Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N2C3C(C(C(C(O)=O)=C2)=O)=CC(F)=C(N2CCN(C)CC2)C=3OC1.FC1C(F)=C(F)C=CC=1[N+]([O-])=O.OC1C(F)=C(F)C=CC=1[N+]([O-])=O.[OH-].[K+].[CH2:53]([O:57][C:58]1[C:63]([F:64])=[C:62]([F:65])[CH:61]=[CH:60][C:59]=1[N+:66]([O-])=O)[C:54]([CH3:56])=O.FC1C=CC2NC(C)COC=2C=1F.[CH2:82]=[C:83]([C:104]([O-])=[O:105])[C:84]([O:86][CH:87]1[CH:92](C)NC2C(CC)=C(CC)C(F)=C(F)C=2O1)=[O:85]>CS(C)=O>[F:65][C:62]1[C:63]([F:64])=[C:58]2[O:57][CH2:53][CH:54]([CH3:56])[N:66]3[CH:82]=[C:83]([C:84]([O:86][CH2:87][CH3:92])=[O:85])[C:104](=[O:105])[C:60]([CH:61]=1)=[C:59]23
Reactant: C=C(C(=O)[O-])C(=O)OC1Oc2c(F)c(F)c(CC)c(CC)c2NC1C
Reactant: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1F
Agent: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: CC1COc2c(ccc(F)c2F)N1
Agent: O=[N+]([O-])c1ccc(F)c(F)c1F
Solvent: CS(C)=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2C

Procedure:
Hayakawa's method of preparation of Ofloxacin is described in EP 0047005A1 and starts with 2,3,4-trifluoronitrobenzene which is converted to the 2-hydroxy-3,4-difluoronitrobenzene in dimethylsulfoxide in the presence of potassium hydroxide. The yield for this reaction is only 29%. The low yield of this step limits the overall yield of Hayaklawa's process. Other patents cite the use of this material in their routes to Ofloxacin; e.g. U.S. Pat. No. 5,136,059 and EP 0333815 A2. The 2-hydroxy-3,4 difluoronitrobenzene is converted to 2-acetonyloxy-3,4-difluoronitro-benzene which is reductively ring closed to give an isomeric mixture of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-berizoxazine (Formula 1). This material is converted to diethyl-(7,8-difluoro-2,3-dihydro-3-methyl 4H 1,4 benzoxazinyl) methylenemalonate by reaction with diethylethoxymethylenamalonate. Cyclization of this malonate ester in ethylpolyphosphate gives (+,-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylate. This benzoxazine carboxylate ester is then hydrolyzed to the corresponding acid. The acid is reacted with N-methylpiperazine in dimethylsulfoxide to form Ofloxacin, 9-fluoro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid. The reaction sequence is shown below: ##STR1##
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33]>OS(O)(=O)=O>[C:32]([O:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Agent: O=S(=O)(O)O
Product: CC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reaction time: 1 h

Procedure:
17-Hydroxymethyltetrabenzo(a,c,g,i)fluorene (0.207 g, 0.522 mmol) was dissolved in acetic anhydride (4 ml). To this solution was added 2 drops of H2SO4 (2M). The reaction mixture was stirred for 1 h. Compound (35) was obtained as a yellow solid which was washed with water (80 ml) and dried to constant weight over P2O5 in a vacuum desiccator (183.8 mg, 80%); m.p. 209°-210°, (Found: C, 87.0; H, 5.08 C32H22O2 requires: C, 87.7; H, 5.02%); t.l.c. Rf (A) 0.32, Rf (F) 0.22; νmax (CH2Cl2) 3060 (CH stretching, aromatic), 1740 (CO, ester), 1610, 1500 (aromatic rings), 1230, 1045 (CO, stretching) cm-1 ; λmax 380 (17885), 368 (19345), 302 (45260), 290 (36865), 254 (72271) nm; δH (CDCl3, 80 MHz), 8.83-8.57 (6H, m, aromatic), 8.29-8.17 (2H, m, aromatic), 7.78-7.54 (8H, m, aromatic), 5.12 (1H, t, 3J=5.5 Hz, CH), 4.60 (2H, d, 3J=5.5 Hz, CH2), 1.84 (3H, s, CH3); δC (CDCl3, 50 MHz) 170.7 (CO, ester), 141.8, 137.0, 131.5, 130.4, 128.6, 128.0 (quaternary aromatic C's), 127.4, 126.8, 126.1, 126.0, 125.0, 124.9, 123.5, 123.3 (aromatic CH's), 67.9 (CH2), 47.1 (CH), 20.7 (CH3); m/z (EI) 438 (M+), 378, 364.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24]([NH:34][C:35]([CH3:40])([C:37](O)=[O:38])[CH3:36])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:37](=[O:38])[C:35]([NH:34][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([CH3:40])[CH3:36])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
The amine obtained in Step B of this Example (300 mg; 1.37 mmol) triethylamine (380 ml; 2.73 mmol) and N-carbobenzyloxy-2-methylalanine (278 mg; 1.37 mmol) were dissolved in dry methylene chloride (3 ml) and BOP (605 mg; 1.37 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and the resultant homogenous yellow solution quenched by addition of brine. The two phase system was extracted with methylene chloride (2×25 ml) and the combined methylene chloride layers dried over powdered anhydrous magnesium sulfate. Filtration of the methylene chloride solution to remove the spent drying agent followed by evaporation of solvent afforded an oil which was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate and hexanes (1:1 v/v) as eluant. The desired product (419 mg; 69.7%) was isolated as a white amorphous solid. FAB-MS:- calculated for C25 H30N2O5 438.2; found 439.3 (M+1).
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)phosphonic acid dimethyl ester (3.0 g, 7.94 mmol) in THF (150 mL) at −78° C. was added LiHMDS (8.8 mL, 8.80 mmol, 1M solution in THF) and the resulting mixture stirred for 30 min then warmed to r.t. before the addition of a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.51 g, 8.82 mmol) in THF (20 mL). The reaction mixture was stirred at r.t. for 16 h then quenched with H2O and MeOH and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 5-100%) affording the title compound as a yellow solid (2.14 g, 63%). LCMS (method A): RT 3.97 min [M+H]+ 423.3
Reaction SMILES: C1OC1CC.[C:6]1([CH2:12][C@H:13]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[C:14](Cl)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H][H].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd]>[CH2:12]([C@H:13]([N:17]1[C:21](=[O:22])[C:20]2[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]1=[O:27])[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CCC1CO1
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 17 h
Yield: 70 %

Procedure:
1 mol of 1,2-butylene oxide and 23.5 g of Pd/C (5% Pd) were added to a solution of 0.5 mol of 3-phenyl-2(S)-phthalimidopropionyl chloride in 1200 ml of toluene. The suspension was hydrogenated at room temperature and atmospheric pressure while stirring vigorously for 17 hours, whereby 11.3 l of hydrogen were taken up. Thereafter, the suspension was filtered over a filter aid and the residue was washed with toluene. The filtrate and washings were combined and treated while stirring with a solution of 0.5 mol of sodium pyrosulphite in 1 l of water. After stirring at room temperature for 4.5 hours the phases were separated. The aqueous phase was washed with 500 ml of toluene. The toluene phases were washed with 350 ml of water. The combined aqueous phases were treated with 1400 ml of toluene and 420 ml of 3N sulphuric acid and stirred at 60° for 6 hours. Thereafter, the phases were separated and the aqueous phase was extracted with 500 ml of toluene. The toluene phases were washed with water, combined, dried over MgSO4 and evaporated. There were obtained 97.8 g (70%) of (S)-α-benzyl-1,3-dioxo-2-isoindolineacetaldehyde as a white solid, melting point 115°-117°, [α]D20 -200° (1% in ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Yield: 52.4 %

Procedure:
In 20 ml of pyridine was dissolved 0.80 g (3.67 mmol) of ethyl 5-amino-1-methyl-2-indolecarboxylate. While stirring at room temperature, 0.57 g (4.03 mmol) of benzoyl chloride was added to the solution. After stirring for 2 hours at 70° C., the reaction mixture was cooled to room temperature and then poured onto ice water. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with 1N hydrochloric acid and then with saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.62 g (52.5%) of ethyl 5-benzamido-1-methyl-2-indolecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C(OCC)C.[Br:18]Br.C(=O)([O-])O.[Na+]>O1CCCC1.O.C(O)(=O)C>[Br:18][CH2:11][C:10]([C:4]1[CH:3]=[C:2]([Br:1])[C:7]([OH:8])=[C:6]([Br:9])[CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
In a 100 ml flask, 1-(3,5-dibromo-4-hydroxy-phenyl)-ethanone (1.2 g, 4.082 mmol) was dissolved in a solvent of anhydrous tetrahydrofuran: anhydrous diethyl ether (1:1, 12 ml). Acetic acid (0.4 ml) and bromine (2.1 ml, 4.082 mmol) were added thereto dropwise under nitrogen atmosphere and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to pH 8 to 9 with saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=2:1. The fractions containing the product were collected and evaporated to obtain 2-bromo-1-(3,5-dibromo-4-hydroxy-phenyl)-ethanone as white solid (785 mg, 51.5%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=1.[CH2:15]([NH:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)[CH3:16].O>C1COCC1.CCOCC>[CH2:15]([NH:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:14][C:12]1[CH:13]=[C:8]([Cl:7])[CH:9]=[N:10][CH:11]=1)[CH3:16]
Reactant: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
To a suspension of potassium t-butoxide (1.5 g) in THF (15 mL) was added 3-chloro-5-hydroxypyridine (1.79 g, mmol). To this solution was added a solution of N-ethyl-2-chloro-5-nitrobenzamide (2.76 g, mmol) in THF (15 mL). The resulting mixture was heated at 50° C. for 84 hr. After cooling, the reaction mixture was diluted into a mixture of water and ether. Solids were collected by filtration, washed with water then with ether, and dried under vacuum to afford N-ethyl 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide (2.0 g, 52%). mp 165-167° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:38](=[O:39])[N:23]3[CH:24]([C:29](=O)[NH:30][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(Cl)=O.[N-:50]=[N+:51]=[N-:52].CN(C)C(=[NH2+])N(C)C>C(Cl)(Cl)Cl.O>[C:1]1([C:7]([NH:20][CH:21]2[C:38](=[O:39])[N:23]3[CH:24]([C:29]4[N:30]([CH2:31][C:32]5[O:36][CH:35]=[CH:34][CH:33]=5)[N:52]=[N:51][N:50]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)NCc1ccco1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.05 g. (5.7 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam, in 8 ml. of chloroform, at 0° C., is added 1.35 ml. (17 mmole) of pyridine, followed by 2.64 ml. of a 4.33 M solution of phosgene in chloroform. Stirring is then continued for 1 hour at 25° C. The chloroform, and excess phosgene and pyridine, are then removed by evaporation in vacuo, and the residue is redissolved in 5 ml. of chloroform. The solution is cooled to 0° C., and then 2.25 g. (14.4 mmole) of tetramethylguanidinium azide is added in several small portions. Stirring is continued for 15 minutes at ambient temperature, and then 20 ml. of chloroform, followed by 30 ml. of water, are added and the pH is adjusted to 6.5. The chloroform layer is separated off, washed with water, followed by brine, and then dried (MgSO4). Removal of the solvent by evaporation in vacuo leaves 3.37 g. of a dark-red foam. The foam is re-dissolved in a small volume of chloroform and absorbed onto a column of chromatographic silica gel. Elution of the column with chloroform, followed by evaporation of the appropriate fractions in vacuo, affords 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam. The NMR spectrum of the product (CDCl3) shows absorptions at 7.40 ppm (m, 16H), 6.40 ppm (m, 2H), 5.50 ppm (s, 2H), 5.20 ppm (s, 1H), 4.90 ppm (m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:15]([O:14][C:12]([NH:11][C:4]1[S:3][C:2]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=2[F:19])=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1nc(Br)sc1NC(=O)OC(C)(C)C
Reactant: COc1ccc(F)c(B(O)O)c1F
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)c1nc(-c2c(F)ccc(OC)c2F)sc1NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 39.2 %

Procedure:
To a vial, methyl 2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (from Example 1 step 3, 104 mg, 0.309 mmol), (2,6-difluoro-3-methoxyphenyl)boronic acid (from Aldrich, 207 mg, 1.10 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (37.5 mg, 0.0477 mmol), and potassium phosphate (276 mg, 1.30 mmol) were added. The vial was sealed with a PTFE screw-cap then purged with nitrogen three times. 1,4-Dioxane (4.0 mL) was added, followed by deoxygenated water (2.0 mL). The mixture was heated at 40° C. for 1 h. The reaction mixture was allowed to cool to room temperature. Additional (2,6-difluoro-3-methoxyphenyl)boronic acid (262 mg, 1.39 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (40.2 mg, 0.0511 mmol) were added. The mixture was stirred at room temperature for 15 h. The mixture was filtered through a pad of diatomaceous earth (eluted with EtOAc) and concentrated. The residue was purified on silica gel (eluting with 0-50% EtOAc in hexanes) to give the sub-title compound as a white solid (48.5 mg, 39%). LCMS calc. for C17H19F2N2O5S (M+H)+: m/z 401.1. Found: 401.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21]CC)=O)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N:44](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([NH2:44])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(N(C)Cc3cccnc3)cc2c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cccnc1)c1cc2c(=O)c(C(N)=O)cn(-c3ccc(F)cc3)c2cc1F
Reaction time: 8 h
Yield: 27 %

Procedure:
Compound U (26 mg, 0.062 mmol, 1.0 eq), ammonium chloride (6.6 mg, 0.12 mmol, 2.0 eq), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (28 mg, 0.074 mmol, 1.2 eq) and N,N-diisopropylethylamine (43 μL, 0.25 mmol, 4.0 eq) were dissolved in DMF (0.5 mL) and stirred overnight. The reaction was diluted with ethyl acetate and washed with water (2×). The aqueous phase was back extracted with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography afforded 7.0 mg (27%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=4.4 Hz, 1H), 8.48-8.45 (m, 3H), 7.76-7.72 (m, 3H), 7.67 (dt, J=7.8, 1.7 Hz, 1H), 7.58 (d, J=4.4 Hz, 1H), 7.51 (t, J=8.7 Hz, 2H), 7.35 (dd, J=7.7, 4.9 Hz, 1H), 6.81 (d, J=14.0 Hz, 1H), 4.41 (s, 2H), 2.83 (s, 3H); ES-MS [M+1]+: 421.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.IC.[C:29]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:29][O:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(OC)cnc23)C1
Yield: 30.5 %

Procedure:
To a solution of 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 (1.71 mmol, 1 eq, 0.6 g) in acetone (100 ml) is added iodomethane (17.1 mmol, 10 eq, 1.065 ml) and K2CO3 (17.1 mmol, 10 eq, 2.36 g). The mixture is refluxed for 5 minutes. Solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (AcOEt/hexane: 1/1) and recrystallized in AcOEt to afford 0.19 g of 1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 204.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[F:25]
Reactant: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(F)c(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
185 mg of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (stationary phase: silica gel, developing solvent: hexane/ethyl acetate=3/1), to obtain 161 mg of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methylpyridazine (hereinafter, referred to as compound (v) of the present invention).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[C:24](Cl)[N:23]=1>C(O)CC(C)C>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:24]3[N:23]=[C:22]([NH2:21])[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(N)c2cc1OC
Temperature: 120 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
Compound 49 (0.57 g, 2.1 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.45 g, 1.9 mmol) in isoamyl alcohol (3-methyl-1-butanol) (20 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.57 g (59%) of the title compound: TLC (Rf =0.41; 80% EtOAc/hexanes); 1H NMR (DMSO) δ 12.20 (br s, 1H), 8.66 (br, 2H), 7.76 (s, 1H), 7.66 (d, 2H, J=8.7), 7.53 (s, 1H), 6.67 (d, 2H, J=8.7), 6.51 (d, 1H, J=7.4), 4.56 (d, 2H, J=13.6), 3.90 (s, 3H), 3.86 (s, 3H), 3.76 (m, 1H), 3.46 (m, 2H), 2.07 (d, 2H, J=11.1), 1.52 (s, 9H), 1.44 (m, 2H); 13C NMR (DMSO) δ 165.3, 161.4, 155.3, 151.4, 151.1, 146.8, 136.4, 131.0, 117.8, 111.3, 105.0, 101.6, 99.2, 79.1, 56.3, 56.1, 48.0, 43.4, 31.0, 28.1; HRMS (FAB) m/z 480.2616 (M+H)+ (C26H33N5O4 requires 480.2611); Anal. (C26H33N5O4 ·1HCl) C, H, N.