Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]([F:15])([F:14])[C:7]1[O:11][C:10]([CH2:12]Cl)=[N:9][N:8]=1.C(O)C>CO>[NH:3]1[CH2:2][CH2:1][NH:4][CH2:12]/[C:10]/1=[N:9]/[NH:8][C:7](=[O:11])[C:6]([F:15])([F:14])[F:5]
Reactant: FC(F)(F)c1nnc(CCl)o1
Reactant: NCCN
Solvent: CCO
Solvent: CO
Product: O=C(N/N=C1/CNCCN1)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
The solution of ethylene diamine (89 g) in methanol (305 mL) is stirred and cooled to −20° C. over about 45 minutes. 5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (79 g) is added slowly to the solution over 90 minutes at −20° C. The resulting slurry is stirred for about 90 minutes at −20° C. Ethanol (482 mL) is added and the slurry is warmed to −5° C. After stirring for about 2 hours at −5° C., the solid is filtered, washed with ethanol (79 mL) and dried at about 55° C. to afford the title compound. (Yield: 46.8%)
Reaction SMILES: COC1C=CC(C[N:8]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([NH2:25])=[O:24])[CH2:19][CH2:18][O:17][C:16]=3[CH:30]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[N:20]([C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23]([NH2:25])=[O:24])[CH2:19][CH2:18][O:17][C:16]=2[CH:30]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (800 mg, 1.48 mmol) in DCM (15 mL) was added TFA (1.6 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by prep purification to obtain 2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (21 mg, 3.38%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.54 (s, 1H), 7.68 (s, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.37 (dt, J=15.2, 7.7 Hz, 3H), 7.21 (d, J=4.6 Hz, 1H), 7.09 (d, J=1.9 Hz, 1H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.26 (d, J=8.5 Hz, 1H), 4.29-4.27 (s, 2H), 3.71-3.68 (m, 2H). LCMS (ESI) m/z; 417.5 (M+H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[Cl:12][C:13]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[ClH:12].[C:2]([C:3]1[CH:15]([C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:13]=2[Cl:12])[C:27]2[C:23](=[N:24][NH:25][CH:26]=2)[NH:22][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C1CCCNC1
Product: Cl
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc(Cl)c1Cl

Procedure:
The title compound was prepared from ethyl nipecotate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([N:23]1[CH:27]=[CH:26][CH:25]([CH3:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Dy+3].C(#N)C>[CH3:28][C@:25]12[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C@H:24]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C@H:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Reactant: CC1C=CN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@]2(C)[C@@H]1c1ccccc1N[C@H]2c1ccccc1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a mixture of benzaldehyde (425 mg, 4.0 mmol), aniline (372 mg, 4.0 mmol) and acetonitrile (8 ml) were added N-Boc-3-methyldihydropyrrole (732 mg, 4.0 mmol) and Dy(OTf)3 (122 mg, 0.19 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 30 min., and at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and eluted with hexane- ethyl acetate (4:1, v/v) to give the title compound (780 mg, 53%) as an amorphous form.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Zn+])=[O:6])[CH3:3].[C:14]1([C:20]2([C:23](Cl)=[O:24])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C:20]2([C:23]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[O:24])[CH2:21][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Reactant: CCOC(=O)c1ccccc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[NH4+:37].[OH-]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.269 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in the microwave at 130° C. for 15 min the title compound was obtained as a light yellow solid (135 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.62-7.73 (m, 1H), 7.44-7.59 (m, 1H), 7.17-7.34 (m, 3H), 6.79 (br. s., 2H), 5.83 (d, J=5.1 Hz, 1H), 1.39 (s, 9H). MS (ESI): 537 [M+H]+.
Reaction SMILES: [Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:22]NC.C(Cl)Cl.C=O>C(O)(C)(C)C>[Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:22])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C=C1C(C)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Yield: 5.6 %

Procedure:
A mixture of t-butyl 7α-bromo-3-methyl-3-cephem -4-carboxylate 1,1-dioxide (700 mg, 1.9 mmol), dimethylamine hydrochloride (460 mg, 5.7 mmol), methylene chloride (3 ml) and t-butyl alcohol (50 ml), formaldehyde (0.57 g, 37% w/v) was heated to reflux at 80°-90° C. for 20 hours. t-Butyl alcohol was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 200 mg of crude product which was purified over silica column using methylene chloride as eluant to give 40 mg of pure t-butyl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:23])[C:20]=2[Br:22])[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:23][C:19]1[C:20]([Br:22])=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH3:24])=[CH:17][CH:18]=1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1Br
Yield: 84.1 %

Procedure:
To a mixture of the compound from Step A (0.90 g, 2.23 mmol), potassium carbonate (0.40 g, 2.90 mmol) in acetone (80 mL) was added ethyl bromoacetate (0.484 g, 0.32 mL, 2.90 mmol) with stirring. The mixture was heated at reflux temperature for 3 h and evaporated to dryness. The residue was mixed with water (100 mL) and extracted with EtOAc (3×60 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography on silica eluting with a gradient of 10% to 30% EtOAc/hexane gave a solid (0.92 g, 84%): mp 89-90° C.; LCMS (+APCI) 490, 492 (M+H).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][NH:18][C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[CH:22]=[C:21]([NH2:28])[CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[ClH:10].[N:11]1([CH2:16][CH2:17][NH:18][C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[CH:22]=[C:21]([NH:28][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1cc(NCCN2CCCC2)c2occc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(Nc1cc(NCCN2CCCC2)c2occc2c1)c1ccccc1
Reaction time: 1 h
Yield: 5 %

Procedure:
To a test tube containing benzenesulfonyl chloride (42 mg, 0.235 mmol) was added a solution of N7-(2-pyrrolidin-1-ylethyl)-1-benzofuran-5,7-diamine* (48 mg, 0.195 mmol) in dichloromethane (3 mL). After addition of triethylamine (55 μl, 0.391 mmol), the mixture was shaken for 1 h and then concentrated. The residue was purified by preparative HPLC. The resulting TFA-salt was treated with HCl/ether and evaporated to provide the title compound. Yield: 5%, HPLC purity=99%, m/z=386 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 1.95-2.26 (m, 4H) 3.03-3.24 (m, 2H) 3.38-3.47 (m, 2H) 3.58-3.65 (m, 2H) 3.64-3.77 (m, 2H) 6.45-6.48 (m, 1H) 6.55-6.57 (m, 1H) 6.65 (d, J=2.23 Hz, 1H) 7.40-7.59 (m, 3H) 7.67 (d, J=2.23 Hz, 1H) 7.68-7.73 (m, 2H). *Prepared in two steps starting from 2-pyrrolidin-1-yl-ethylamine: i) Pd-catalysed amination of 7-iodo-5-nitro-benzofuran according to the procedure of Intermediate 31 to provide (5-nitro-benzofuran-7-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and ii) reduction of the nitro group of (5-nitro-benzofuran-7-yl)-(2-pyrrolidin-1-yl-ethyl)-amine to provide N7-(2-pyrrolidin-1-ylethyl)-1-benzofuran-5,7-diamine according to the procedure of Example 48 (Step 1).
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26](F)[C:27]=2[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]1)[CH3:18].Cl>O.CS(C)=O>[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26]([N:7]3[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]3)[C:27]=2[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]1)[CH3:18]
Reactant: ON1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(O)CC3)c(F)c21
Temperature: 100 °C
Yield: 81.1 %

Procedure:
1-Hydroxypiperazine dihydrochloride (3.94 g) (which is prepared in Preparation 1), triethylamine (21 ml) and dimethylsulfoxide (30 ml) are added to 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.07 g), which is prepared according to the procedure described in Japanese Patent First Publication No. 30964/1981, and the mixture is heated at 100° C. for 30 minutes. After cooling to room temperature, water (200 ml) is added to the mixture and the pH is adjusted to 7.0 with dil. HCl. The precipitated crystals are filtered, washed with water and dried. The product is recrystallized from a mixture of dimethylformamide and water to yield 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.3 g) as pale yellow needles, m.p. 253°-260° C. (decomposed with foaming) (which starts to color brown at around 234° C.).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C2CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane solution (10 ml/mmol) of tert-butyl 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)ethoxy)acetate (1 equiv.) was added TFA (13 equiv.) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated off and the product dried under vacuum to remove traces of TFA. The crude acid was used directly for the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 24.6 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoquinoline (1.6 g, 11.1 mmol), 5-fluoro-2-nitro-benzenesulfonyl chloride (Intermediate 450) (3.4 g, 14.4 mmol), pyridine (4.48 ml, 55.5 mmol), DMAP (cat.) and DCM (6 ml) gave the title compound (0.95 g, 25%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent. The structure was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[N:17]1([C:23]2[N:28]=[C:27]3[NH:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]3=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)C>C(O)CC(C)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:20]2[CH2:19][CH2:18][N:17]([C:23]3[N:28]=[C:27]4[NH:29][N:30]([CH3:33])[C:31](=[O:32])[C:26]4=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[N:3]=1
Reactant: Cn1[nH]c2nc(N3CCNCC3)ncc2c1=O
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Solvent: CCO
Product: COc1cc2nc(N3CCN(c4ncc5c(=O)n(C)[nH]c5n4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 83.8 %

Procedure:
Refluxed for 5 hours in isoamyl alcohol (30 ml) were 1.74 g (7.3 mmol) of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 1.60 g (7.3 mmol) of the 6-piperazino-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine synthesized in Referential Example 82. After allowing the reaction mixture to cool down, the resultant crystals were collected by filtration and then washed with ethanol. The thus-obtained crude crystals were added with ethanol and refluxed for 2 hours. After allowing the mixture to cool down, crystals were collected by filtration and then dried to obtain 2.90 g of the above-identified compound (yield: 84%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:31]#[N:32])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:24]([C:26]4[S:27][CH:28]=[CH:29][C:30]=4[C:31]#[N:32])=[CH:23][C:22](=[O:33])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccsc1C1=CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2N1

Procedure:
Prepared from {3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K54) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (209 mg).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:18]([CH3:46])[N:17]=[C:16]([NH2:47])[N:15]=1)(=O)=O.C(O)(C(F)(F)F)=O.[CH2:55]([NH2:60])[CH2:56][CH2:57][CH2:58][CH3:59]>CCOC(C)=O>[NH2:47][C:16]1[N:17]=[C:18]([CH3:46])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36](=[O:37])([O:38][CH2:39][CH3:40])[O:41][CH2:42][CH3:43])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:14]([NH:60][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[N:15]=1
Reactant: CCCCCN
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-5-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methoxybenzyl)-6-methylpyrimidin-4-yl 2,4,6-trimethylbenzenesulfonate (1 equiv.) in EtOAc (0.20 M) was added TFA (1.1 equiv.) and amylamine (3.3 equiv.). The reaction mixture was then heated to 100° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (76%) as a solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:14])[CH3:16]
Reactant: CC(=O)CC(C)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
Sodium hydride (0.1702 g, 7.09 mmol) was added slowly to a NaCl ice bath containing EtOH (2.6 mL, 2.7 M) stirring under N2. 4-Phenylpentan-2-one (55) (1.0493 g, 6.47 mmol) and diethyloxalate (0.88 mL, 6.47 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 90 min, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated to provide 56 (0.7230 g, 42.6%) which was used without further purification in the next step. 1H (CDCl3, 400 MHz): δ 7.34-7.16 (5H, m), 6.30 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.39-3.26 (1H, m), 2.82 (1H, dd, J=15.1, 6.8 Hz), 2.72 (1H, dd, J=15.1, 7.8 Hz), 1.36 (3H, t, J=7.0 Hz), 1.32 (3H, d, J=6.8 Hz) ppm. HPLC: 10.934 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=O)=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1.CC1(C)C2C(=CC(C(O)=O)=CC=2)[NH:23]C(=O)C1.CC1(C)C2C(=CC(C#N)=CC=2)NC(=O)C1.ICC.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:23])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4](=[O:17])[CH2:3]1
Reactant: CCN1C(=O)CC(C)(C)c2ccc(C(=O)O)cc21
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Agent: CC1(C)CC(=O)Nc2cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1C(=O)CC(C)(C)c2ccc(C#N)cc21
Temperature: 25 °C
Yield: 48 %

Procedure:
One prepared 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid analogously to the procedure for 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (DE-A-3,818,830) as follows: one stirred 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (2.0 g, 10.0 mmol), iodoethane (1 ml, 12.0 mmol) and potassium carbonate (1.70 g, 12.0 mmol) for one hour at 60° C., again added iodoethane (2 ml, 24 mmol) and potassium carbonate (2.5 g, 25 mmol) thereto and stirred for one hour at 60° C. One allowed to cool to room temperature, stirred the solution into water, filtered off the precipitate with suction and dried in a vacuum. One obtains 4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarbonitrile (1.1 g, 48%) with the m.p.=120°-121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH:15]1[CH2:18][NH:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:15]1[CH2:18][N:17]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of azetidin-3-yl-benzyl-carbamic acid tert-butyl ester (0.20 g, 0.76 mmol) in dichloromethane (2 ml) was added triethylamine (0.15 g, 1.5 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.17 g, 0.84 mmol). The mixture was stirred at room temperature for 18 h. It was then quenched with 50% sodium carbonate solution and the volatiles were evaporated. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was washed with hexanes to give 0.29 g of a colorless gum; MS (ES) m/z 420.9 (MH+); HRMS (FAB) Calcd. for C21H26FN2O4S (MH+): 421.1597, Found: 421.1633.