
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:6]1[C:5]2[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
5-Amino-1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-one (46.2 mg) was dissolved in dimethyl sulfoxide (1 ml), and to the solution was added CuCN (16.4 mg). The mixture was heated at 55° C. At the same temperature, a solution of t-butyl nitrite (43.6 mg) in dimethyl sulfoxide (0.5 ml) was added dropwise during about 1.5 hours. After the addition was completed, the mixture was stirred at about 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted 2 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (20 g, CHCl3-methanol=20:1) to give the title compound (17.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([CH2:23][C:24]#[CH:25])[C:14]([NH:16][CH2:17][CH:18](OC)OC)=[O:15])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:18]=[CH:17][NH:16][C:14](=[O:15])[C@H:13]2[CH2:23][C:24]#[CH:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)NCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A solution of (R)-2-(3,4-dichlorobenzenesulfonamido)-N-(2,2-dimethoxyethyl)pent-4-ynamide (36.7 g, 89.6 mmol) in 500 mL p-dioxane was treated with TsOH.H2O (5.11 g, 26.9 mmol). The reaction was heated to 60° C. for 7 h and then at 80° C. for 19 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 400 mL EtOAc stirred with 400 mL 5% NaHCO3. The resulting precipitate was filtered and washed with H2O. The solid was suspended in hot EtOH and cooled to rt. The solid was collected by filtration, washed with EtOH and dried in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][C:4]=1[CH3:13].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH3:11])=[CH:5][C:4]=1[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CC(C)N)cc1C
Product: COc1ccc(CC(C)NS(=O)(=O)c2ccccc2)cc1C

Procedure:
(±)-1-(4-methoxy-3-methylphenyl)-2-aminopropane and benzenesulfonyl chloride are treated in the same manner as described in Example 61-(1) to give (±)-1-(4-methoxy-3-methylphenyl)-2-benzenesulfonylaminopropane.