Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:44])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][OH:43])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][OH:43])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:44])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(NCCO)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)nc(NCCO)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-{3-[2-(2-hydroxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K50) (251 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (136 mg).
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:21])\[C:8]#[C:9][C:10]12[O:20][C:11]1([CH3:19])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16])(=O)C.C([O-])([O-])=O.[K+].[K+].CO>O>[OH:4][CH2:5]/[CH:6]=[C:7](/[CH3:21])\[C:8]#[C:9][C:10]12[O:20][C:11]1([CH3:19])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16]
Reactant: CC(=O)OC/C=C(/C)C#CC12OC1(C)CC(O)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C/C(C#CC12OC1(C)CC(O)CC2(C)C)=C/CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of Z-4-(5-acetoxy-3-methyl-pent-3-en-1-ynyl)-3,4-epoxy-3,5,5-trimethylcyclohexan-1-ol (36 mg, 0.12 mmol), K2CO3 (26 mg, 0.18 mmol), methanol (1 mL) and H2O (1 mL) was stirred at room temperature for 1 h. It was then concentrated by evaporation and the residue was diluted with H2O and extracted with CHCl3. The organic extract was dried over anhydrous Na2SO4. Evaporation of solvent gave compound (5) as a colorless oil (21 mg, 69%), ir: 3620 (sharp, medium, OH) and 3450 (broad, weak, OH) cm-1; 1H nmr d: 5.87 (ddq, J=6.7, 6.7, 1.4 Hz, 1H, =CH), 4.27 (dd, J=6.7, 1.0 Hz, 2H, CH2O), 3.82 (m, 1H, CHOH), 2.18 (ddd, J=14.8, 6.8, 1.4 Hz, 1H, CH2), 1.86 (m, 3 H, vinyl CH3), 1.79 (dd, J=14.8, 9.0 Hz, 1H, CH2), 1.46 (s, CH3), 1.36 (ddd, J=12.7, 4.1, 1.5 Hz, 1H, CH2), 1.16 and 1.17 (2s, 6H, 2CH3); 13C nmr d: 136.36 (d, =CH), 119.95 (s, =C), 90.95 and 83.99 (2s, 2 acetylenic C), 65.08 and 64.52 (2s, C--O--C), 63.29 (d, CHOH), 61.15, 41.84 and 38.16 (3t, 3 CH2), 34.83 (s, C), 27.03, 25.60, 22,98 and 22.92 (4q, 4CH3); ms (NH4Cl CI) m/z: 268 (M+18), 251 (M+1), 233 (M-17).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH3:8].[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=2[OH:33])=[CH:12][CH:11]=1.O>CN(C)C=O>[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:20][C:19]=2[O:33][CH2:7][CH3:8])=[CH:12][CH:11]=1
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(CNC(=O)OC(C)(C)C)ccc1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
Potassium carbonate (40 mg) and ethyl bromide (56 mg) were added to a solution of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide (100 mg) in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The obtained crystals were recrystallized form ethyl acetate-hexane to give 60 mg of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-ethoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16](F)[CH:15]=3)=[CH:12][N:11]=[C:10]([NH2:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:22].C(O)C.N>C(O)C>[NH2:22][C:16]1[CH:15]=[C:14]([C:13]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][C:10]([NH2:21])=[N:11][CH:12]=2)[CH:19]=[CH:18][N:17]=1
Reactant: N
Reactant: Nc1ncc(-c2ccnc(F)c2)c(-c2cccc(F)c2)n1
Solvent: CCO
Product: Nc1cc(-c2cnc(N)nc2-c2cccc(F)c2)ccn1
Temperature: 150 °C
Yield: 12 %

Procedure:
A mixture of 4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinylamine (100 mg, 0.352 mmol) and ammonia/ethanol (ethanol saturated with an ammonia gas under ice-cooling) (20 mL) was sealed in a test tube and stirred at 150° C. for 2 weeks. After cooling as it was, the reaction solution was concentrated. The residue was dissolved by adding ethyl acetate and water thereto. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate and concentrated. The residue was purified by TLC plate (eluting solvent: dichloromethane/methanol=10/1), to give the title compound (12 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccc1Cl

Procedure:
A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:29](I)[CH3:30]>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:29][CH3:30])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: CCI
Agent: Cl
Product: CCN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m.p. 197° C. (dec.) and MS: m/e=398.4 M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and ethyliodide.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[C:9]([Cl:27])=[CH:10][C:11]4[N:15]=[C:14]([NH:16][C:17]5[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=5[Cl:25])[CH2:20][NH2:21])[NH:13][C:12]=4[CH:26]=3)[CH2:4]2)[CH2:2]1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH2:2]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[C:9]([Cl:27])=[CH:10][C:11]4[N:15]=[C:14]([NH:16][C:17]5[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=5[Cl:25])[CH2:20][NH:21][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[NH:13][C:12]=4[CH:26]=3)[CH2:4]2)[CH2:1]1
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1

Procedure:
The sub-title compound was prepared from 3-[6-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzylamine (60 mg, 0.1), pivaloyl chloride (20 μL, 0.1 mmol) and TEA (160 μL, 1.1 mmol) in THF (5 mL) in analogy to example 3, step (e).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][CH2:12][O:13][C:14]([CH2:16]P(OCC)(OCC)=O)=[O:15].CC([O-])(C)C.[K+]>C1COCC1>[CH2:12]([O:13][C:14](=[O:15])/[CH:16]=[CH:4]/[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[CH3:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Cl)cccc1Cl
Reaction time: 10 h

Procedure:
To a stirred solution of 2,6-dichlorobenzaldehyde (5.0 g, 28.56 mmol) in THF was added triethyl phosphono acetate (6.4 g, 28.56 mmol) at 0° C. The reaction mixture was added t-BuOK (3.2 g, 28.56 mmol) at room temperature. The mixture was stirred for 10 h then the resulting mixture was quenched with 1N HCl, diluted with ether, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 gel column chromatography (4.3 g 40˜60%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:14]2)[CH3:10].C(OC(C)C)(=O)C>Cl>[C:1]([C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[CH2:9][CH3:10])[CH2:14][CH:15]([NH:20][C:21](=[O:26])[C:22]([F:24])([F:23])[F:25])[CH2:16]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)C
Product: CCc1cc2c(cc1C(C)=O)CC(NC(=O)C(F)(F)F)C2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
A 250 mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (37.68 g, 480 mmol) and cooled to 0±5° C. Aluminum chloride (13.33 g, 100 mmol) was added in 4×3.33 g portions at 0±5° C. while maintaining the temperature below 15° C. The resulting solution was cooled to 0±5° C. and stirred for 5 minutes. N-(5-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (10.29 g, 40 mmol) was added in 5×2.06 g portions over 40 minutes at 10-minute intervals, while maintaining the temperature 0-10° C. The tan solution was stirred at 0±5° C. for an additional 30 minutes. The solution was added to a pre-cooled (0-5° C.) mixture of 1 N HCl (120 mL) and isopropyl acetate (13 mL) in a 500 mL, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the temperature at 0-25° C. over a period of 20 minutes. The 250 mL, round-bottomed flask was rinsed with 3 mL of acetyl chloride followed by 13 mL of heptane and added to the batch. The resulting slurry was warmed to 40-45° C. over a period of 30 minutes and then stirred for additional 1 hour. Heptane (39 mL) was added and the slurry was stirred at 40-45° C. for an additional 15 minutes. The slurry was cooled to 20-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over polypropylene filter paper. The filter cake was washed with 2×10 mL heptane/isopropyl acetate (80:20 v/v), followed by 1 N HCl (36 mL) and deionized water (2×25 mL). The solids were dried at 60-65° C. under vacuum (13-40 mbar, 10-30 torr) with nitrogen bleeding to obtain 11.3 g (94% yield) of N-(5-acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 124-127° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1csc2cncn12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1csc2cncn12
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To an ice-cooled solution of 3.39 g of 3-hydroxymethylimidazo[5,1-b]thiazole in 22 ml of DMF were added 1.95 g of imidazole and 3.81 g of t-butyldimethylsilyl chloride. After the reaction mixture was reacted at room temperature for 6 hours, it was diluted with 150 ml of ethyl acetate, and washed three times with saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 5.83 g of 3-(t-butyldi methylsilyloxy)methylimidazo[5,1-b]thiazole.
Reaction SMILES: [H-].[Na+].[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][CH:4]=1.Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29]>CN(C=O)C>[C:3]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[N:12]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(C(=O)CCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CN(C(=O)OC(C)(C)C)[C@@H]2C[C@H]2c2ccc(-c3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.5 equiv of NaH in dry DMF (10 vols) at 0° C. was added a solution of tert-butyl(trans)-2-(1,1′-biphenyl-4-yl)cyclopropylcarbamate derivative (1 equiv) in dry DMF (2 vols) and stirr for 30 mins. Then, added a solution of 1-(chloroacetyl)-4-methylpiperazine (1.5 equiv) in dry DMF (10 mL) at 0° C., stirred for 1 h at 0° C. to RT. The progress of the reaction was monitored by TLC. After completion, reaction mixture was poured into ice water and extracted with EtOAC. The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purifying by preparative HPLC to get tert-butyl (trans)-2-(1,1′-biphenyl-4-yl)cyclopropyl(2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate derivative
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[CH:13][C:14]([O:16][C@@H:17]2[CH:21]3[O:22][CH2:23][C@@H:24]([O:25]C4CCCCO4)[CH:20]3[O:19][CH2:18]2)=[O:15])=[CH:10][CH:9]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][C@@H:17]2[CH:21]3[O:22][CH2:23][C@@H:24]([OH:25])[CH:20]3[O:19][CH2:18]2)=[O:15])=[CH:32][CH:33]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)O[C@H]1COC2C1OC[C@H]2OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(O)cc1)O[C@H]1COC2C1OC[C@H]2O
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A mixture of 9.1 g of 3-(R)-(tetrahydropyran-2-yloxy)-hexahydro-furo[3,2-b]furan-6-(S)-yl 4-(tetrahydropyran-2-yloxy)cinnamate (25), 0.48 g of pyridinium 4-toluenesulfonate and 60 ml of absolute ethanol was heated at 60° C. for 3 hours under a nitrogen atmosphere. A clear solution was obtained which was added dropwise to 50 g of ice and 100 g of water with vigorous stirring. A white solid precipitated. It was filtered off, washed with water and dried in a dessicator over silica. 3.7 g of a white powder was obtained (yield: 66%).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Cl.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10].C(I)C>CN(C=O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:23][CH2:24][N:25]([CH2:1][CH3:2])[CH2:26][CH2:27]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
Triethylamine (0.2 g), 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (0.3 g), ethyl iodide (0.19 g), and DMF (5 ml) were mixed, heated with stirring at 90° C. for 3 hours, and the solvent was evaporated. The residue was dissolved in 2N sodium hydroxide solution. The alkaline solution was neutralized with aqueous acetic acid and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-7-(4-ethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), mp 236°-239° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25].O>CN(C=O)C>[CH3:3][N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc([N+](=O)[O-])cc2C)cc1
Yield: 34.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in 2.0 ml of DMF, N-methyl-p-toluenesulfonamide (0.37 g (2.00 mmol)) was added at room temperature with stirring. To the resulting mixture, after 15 minutes' stirring at room temperature, 2-fluoro-5-nitrotoluene (0.31 g (2.00 mmol)) was added. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated was filtered and washed to give 0.22 g (36%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>COCCOCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>[N:9]1([NH:8][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: Clc1ccncc1
Reactant: Nn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: c1ccn(Nc2ccncc2)c1
Yield: 57.1 %

Procedure:
A solution of 4-chloropyridine (15 g) and N-aminopyrrole (18 g) in 225 ml of diglyme was stirred at 150° C. for one hour and thereafter cooled, diluted with water and basified with sodium carbonate. The mixture was extracted with ethyl acetate, and the organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. This oil was purified by high performance liquid chromatography (HPLC hereafter) using silica gel and ethyl acetate to give 12 g of a solid, m.p. 150° C. Five grams of the solid was recrystallized twice from benzene to give 2.8 g of crystals, m.p. 153°-154° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:14](=[O:15])[N:13]([CH3:12])[S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1O
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1OC(=O)N(C)SSc1ccc(C(C)(C)C)cc1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 4.0 g (0.026 m) of 2-isopropoxyphenol and 7.11 g (0.026 m) of N-methyl-N-(p-tert-butylphenylthiosulfenyl)carbamoyl fluoride in 75 ml of toluene was added 2.63 g (0.026 m) of triethylamine. After stirring for 48 hours the reaction mixture was washed with water and dried over anhydrous MgSO4. The product was purified by dry column chromatography to give 2.5g of a white solid. m.p. 84°-85° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[N:16]([CH:27]=[N:28][CH:29]=3)[C:17]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[N:16]([CH:27]=[N:28][CH:29]=2)[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOC[C@H](O)CO)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a heterogeneous mixture of (R)—N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide (69.5 mg, 0.13 mmol) in anhydrous methanol (1.6 mL) was added 4M HCl in 1,4-dioxane (0.13 mL, 0.5 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 10 minutes. Solid sodium sulfate (200 mg) was then added. The reaction mixture was absorbed onto silica and then subjected to flash chromatography (Si-PPC, gradient 0% to 40% methanol in dichloromethane) to give the title compound as yellow foam (43.2 mg, 67.3%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.90 (s, 1H), 10.30 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.60 (t, J=8.4 Hz, 1H), 4.86 (d, J=4.4 Hz, 1H), 4.55 (broad s, 1H), 3.99-3.91 (m, 1H), 3.79-3.69 (m, 2H), 3.39 (broad s, 2H); LCMS (method E2): RT=8.40 min, [M+H]+=488.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH:8]([NH2:11])[CH2:9][CH3:10].[CH3:23][N:24]=[C:25]=[O:26]>ClC(Cl)C>[CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH:8]([NH:11][C:25]([NH:24][CH3:23])=[O:26])[CH2:9][CH3:10]
Reactant: CCC(N)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reactant: CN=C=O
Solvent: CC(Cl)Cl
Product: CCC(NC(=O)NC)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C

Procedure:
A mixture of 1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propylamine (26.5 mg), methyl isocyanate (0.05 ml), in dichloroethane (1 ml) was heated at reflux overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give 27.1 mg of white solid. The solid was purified by preparative thin layer chromatography using 5% methanol in chloroform as solvent to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>O.C(O)C>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:16][OH:17])[CH3:2]
Reactant: CCC1CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC1CCCCC1=NO
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of 2-ethylcyclohexanone (104.3 mmol) in water and ethanol, and sodium acetate (125.1 mmol) were added hydroxylamine hydrochloride (156.4 mmol), the reaction was heated at 70° C. overnight. The ethanol was removed under reduced pressure, and the reaction mixture was dissolved in water. The aqueous layer was extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give 2-ethyl-1-(hydroxyimino)cyclohexane (52%) as a thick oil.