Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=[C:6]([F:32])[CH:5]=1)(=[O:3])[NH2:2]>ClCCl.FC(F)(F)C(O)=O>[F:32][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cc(F)cc3[nH]2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12

Procedure:
A solution of EXAMPLE 55A (360 mg) in dichloromethane (25 mL) and trifluoroacetic acid (5 mL) was stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 2.20-2.37 (m, 3H), 2.56-2.62 (m, 1H), 3.47-3.57 (m, 2H), 4.76 (dd, J=9.31, 7.17 Hz, 1H), 7.50-7.54 (m, 3H), 7.71 (dd, J=10.37, 2.44 Hz, 1H), 8.43 (t, J=7.93 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1.[CH3:23][CH2:24][O:25]C(C)=O>C(OC(=O)C)(=O)C.OS(O)(=O)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:24](=[O:25])[CH3:23])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1
Reactant: COc1c(C)cnc(Cn2cnc3c(Cl)nc(N)nc32)c1C
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c(C)cnc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (80 mg, 0.25 mmol) in acetic acid anhydride (2.2 g) was treated with one drop of concentrated H2SO4 and stirred at r.t. for 5 min. Work-up (EtOAc), drying (MgSO4) and evaporation gave the title compound as a white solid. HPLC Rt: 4.093 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 2.54 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCNc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
1,4-Diaminobutane (4.19 g) was dissolved in tetrahydrofuran (THF: 300 ml) to which, at -10° C., was subsequently added dropwise 2,4-difluoronitrobenzene (3.00 g) dissolved in THF (100 ml). The reaction solution was warmed up to room temperature, stirred for 3 hours and then mixed with di-tert-butyl dicarbonate (8.22 g). The reaction solution was further stirred overnight, the thus formed insoluble matter was separated by filtration, the resulting filtrate was concentrated, and a mixed solution (150 ml) of n-hexane:ethyl acetate=1:2 was added to the residue. The thus formed insoluble matter was again separated by filtration and then the filtrate was concentrated under a reduced pressure. The resulting yellow solid was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give N-(4-tert-butoxycarbonylaminobutyl)-5-fluoro-2-nitroaniline (4.67 g). The resulting aniline compound (3.20 g) and imidazole (4.00 g) were dissolved in DMSO (50 ml). The solution was stirred at 150° C. for 4 hours, spontaneously cooled down to room temperature and, after addition of water (500 ml), extracted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting solid substance was washed with water and dried under a reduced pressure to give N-(4-tert-butoxycarbonylaminobutyl)-5-(1H-imidazol-1-yl)-2-nitroaniline (3.13 g). In an atmosphere of hydrogen, the thus formed product (3.00 g) was subjected to 4 hours of reduction in ethanol under ordinary pressure, using palladium-carbon as the catalyst. The reaction solution was filtered and concentrated under a reduced pressure. Then, oxalic acid (2.16 g) and 4 N hydrochloric acid (40 ml) were added to the residue, followed by heating under reflux for 8 hours. The reaction solution was filtered, and the resulting filtrate was concentrated to about half of the volume. The thus precipitated crystals were collected by filtration and dried under a reduced pressure to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-2,3(1H,4H)-quinoxalinedione dihydrochloride (2.87 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH:3]=1.[H][H]>[Ni].[Pd].C(O)(C)C>[CH3:1][CH:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[O:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1=CCOC2(CCCC2)C1
Agent: [Ni]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CCOC2(CCCC2)C1
Yield: 90.8 %

Procedure:
A solution of 9-methyl-6-oxaspiro[4.5]dec-8-ene (1.52 kg, 10.0 mols), isopropyl alcohol (1000 ml) and Raney nickel (100 g), Pd/C (100 g) or other suitable sponge-metal catalyst was hydrogenated at 450 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 9-methyl-6-oxaspiro[4.5]decane (1.4 kg, yield: 95%, purity: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 59.2 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (0.100 g, 0.206 mmol), 3-(trifluoromethyl)aniline (0.041 g, 0.247 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (10.0 mL) to afford 0.075 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.19-8.03 (m, 9H), 8.25 (s, 1H), 10.36 (s, 1H), 12.65 (s, 1H); MS (m/z): 614.98 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cc(Br)cnc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc(Br)cc1C
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 5-bromo-3-methylpicolinic acid (10000 g, 1 equiv, 46.29 moles) in ethanol (50 L) at 0° C. was added sulfuric acid (2.52 L, 1 equiv, 46.29 moles) over 1 h. Following addition of sulfuric acid, the mixture was heated at 95° C. for 20 h. Reaction progress was monitored by using TLC and LCMS. After 20 hours, LCMS showed 12.61% unreacted SM, at RT-0.67 ((M−1)−215.92) and 86.95% product at RT-2.04 ((M+1)−244.2). The reaction mass heated for additional 6 h and LCMS analysis following the additional heating showed 10.07% unreacted SM, at RT-0.7 and 89.93% product at RT-2.08 ((M+1)−244.2. The reaction was stopped by concentrating the reaction mixture under reduced pressure to remove as much solvent as possible. To the residue was added dichloromethane (DCM), (25 L) and the reaction mixture was poured into ice cold water (20 L). The organic (DCM) layer was separated from the aqueous layer and the latter was further extracted twice with DCM (10 L). The combined organic layers were washed with saturated sodium bicarbonate solution (30 L), dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. This brown oil was used in the next step without further purification. Yield: 10.1 Kg, (89.4%); MS (ESI) m/z 244.2 [M+1]+; LCMS purity: 99.11%; 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.13 (s, 1H), 4.29 (q, 2H), 2.44 (s, 1H), 1.28 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH2:29])=[O:28])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: NC(=O)c1ccccc1Br
Product: NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromobenzamide. MS (ESI): mass calcd. for C17H13FN4O, 308.11; m/z found, 309.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.86 (m, 1H), 7.75 (s, 1H), 7.55-7.26 (m, 7H), 6.70 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O.C(C(C)=O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNc1nc(Cl)c(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNc1nc(Cl)c(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
Methyl-(4,5,6-trichloro-pyrimidin-2-yl)-amine (2.8 g, 12.2 mmol), 1-Boc-piperazine (2.27 g, 12.2 mmol), potassium carbonate (0.84 g 6.1 mmol) in water (2.5 ml) and methyl ethyl ketone (50 ml) were refluxed for 12 hours. After cooling to room temperature the precipitate was filtered, and washed with water to give the title compound (2.6 g, 59%), melting point: 205-206° C.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:20]I>O>[CH3:20][O:11][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)(C(=O)c1ccccc1)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(C)(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Portions of 2.85 g α-methyl-benzoin are dissolved in a nitrogen atmosphere in 25 ml of solvent and mixed with 5.5 ml of a 10% by weight sodium hydroxide solution and then with 0.8 ml methyl iodide, while maintaining a temperature of 25°C. After stirring for 2 hours, the reaction products are poured into water, isolated and analysed by NMR-spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][S:11](=[O:13])(=[O:12])[NH2:14]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Yield: 71.5 %

Procedure:
This compound was prepared according to the procedure of Example 84 from a mixture of 16.3 g (0.10 mole) of 2,6-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene to obtain 17.3 g (71%) of the title compound after recrystallization from benzene, mp 114.5°-116° C.
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4](=O)[C:3]=1[CH:14]=O.[NH2:16]/[C:17](/[CH3:21])=[CH:18]\[C:19]#[N:20]>C(O)C>[CH3:21][C:17]1[N:16]=[CH:14][C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]=2[C:18]=1[C:19]#[N:20]
Reactant: O=CC1=C(O)c2ccccc2OCC1=O
Reactant: C/C(N)=C/C#N
Solvent: CCO
Product: Cc1ncc2c(c1C#N)COc1ccccc1C2=O

Procedure:
A solution of 8.16 g (0.04 mole) of 2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde, 4.92 g (0.06 mole) of 3-aminocrotononitrile and 50 ml of absolute ethanol was maintained at reflux for 10 min. and cooled. The separated crystals were filtered, washed with 10 ml ethanol and dried, wt. 5.2 g (52%); mp 124°-126°. Recrystallization was effected by dissolution in 75 ml of 50% dichloromethane-ethanol and removal, by distillation, of most of the dichloromethane. The pure product separated as tan crystals; wt. 2.9 g (29%), mp 126°-128°.
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[OH:23])[O:13][CH3:14])=[CH:7][CH:6]=1)=[NH:4]>C(O)C.C(O)(=O)C.[Pd]>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[OH:23])[O:13][CH3:14])=[CH:25][CH:26]=1)(=[NH:2])[NH2:4]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)NO)cc2)c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)N)cc2)c(O)c1
Reaction time: 7.5 h

Procedure:
A suspension of (RS)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (240 mg) in ethanol (9 ml) and acetic acid (0.38 ml) was hydrogenated for 7.5 h using 10% Pd/C as a catalyst. The reaction mixture was filtered and the solvent was evaporated. The product was purified by chromatography (silica gel, CH2Cl2=>CH2Cl2/MeOH 4:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide actetate (12 mg) as an off-white, amorphous solid. MS 344.2 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C>[Pd].C1COCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[CH:2][CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2ccnc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round bottom flask fitted with a 3-way inlet was placed 10% Pd/C (0.071 g, 0.033 mmol) followed by degassing with N2, and then addition of 2 mL ethanol. Added next to the stirring slurry was 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.669 mmol). Additional ethanol (8 mL) and THF (10 mL) were added with slight warming to facilitate dissolution. The stirring contents were allowed to cool (15 min.) then fitted with a balloon of H2 and allowed to stir at room temperature overnight. The contents were then purged with N2. The mixture was then diluted with 10% MeOH/DCM (20 mL), stirred for 10 min., and filtered through Celite. The filtrate was concentrated in vacuo and the crude solid was triturated with ethanol. After filtration and washing the collected solid with additional ethanol (cold), the solid was air-dried for 15 min, then in vacuum oven at 40° C. overnight. The final product was collected as 185 mg (80%). LCMS E-S (M+H)=340.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.82 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.37 (d, J=4.80 Hz, 2H), 5.18-5.31 (m, 1H), 5.89 (s, 1H), 7.54 (d, J=4.80 Hz, 1H), 8.36 (s, 1H), 8.63 (d, J=4.55 Hz, 1H), 8.82 (t, J=4.93 Hz, 1H), 11.56 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>C(OCC)C>[CH3:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
4,6-Dimethylpyrimidin-2-ol (10.0 g, 80.6 mmol) was added to sulfuric acid (80 mL) at 0° C. Then potassium nitrate (16.29 g, 161.1 mmol), was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 24 hr. The reaction mixture was poured slowly into diethyl ether (1000 mL) at 0° C. The precipitated solid was collected by filtration and washed with diethyl ether. A suspension of the solid in ethanol (50.0 mL) was neutralized with sodium hydrogen carbonate at room temperature. The solid was removed by filtration and the filter cake was washed with ethanol (ca. 3000 mL). The filtrate was concentrated in vacuo to give the title compound (13.15 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:27](Br)[C:28]([OH:30])=[O:29]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[O:18][CH:27]([C:28]([OH:30])=[O:29])[O:19][C:13]=2[CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)c1cc(O)c(O)cc1C
Reactant: O=C(O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)c1cc2c(cc1C)OC(C(=O)O)O2

Procedure:
27.5 g (0.097 mol) of 4-(2-methylphenylsulphonyl)-5-methyl-1,2-benzenediol, 62.1 g (0.45 mol) of potassium carbonate and 32.7 g (0.145 mol) of dibromoacetic acid (97% strength) are reacted in 300 ml of dimethylformamide under an inert gas atmosphere in a manner analogous to that described in Example 27. After working up, purification by way of the ethyl ester and hydrolysis, in a manner entirely analogous to that described in Example 27, 5-(2-methylphenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of colourless crystals having a melting point of 178°-180° (from toluene).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:7]([CH3:21])[C:6]=1[CH3:22])=[O:4].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:11]([C:8]1[N:7]([CH3:21])[C:6]([CH3:22])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:9]=1[CH3:10])=[O:20]
Reactant: C1CCNCC1
Reactant: Cc1c(C(=O)CCl)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CC(C)O
Product: Cc1c(C(=O)CN2CCCCC2)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 66.6 %

Procedure:
A solution of 8.0 g (0.022 mole) of 2-chloro-1-[5-(2,4-dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-ethanone (6) and 4.64 mL (0.066 mole) of piperidine in 130 mL of 2-propanol was heated under reflux for 1.5 h. The reaction was cooled and the solvent evaporated in vacuo. The residue was partitioned between diethyl ether and water and the organic solution was extracted twice with 1N HCl. A solid was removed by filtration and the filtrate was made basic with sodium bicarbonate. The mixture was extracted with diethyl ether and the ether solution was washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo. The product was converted to the hydrochloride salt and recrystallized from 2-propanol to give 5.97 g of product: mp 177-179° C.; mass spectrum (Cl—CH4) m/z=393 (m+1); NMR 300 MHz (Me2SO-d6) d 7.85 (s,1H); 7.6-7.5 (m, 2H); 4.7 (s, 2H); 3.8 (s, 3H); 3.6-3.4 (m, 2H); 3.2-3.0 (m, 2H); 2.6 (s, 3H); 2.0 (br s, 4H); 1.8 (s 3H). Anal Calcd for C20H22Cl2N2O2: C, 55.22; H, 5.87; N, 6.05. Found: C, 55.06; H, 5.89; N, 6.05.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[C:27]([Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40]Br)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[Si:31]([O:34][CH2:35][CH:36]1[CH2:38][CH:37]1[CH2:39][CH2:40][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:32])[CH3:33]
Reactant: C#CCOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A tetrahydrofuran solution (15 ml) of propargyl alcohol tetrahydropyranyl ether (1.44 g, 10.3 mmol) was cooled to -78° C., and butyllithium (factor=1.5, 6.9 ml, 10.3 mmol) was added thereto. Fifteen minutes later, the temperature was raised to 0° C. Hexamethylphosphoric triamide (3.76 ml, 21 mmol) was added thereto, and the mixture was stirred for 15 minutes. A tetrahydrofuran solution of 2-(2-bromoethyl)cyclopropylmethyl t-butyldimethyl silyl ether (2.73 g, 10.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added thereto, and the product was extracted with ethyl ether. The crude product was purified by silica gel column chromatography to obtain 2-(5-tetrahydropyranyloxy-3-pentynyl)cyclopropylmethyl t-butyldimethylsilyl ether (3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(F)cc(F)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2,4,6-trifluorophenylacetic acid (570 mg, 3.0 mmol), iodoethane (1.56 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) in 5 mL of dimethylsulfoxide is stirred at 50° C. for 3 h, and cooled to room temperature. The mixture is partitioned between diethyl ether and water. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The filtrate is concentrated to give ethyl 2,4,6-trifluorophenylacetate as a light yellow oil (581 mg, 2.66 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][C:43]([CH3:45])=[CH2:44])=[O:41].CCCCCC>CCOC(C)=O>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:40](=[O:41])[O:42][C:43]([CH3:45])=[CH2:44])=[C:25]([F:29])[CH:24]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A bi-phasic mixture of Example A4 (1.00 g, 2.142 mmol) in EtOAc (25 mL) and satd. NaHCO3 (25 mL) was treated with isopropenyl chloroformate (516 mg, 4.28 mmol) and stirred vigorously at RT for 3 h. Hexane (10 mL) was added and the resulting solid collected via filtration and dried. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and combined with the above-isolated solid to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (1.168 g, 98% yield). MS (ESI) m/z: 551.2 [M+H]+.