Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:25][CH:26]([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:21])[F:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH:26]([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.90 g, 5.49 mmol), 1-bromo-2-methyl propane (1.19 mL, 10.97 mmol) and K2CO3 (1.51 g, 10.97 mmol) in DMF (20 mL) was heated at 100° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-30% EtOAc in cyclohexane) gave N-isobutyl-4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.69 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.78-7.70 (m, 1H), 7.61-7.47 (m, 2H), 7.23-7.16 (m, 1H), 3.48-3.31 (m, 2H), 1.76-1.60 (m, 1H), 0.88 (dd, J=10.1, 6.6 Hz, 6H). LCMS (m/z, Method A) ES+ no mass ion observed.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][NH:3][CH2:2]1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(C(=O)OCC)ccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(C(=O)OCC)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using diethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5,8-dicarboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.78 (1H, br s), 8.13 (2H, m), 7.81 (1H, m), 7.63 (2H, m), 7.53 (1H, d), 7.17 (2H, m), 4.39 (2H, q), 4.26 (4H, m), 3.28 (2H, t), 1.42 (3H, t), 1.23 (3H, t); MS (ES): 451 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CC1(C)CCC(=O)CC1
Yield: 90.3 %

Procedure:
To 0.1 g of palladium on activated carbon (10%) was added a solution of 4,4-dimethylcyclohex-2-enone (6.23 g, 50 mmol) in petroleum ether. This mixture was stirred under 1 atmosphere of hydrogen for 20 hours. After filtration through celite, the solvent was removed under reduced pressure to afford a white solid (5.7 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.27 g of N-(tert-butoxycarbonyl)aspartic acid-4-benzyl ester and 1.31 mL of n-butyl amine were dissolved in 25 mL of DMF, and then 2.93 g of WSC hydrochloride and 1.93 g of HOBt were added thereto, and the reaction solution was stirred at room temperature overnight. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and then distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 5.12 g of Compound 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1.[H][H]>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2c(N)cnc3ccc(Br)cc23)cn1

Procedure:
6-bromo-N-(6-methoxypyridin-3-yl)-3-nitroquinolin-4-amine (compound of step 2, 13.3 mmol) was hydrogenated using Raney-Ni (1 g) in THF-MeOH [(1:1), 50 mL] under 40 psi of hydrogen for 4 h at RT. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 3H), 7.47 (dd, J=2.1, 9.0 Hz, 2H), 6.93 (dd, J=3.0, 8.7 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H); MS (m/z): 345.0 (M+1)+.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13](=[O:24])(=[O:23])[N:12]=2)=[CH:7][CH:6]=1.Cl>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2([CH3:1])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([Cl:4])=[CH:10][CH:9]=3)=[N:12][S:13](=[O:24])(=[O:23])[NH:14]2)=[CH:17][CH:18]=1
Reactant: C[Mg]Br
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=N1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2)NS(=O)(=O)N=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (0.89 M tetrahydrofuran solution, 43.1 ml) was added dropwise to a toluene (200 ml) suspension of the compound (10.0 g, 29.5 mmol) obtained in Step 1 above at 0° C. The resulting mixture was stirred at room temperature for 1 hour and then 1 N aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (11.1 g, quantitative) as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:51])[O:48][CH2:49][CH3:50]>C1COCC1>[CH2:49]([O:48][C:47]([O:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1)=[O:51])[CH3:50]
Reactant: N=C(NO)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)ONC(=N)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
A solution of compound 42a (0.16 g, 0.33 mmol), DIEA (0.17 g, 1.3 mmol) and ethyl carbonochloridate (0.10 g, 0.93 mmol) in THF (10 mL), was stirred at rt for 2 h. The reaction was then quenched with water (50 mL). The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 42b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26N8O4: 563.2 (M+H). Found 563.2.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH:13]=[CH2:14]
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: C=CCN
Product: C=CCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1000 mg, 4.32 mmol) and allylamine (6.0 mL, 80 mmol) was heated at 80° C. (sealed tube) for 6 h. The resulting mixture was cooled to room temperature and purified on silica gel (eluting with ethyl acetate) to afford N-allyl-3-bromoimidazo[1,2-b]pyridazin-6-amine (550 mg, 51% yield) as a yellow solid: LRMS (ESI) m/z 253.0, 255.0 [(M+H)+, calcd for C9H9BrN4 252.0]
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[CH3:38][C:36]1[CH:37]=[C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)[CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)cc(C)n1
Yield: 52 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (139 mg, 52%). MS (ISP) 535.4 [(M+H)+]; mp 245° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:21][N:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=3)[CH2:19][CH2:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:17])=[CH:11][NH:12]3)[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]1>CN(C)C(=O)C>[CH:28]([C:24]1[CH:23]=[C:22]([N:20]2[CH2:19][CH2:18][C:2]3[N:7]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:17])=[CH:11][NH:12]5)[N:5]=[C:4]([N:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C@@H:41]4[CH3:40])[C:3]=3[CH2:21]2)[N:26]([CH3:27])[N:25]=1)([CH3:29])[CH3:30]
Reactant: C[C@H]1CCCCN1
Reactant: Cc1c[nH]c2cccc(-c3nc(Cl)c4c(n3)CCN(c3cc(C(C)C)nn3C)C4)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCCC[C@@H]5C)n3)CN(c3cc(C(C)C)nn3C)CC4)c12
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (50 mg, 0.123 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.15 mL, 0.86 mmol) and (S)-2-methylpiperidine (37 mg, 0.37 mmol). The reaction was stirred and heated to 125° C. for 24 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile)/water=35%-100%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.23 (br. s., 1 H), 7.42 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.1 Hz, 1 H), 7.16-7.26 (m, 1 H), 7.04 (s, 1 H), 5.69 (s, 1 H), 4.06-4.16 (m, 1 H), 3.90-4.06 (m, 2 H), 3.67 (s, 3 H), 3.53 (d, J=13.4 Hz, 1 H), 3.29-3.40 (m, 2 H), 3.16-3.29 (m, 1 H), 3.10 (d, J=4.5 Hz, 2 H), 2.85 (dt, J=13.8, 6.9 Hz, 1 H), 2.10 (s, 3 H), 1.74-1.91 (m, 2 H), 1.65-1.74 (m, 2 H), 1.48-1.65 (m, 2 H), 1.22 (d, J=6.8 Hz, 6 H); MS (ESI+) m/z 484.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH:28]([CH3:30])[CH3:29])[NH:5][C:6](=[O:27])[C:7]([CH3:26])([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C:7]([CH3:25])([CH3:26])[C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH:28]([CH3:29])[CH3:30])=[O:27])=[O:24])[CH2:19][O:20][CH2:21][CH:22]=[CH2:23])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl α,α-dimethylglycyl L-valine methyl ester 12 (8.56 g, 19.3 mmol) was dissolved in THF (150 mL). The solution was cooled to 0° C. (icebath). LiOH monohydrate (0.891 g, 21.2 mmol) was dissolved in de-ionized water (75 mL) and the solution cooled to 0° C. The solution was added dropwise to the solution of 12 over 20 min. The reaction mixture was stirred for an additional 2 h 40 min before solid NaHCO3 (3.24 g, 38.6 mmol) was added. The mixture was stirred for 5 min and the bulk of THF evaporated. The solution was diluted with water (150 mL), washed with Et2O (2×150 mL), acidified to pH 2 by addition of 2 M aqueous H2SO4 and extracted with EtOAc (3×300 mL). The combined organic fractions were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.30 g, 88%); δH (300 MHz; d6-DMSO) 12.62 (1H, br s, COOH), 8.01 (1H, s, NH(Aib)), 7.12 (1H, d, J 9, NH(Val)), 6.85 (1H, d, J 8, NH(Ser(All))), 5.92-5.79 (1H, m, CH═CH2), 5.29-5.21 (1H, m, CH═CHH), 5.15-5.10 (1H, m, CH═CHH), 4.19-4.10 (2H, m, CαH(Ser(All))/CαH(Val)), 3.94 (2H, dt, J 1 and 5, CH2CH═CH2), 3.57-3.45 (2H, m, CH2), 2.08-1.97 (1H, m, CH(CH3)2), 1.38 (12H, s, CH3(Aib)/(CH3)3), 1.35 (3H, s, CH3(Aib)), 0.84 (3H, d, J 7, CH3(Val)), 0.81 (3H, d, J 7, CH3(Val)); δC (75 MHz; d6-DMSO): 173.6, 172.7, 169.5, 155.1, 134.9, 116.3, 78.2, 70.9, 69.5, 57.0, 56.1, 54.4, 30.1, 28.1, 25.7, 23.8, 19.0, 17.8; m/z (ESI) 452.2357 ([M+Na]+; C20H35N3O7Na requires 452.2372)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:14])[C@H:7]([C:9]([CH2:12][OH:13])([CH3:11])[CH3:10])[OH:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:22][C:23]([CH3:25])=O>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@H:7]1[C:9]([CH3:11])([CH3:10])[CH2:12][O:13][C:23]([CH3:25])([CH3:22])[O:8]1)=[O:14]
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Reactant: CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC1(C)OCC(C)(C)[C@H](C(=O)NCCCO)O1
Yield: 59 %

Procedure:
D-panthenol (10 mmol), anhydrous Na2SO4 (35.20 mmol) and PTSA monohydrate (0.99 mmol) was stirred in anhydrous acetone (40 mL) at room temperature during 4 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude was purified by chromatography on a silica gel column (eluent: CH2Cl2/CH3OH 0 to 10%) to give the expected compound as a white crystallized solid in 59% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.89 (s, 3H), 0.91 (s, 3H), 1.37 (s, 6H), 1.55 (quintuplet, J=6.52 Hz, 2H), 3.03-3.11 (m, 1H), 3.17-3.25 (m, 2H), 3.38-3.43 (m, 2H), 3.63 (d, J=11.48 Hz, 1H), 4.02 (s, 1H), 4.49 (t, J=5.18 Hz, 1H), 7.45-7.48 (m, 1H).
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21]([CH2:23][C:24](OCC)=[O:25])#[N:22].Cl>C(O)C.O>[NH2:22][C:21]1[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=[C:24]([OH:25])[CH:23]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)nc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Yield: 84.1 %

Procedure:
To a solution of sodium (23 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and ethyl cyanoacetate (113 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (2 ml) and water (5 ml). The separated solid was collected, washed with water and dried to give 7-amino-2-(4-fluorophenyl)-5-hydroxy-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (270 mg).
Reaction SMILES: [C:1]([N:4]([C:8]1[N:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[N:18][N:19]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=23)=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].Cl.O>N.C1COCC1>[F:27][C:25]([F:26])([F:28])[C:24]1[N:19]2[N:18]=[CH:17][C:16]([C:15]#[C:14][C:11]3[CH:12]=[N:13][C:8]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:10]=3)=[C:20]2[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=2)[CH:23]=1
Reactant: CC(=O)N(C(C)=O)c1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Yield: 99.9 %

Procedure:
N-Acetyl-N-{5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyrimidin-2-yl}-acetamide (example 244) (56 mg, 0.1 mmol) was dissolved in ammonia (200 uL) and THF (5 mL), stirred for 15 minutes at 23° C., then 1N HCl and water added until pH=1. The product was filtered off, washed with water and dried in vacuum to give the title compound as a yellow solid (49 mg, 95%). MS (ISP) 491.2 [(M+H)+]; mp 293° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(C)C>CC(N(C)C)=O>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 110 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
10 g (35.6 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 5 mL of DMA (dimethyl acetamide) and 8.3 mL (75 mmole) of N-methyl piperazine. The reaction mixture was heated to 110° C. until the complete conversion of the starting material, about 1.5 h. The reaction mixture was then cooled to 80° C. and 60 ml of isopropyl alcohol was added. The reaction mixture was then slurried for 3 hours at ambient temperature filtered under vacuum, washed with 40 ml IPA and dried in vacuum oven overnight to obtain 11.48 g (89.3%) of levofloxacin.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1)=[O:5]
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid (Example 26b) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 203° C. (isopropanol)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS(O)(=O)=O.[CH:12]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH:12]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:14])[CH3:13]
Reactant: C1CNCCN1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)[Si](C(C)C)(C(C)C)N1CCNCC1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 189.4 g (2.2 mol) of piperazine, 200 ml of xylene, and 1.0 g (0.01 mol) of methanesulfonic acid and heated at 130° C. Once the internal temperature became steady, 192.8 g (1.0 mol) of triisopropylchlorosilane was added dropwise over 2 hours. Stirring was continued for 10 hours at the temperature. The reaction solution was cooled to room temperature, to which 500 g of a 10 wt % sodium hydroxide aqueous solution was added. The organic layer was separated. On distillation, 132.6 g of a fraction having a boiling point of 109-111° C./0.4 kPa was collected, which was 1-triisopropylsilylpiperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])C)=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.Cl>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][C:15]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:30]=2)=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc(CCN2CCOCC2)c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(CCN2CCOCC2)c1)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 9.7 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (250 mg, 0.80 mmol), and 3-[2-(4-morpholinyl)ethyl]aniline (165 mg, 0.80 mmol) were combined in a vessel with 10 mL of isopropanol and 12N HCl (67 μL, 0.80 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction mixture was concentrated to dryness. The crude product was purified by HPLC to afford the title compound as a white solid (25 mg, 6%): Mass (M+H)+=642, 644.
Reaction SMILES: [NH2:1][C:2]1([CH2:16][OH:17])[C:11]2([CH2:14][O:13][CH2:12]2)[CH2:10][O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:15])=[CH:6][CH:7]=2.C([O-])(O)=O.[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:15][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][CH2:10][C:11]1([CH2:14][O:13][CH2:12]1)[C:2]2([NH:1][C:25](=[O:26])[CH2:24][Cl:23])[CH2:16][OH:17]
Reactant: NC1(CO)c2cc(Br)ccc2OCC12COC2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NC1(CO)c2cc(Br)ccc2OCC12COC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (4-amino-6-bromo-4H-spiro[chromene-3,3′-oxetan]-4-yl)methanol (280 mg, 0.933 mmol), CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (10 mL) was added a mixture of chloroacetyl chloride (0.083 mL, 1.02 mmol) and CH2Cl2 (1 mL) at ambient temperature. After stirring for 30 minutes at ambient temperature, chloroacetyl chloride (0.016 mL, 0.197 mmol) was added to the reaction mixture. The mixture was stirred for 10 minutes at ambient temperature, diluted with CH2Cl2 and separated. The organic layer was washed with water, dried over MgSO4 and filtered. Concentration of the filtrate at reduced pressure gave crude N-[6-bromo-4-(hydroxymethyl)-4H-spiro[chromene-3,3′-oxetan]-4-yl]-2-chloroacetamide, which was used for the next reaction without further purification.