Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]([C:32]3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH3:39][O:40]CCCl>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH2:32][O:40][CH3:39])=[C:14]([F:38])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Reactant: COCCCl
Solvent: CN1CCCC1=O
Product: COCCSc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reaction time: 2 h

Procedure:
Prepared according to Method B of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]oxazolidine-2-one with 2-chloroethyl methyl ether (0.036 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. for 2 h. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.034 g (52%). MS (m/z): 343 [M+H]+. 1H NMR.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][NH:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19]([NH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[I:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:23]([C@@H:22]([NH:21][C:19](=[O:20])[O:18][CH3:17])[CH:26]([CH3:28])[CH3:27])=[O:24])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@@H]1CN[C@H](c2nc3cc(I)ccc3[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To 5-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-benzimidazole (2.29 g, 7.00 mmol) and (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (1.49 g, 7.70 mmol) in DMF is added HATU (3.46 g, 9.1 mmol) and DIPEA (2.4 mL, 14.0 mmol) at rt. The reaction mixture is stirred at rt overnight. To the reaction mixture is added water (350 mL) with fast stirring upon which a white solid precipitated out. The solid is suction filtered and dried under vacuum to give methyl N-[(1S)-1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.73 g, 81%).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])(=[O:24])=[O:23]>N1C=CC=CC=1>[CH2:9]([O:8][C:6]([C:3]1([NH:2][S:22]([C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])=[O:29])(=[O:23])=[O:24])[CH2:5][CH2:4]1)=[O:7])[CH3:10]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 774 mg of ethyl 1-aminocyclopropane-1-carboxylate hydrochloride, 1.4 mL of triethylamine, and 15 mL of dichloromethane was stirred at room temperature for 30 minutes, and 15 mL of pyridine and 1.50 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.80 g of 2-(trimethylsilyl)ethyl 3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoate as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:36].[Na+].[CH:38]([NH:40][C:41]1[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[N:44]=[CH:43][CH:42]=1)=[O:39].O>CN(C)C=O.C(OCC)(=O)C>[I-:36].[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][N+:44]3[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41]([NH:40][CH:38]=[O:39])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CNc1ccnn1CCOC=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a mixture of benzhydryl 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephem 4-carboxylate (20 g) and sodium iodide (5.82 g) in N,N-dimethylformamide (20 ml) was added 5-formamido-1-(2-formyloxyethyl)pyrazole (21.34 g) at ambient temperature. After being stirred for 24 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, aqueous sodium chloride solution, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate iodide (29.6 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1)(=O)C.C(O)C.[O-]CC.[Na+].[Na]>C(Cl)(Cl)Cl.C(O)(=O)C.O>[OH:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1ccc(COC(C)=O)nc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a solution of 9.2 g of ethyl 6-acetoxymethylnicotinate in chloroform (40 ml) was added an ethanol solution of sodium ethoxide prepared from 0.92 g of sodium and 23 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The reaction liquid was poured into water containing 6 ml of acetic acid and the chloroform layer was separated and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, carbon tetrachloride was added to the residue, and the insoluble substance was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate/hexane to obtain 5.1 g of ethyl 6-hydroxymethylnicotinate. ##STR8##
Reaction SMILES: [C:1](/[C:3](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)/[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]>CC(O)=O.C1(C)C=CC=CC=1.[Cl-].[Na+].O.[Zn]>[C:1]([CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C#N)Cc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A suspension of (E)-tert-butyl 2-cyano-3-(3,4-dichlorophenyl)acrylate (1.05 g, 3.52 mmol) and zinc (3.45 g, 52.8 mmol) in AcOH (20 ml) was allowed to stir at 100° C. After stirred for 1 hour, the reaction mixture was cooled to ambient temperature, and diluted with toluene and brine. The phases were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-cyano-3-(3,4-dichlorophenyl)propanoate (819 mg); Retention time=1.41 minutes (condition B); MS (ES+)=317.0 (m+18).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CC(C)(N)CO
Solvent: O
Product: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 2,4-dichloronitrobenzene (VII, 20.0 g) and 2-amino-2-methyl-1-propanol (VIII, 80 ml) is stirred at 110° for 68 hr. After cooling to 20°-25°, adding water, extracting with methylene chloride, separating the phases and drying the organic phase over magnesium sulfate) gives the desired product sufficiently pure (>90%) to be carried on without further purification. An analytical sample is prepared by recrystallization from ethyl acetate/hexane to give the title compound, mp 102°-104°; IR (mineral oil) 3335, 2954, 2925, 1610, 1577, 1492, 1467, 1331, 1251, 1154 and 748 cm-1 ; NMR (CDCl3) 8.55, 8.13, 7.09, 6.59, 3.71, 2.11 and 1.48 δ; MS (m/z) 244, 213 and 166.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](Br)[CH3:12])=[CH:7][CH:6]=1)(=O)C.[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=3)[C:23]([CH3:24])=[C:15]2[CH3:14])[CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(C(C)Br)cc1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using 4-(1-bromoethyl)phenyl acetate and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:16])[CH2:6]2.[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:14][C:13](=[O:15])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:16]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)CC(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 26.4 %

Procedure:
To a solution of 2-(5-methoxy-2-oxoindolin-1-yl)acetic acid (200 mg, 0.904 mmol) in DCM (30 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (380 mg, 0.904 mmol), EDC (520 mg, 2.71 mmol) and DMAP (55.2 mg, 0.452 mmol) were added, and the mixture was reacted at room temperature overnight. The solvent was evaporated, and the resulting crude was partitioned between DCM (20 ml) and a 1N HCl (20 ml), and the desired compound was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (DCM:MeOH 98:2) recovering the title compound (149.2 mg, 0.239 mmol, 27% yield). MS/ESI+ 623.12 [MH]+; [αD]=+19.12 c=0.5 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92-6.98 (m, 2H), 7.07 (t, 1H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.02 (dd, 1H), 4.54 (d, 1H), 4.46 (d, 1H), 3.91 (d, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.03-1.41 (m, 1H), 0.50-0.70 (m, 2H), 0.21-0.50 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27](=[O:29])[NH2:28])([CH3:25])([CH3:24])[CH3:23].CNCCNC>O1CCOCC1.[Cu]I>[C:22]([O:26][C:27](=[O:29])[NH:28][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Yield: 14.6 %

Procedure:
Stir a mixture of 3-bromo-5-phenylethynyl-pyridine, (prepared as described in EXAMPLE 9), (2.5 g, 10 mmol), copper (I) iodide (0.190 g, 1 mmol), potassium carbonate (2.76 g, 20 mmol), carbamic acid tert-butyl ester (1.17 g, 10 mmol), N,N′-dimethylethylenediamine (0.220 mL, 2 mmol) in 1,4-dioxane (10 mL) at 110° C. in a sealed tube for 36 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 dichloromethane:methanol to 90:10 dichloromethane:methanol, and then crystallizing from ethyl acetate to give the title compound (430 mg, 15%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:20]([CH3:22])[CH3:21])[CH:5]=[O:6]
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1Br
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzaldehyde (2.5 g, 12.4 mmol), potassium carbonate (2.57 g, 18.6 mmol), potassium iodide (0.21 g, 1.24 mmol) and N,N-dimethylformamide (30 mL) was added 2-bromopropane (1.46 mL, 15.5 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give the title compound (1.77 g, yield 59%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[F:33].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[F:33])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Yield: 54.2 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (0.20 g, 0.63 mmol, 1 eq), 4-amino-3-fluorobenzoic acid (0.30 g, 1.9 mmol, 3 eq) and TFA (0.24 mL, 3.2 mmol, 5 eq) were heated to reflux in TFE for 18 hours. Further 4-amino-3-fluorobenzoic acid (0.20 g) and TFA (0.1 mL) were added and the reaction was heated to reflux again for 2 days. Further TFA (0.24 mL) was added and the reaction was heated to reflux again for 3 days. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (0.15 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Oc3ccccc3)cc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccc(Oc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-[3-fluoro-4-(4-phenoxybenzyloxy)phenyl]propanoate (0.16 g, 0.41 mmol) in ethanol (3 mL) was added a 2 N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 2 N hydrochloric acid (3 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.14 g, yield 94%) as white powders.
Reaction SMILES: C([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([OH:24])=[O:23])[CH:16]=[CH:15]2)CCCCCCCCC.Br>C(O)(=O)C>[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)C1CCc2cc(O)ccc2C1
Yield: 100 %

Procedure:
16.6 g (50 mmol) of the 6-decyloxynaphthalene-2-carboxylic acid obtained in the first stage was heated under reflux at 130° C. for 7 hours in the presence of 250 cc of acetic acid and 86.5 g (0.5 mol) of 47% hydrobromic acid. To the reaction mixture was added distilled water, and then the resulting mixture was concentrated under reduced pressure to obtain 10.60 g (50 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid.
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][N+:13]([O-:3])=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)OO
Reactant: Clc1nccc2cnccc12
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: [O-][n+]1ccc2c(Cl)nccc2c1

Procedure:
Under stirring, 205 ml (1.2 mol) peracetic acid (39% solution in acetic acid) was added to a solution of 98.8 g (0.60 mol) 1-chloro-[2,6]naphthyridine in 500 ml ethyl acetate and the mixture was stirred 18 hours at room temperature. The reaction mixture was diluted with water and acetic acid, treated with portions of sodium disulfite under stirring until a peroxide test was negative. Then the mixture was adjusted to pH value of 8 with aqueous NaOH. The solids were filtered off, washed with water and dried yielding 1-chloro-[2,6]-naphthyridine 6-oxide as slightly yellow crystals. The organic phase of the filtrate was separated, dried over sodium sulfate and evaporated. The residue was crystallized from tert-butyl-methyl-ether yielding another crop of product. HPLC/MS (A): 1.16 min, [M+H] 181.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(I)ccc1OC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)ccc1OC

Procedure:
1.06 g (3.64 mmol) of methyl 2-Methoxy-5-iodobenzoate, 460 mg (3.78 mmol) of phenylboronic acid, 83 mg (2 molar %) of tetrakistriphenylphosphine palladium and 1.52 g (14.4 mmol) of sodium carbonate were heated under reflux in 12 ml of toluene/ethanol/water (2/1/1) solvent mixture for 2 hours. After the filtration through Celite followed by the after treatment conducted by an ordinary method, the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(F)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(F)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-fluoro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10]CC2C=CC=CC=2)=[C:4]1[CH2:18][O:19]C)[CH3:2].CO.C(OCC)C.[ClH:28]>>[ClH:28].[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([OH:10])=[C:4]1[CH2:18][OH:19])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCn1ccc(=O)c(O)c1CO
Yield: 73 %

Procedure:
2.0 g (7.33 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one was dissolved in 50 ml of 4N hydrochloric acid and refluxed for 6 hours. Concentration to dryness in vacuo afforded the crude product. Recrystalissaion from methanol/diethyl ether gave the pure title compound (1.1 g, 73%) as a white crystalline solid. m.p. 168-169° C.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])(=O)[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]=[C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(C#N)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To the methyl triphenylphosphoniumbromide (4.3 grn, 12 mmol) in THF at 0° C., n-BuLi (1.6M, 7.5 ml, 12 mmol) was added and stirred for 30 min. Then 3-acetylbenzonitrile in THF was slowly added and the reaction mixture was stirred at 0° C. for further 3 h. Then reaction mixture was quenched with aqeous ammonium chloride and diluted with ethyl acetate. Organic layer was washed with water, brine and dried. Crude residue after column purification yielded 3-(prop-1-en-2-yl)benzonitrile in 86% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[F-].[K+].O>CS(C)=O>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH2:22][CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(O)[C@H]1CC[C@H](CNc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol), 2-(trans-4-(aminomethyl)cyclohexyl)propan-2-ol (140 mg, 0.76 mmol) and KF (51 mg, 0.88 mmol) in DMSO (2 mL) was stirred at 130° C. overnight. LCMS showed the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-76 (12 mg, 8%) as a yellow solid.