Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].S(OC)(O[CH3:24])(=O)=O.[H-].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:24][O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Yield: 20.5 %

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (25.9 mg, 0.1 mMol) in anhydrous hexamethylphosphoramide (1.0 ml) is cooled in an ice-bath and stirred under a nitrogen atmosphere. Dimethyl sulfate (11.4 μl, 0.12 mMol) and 57% sodium hydride in mineral oil (5.0 mg, 0.12 mMol) are added to the solution. The cooling bath is removed and the resulting mixture is stirred at room temperature for 60 minutes. The mixture is diluted with ethyl acetate (10 ml) and water (20 ml), shaken, and the layers separated. The organic layer is washed with water (3×5 ml) and brine, dried with magnesium sulfate, diluted with toluene (10 ml), and evaporated under vacuum to an oil. This material is chromatographed on a 0.25 mm×10×20 cm silica gel GF plate using 3:1 toluene-ethyl acetate as developing solvent. The major UV visible band at Rf 0.1 was removed and eluted with ethyl acetate to provide benzyl 3 -methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (5.6 mg) as a clear oil: IR (CH2Cl2) 1775 and 1700 cm-1 ; UV (EtOAc) 288 nm; NMR (CDCl3) δ2.87 (dd, 1, J=2.8 and 16, H6β), 3.03 (m, 2, H4a and H4b), 3.50 (dd, 1, J=5.5 and 16, H6α), 3.80 (m, 1, H5), 3.92 (s, 3, CH3), 5.28 (s, 2, CH2 φ), and 7.40 (m, 5, C6H5); mass spectrum m/e 273 (M+) and 231 (M+-42).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1([C:15]2[N:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:18][C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.ClCCl>C(Cl)(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:17]1[NH:18][C:19](=[O:21])[C:20]([Cl:1])=[C:15]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:16]=1)[CH3:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
1.87 g of N-chlorosuccinimide are added to a solution of 3.75 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate described in example 6a (step (2′a)a) in 50 ml of chloroform. The reaction medium is stirred at ambient temperature for 2 hours. 20 ml of water and 50 ml of dichloromethane are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 99/01 then 98/02 then 97/03 dichloromethane/methanol, so as to give 2.81 g of (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([O:28][CH3:29])[N:21]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1nc(Cl)ccc1C#N
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(C)c2)ccc1C#N
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To a solution of tert-butyl 4-bromo-3-methylphenylcarbamate (4.36 g, 15.24 mmol) in N,N-dimethylformamide (60 mL) on an ice bath under a nitrogen balloon was added sodium hydride (0.610 g, 15.24 mmol). The reaction was stirred on an ice-water bath for 10 min. The ice bath was removed and to the solution was added a solution of 6-chloro-2-methoxynicotinonitrile (3.85 g, 22.86 mmol) in N,N-dimethylformamide (40 mL) dropwise. After addition completed, the mixture was stirred overnight at 50° C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product. The crude was then purified by silica gel column (100% hexanes to 8:2 hexanes/ethyl acetate) to give tert-butyl 4-bromo-3-methylphenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (3.15 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9H), 2.30 (s, 3H), 3.55 (s, 3H), 7.00 (dd, J=2.6, 8.4 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:14]=[C:15]=[O:16])[CH2:12][CH3:13].[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[N:14]([CH2:11][CH2:12][CH3:13])[C:15](=[O:16])[N:6]2[C:2]([N:3]([C:15]([NH:14][CH2:11][CH2:12][CH3:13])=[O:16])[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: CC(C)=O
Reactant: CCCN=C=O
Reactant: Nc1nc2ccccc2[nH]1
Product: CCCNC(=O)N1C2=NC(C)(C)N(CCC)C(=O)N2c2ccccc21

Procedure:
The subject compound was prepared by reaction of 2-aminobenzimidazole, acetone and propyl isocyanate with workup all essentially as described in the first paragraph of Example 1. The product was purified by column chromatography on silica, eluting with chloroform, giving, on evaporation, white crystals, mp 72°-74° C. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.CN(C)CCN(C)C.[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>O1CCCC1>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([B:27]([OH:32])[OH:28])=[CH:8][C:7]=2[CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(C(F)(F)F)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of 5-(trifluoromethyl)-1-benzofuran (5.0 g, 26.86 mmol) in dry tetrahydrofuran (120 mL) were added tetramethylethylenediamine (3.74 g, 32.2 mmol). The solution was kept below −60° C. under nitrogen, while n-BuLi (12.8 mL, 32.2 mmol, 2.5 M solution in hexane) was added dropwise. The solution was warmed to −10° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (10.0 g, 53.19 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give [5-(trifluoromethyl)-1-benzofuran-2-yl]boronic acid (2.0 g, crude) as light yellow oil; which was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH2:64])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]>CN(C=O)C>[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH:64][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:14]=3)=[O:17])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]
Reactant: O=C(O)c1cccc(C#Cc2ccccc2)n1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cccc(C#Cc4ccccc4)n3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a solution of 4.4 g (20 mmol) of 6-phenylethynyl-pyridine-2-carboxylic acid in DMF (30 mL) was added 7.6 g (20 mmol) of HBTU and DIEA (4 mL). The resulted mixture was stirred at room temperature for 10 min, then 4 g (21 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) was added, and stirred at room temperature for 1 h. After usual workup as described in general procedure A, 7 g (88%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was obtained after column chromatography purification eluting with DCM/EtOAc. LCMS: 397 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (dd, 1H), 8.13 (dd, 1H), 7.96 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.31 (t, 1H), 3.95 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[CH:18]([N:31]1[CH2:34][C:33](OS(C)(=O)=O)([CH3:35])[CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[CH:18]([N:31]1[CH2:34][C:33]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)([CH3:35])[CH2:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
A mixture of (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 172 mmol), methansulfonic acid 1-benzhydryl-3-methylazetidin-3-yl ester (Preparation #14, Step B, 95 g, 258 mmol) and K2CO3 (47.6 g, 344 mmol) in iPrOH (1 L) was stirred at 90° C. for 16 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in water (1 L) and extracted with EtOAc (3×500 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluting with 30-60% EtOAc in petroleum ether) to give (R)-6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (31 g, 38%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (s, 1H), 7.45-7.40 (m, 4H), 7.30-7.26 (m, 4H), 7.22-7.16 (m, 2H), 6.78 (d, J=9.0 Hz, 1H), 6.08-6.02 (m, 2H), 4.64-4.57 (t, J=6.8 Hz, 1H), 4.53-4.41 (d, J=14.8 Hz, 3H), 3.30 (m, 2H), 3.15 (m, 2H), 1.65 (s, 3H), 1.46 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 1) Rt=4.36 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18](O)[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:23].P(Cl)(Cl)(Cl)=O>O>[Cl:23][C:18]1[C:17]([F:21])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Yield: 34.7 %

Procedure:
A mixture of 9.5 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride was subjected to reaction at 70°-80° C. for 4 hours. Subsequently, the reaction mixture was gradually added to 285 ml of water, and the crystals thus deposited were collected by filtration and then washed with 57 ml of water. The crystals thus obtained were purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene] to obtain 3.5 g (yield 34.7%) of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 137°-139° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:40](B(O)O)[CH:41]([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)CB(O)O
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(CC(C)C)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and isobutylboronic acid replacing phenylboronic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:17]#N)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.[OH-:19].[Na+].C[OH:22].Cl>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1([C:17]([OH:22])=[O:19])[CH2:8][CH2:9][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:15][CH2:16]1
Reactant: [OH-]
Reactant: N#CC1(c2ncccn2)CCC2(CC1)OCCO2
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C1(c2ncccn2)CCC2(CC1)OCCO2

Procedure:
To a solution of 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carbonitrile (220 mg, 0.897 mmol) in THF (1.3 mL) was added 25% aqueous NaOH (2.3 mL) and MeOH (1.3 mL). After being refluxed for 5.5 h, the reaction was cooled, adjusted to pH 7 (3 N aqueous HCl, ˜5 mL), and extracted (3×EtOAc). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to provide crude 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)([O-])=O.C(O)C.O>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:17]1
Reactant: O=C(NC1CCN(CCc2ccccc2[N+](=O)[O-])CC1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1CCN1CCC(NC(=O)c2ccccc2)CC1
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A solution of 1-[2-(o-nitrophenyl)ethyl]-4-benzamidopiperidine (4.25 g.) inabsolute ethanol (150 ml.) was added over 50 minutes to stirred stannous chloride (10.82 g.) in concentrated hydrochloric acid (12 ml.). and water (7.5 ml.) at 60°-70° C. After addition, the mixture was stirred at this temperature for 4 hours before cooling and evaporating theethanol. Continuous extraction into chloroform of the neutralised (with 2N sodium hydroxide solution) aqueous fraction gave the title compound (1.65 g.). The aqueous layer after extraction was made alkaline with 2N sodium hydroxide solution and extracted with more chloroform to give a further batch of the title compound (2.36 g.). The total product was crystallised from ethanolic hydrogen chloride and ether to give the hydrochloride of the title compound (2.75 g.), m.p. 263.8° C. (Found: C, 60.3; H, 7.0; N, 10.5. C20H25N3O. 2HCl requires C, 60.6; H, 6.9; N, 10.60%).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[C:8]([OH:31])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]3[O:31][CH2:33][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[O:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=5)[C:12]4=[O:30])[C:9]3=[CH:10][C:4]=2[O:3]1
Reactant: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OC(F)(F)O3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (55%) as an off-white solid: mp 59-60° C. (recrystallized from the melt); 1H NMR (300 MHz, CDCl3) δ7.37-7.30 (m, 1H), 7.21-7.15 (m, 1H), 7.14-7.07 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.79-6.74 (m, 1H), 6.72 (s, 1H), 6.44-6.40 (m, 1H), 6.36 (s, 1H), 5.12-4.83 (m, 3H), 4.73 (d, J=9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.7, 157.0, 151.8, 144.7, 142.2, 141.7, 141.5, 138.5, 135.4, 132.0, 131.4, 129.6, 128.6, 124.2, 122.4, 120.7, 117.1, 112.8, 109.6, 109.3, 104.6, 94.4, 80.6, 58.0, 37.1; MS (ES+) m/z 465.7 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:22][CH:21]=1>CN(C)C=O.CO>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(CCCC)n1
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Temperature: 25 °C
Yield: 4 %

Procedure:
Under a static nitrogen atmosphere, 2.01 g (11.0 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole was added in small portions to 12 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to −10° C. (ice/methanol) and treated with a solution of 3.37 g (11.0 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl in 20 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography (Waters Prep-500A) using 40% ethyl acetate/hexane gave 2.0 g (4%) of compound as an oil: NMR (CDCl3) δ 0.90 (t, J=7 HZ, 3H), 0.94 (t, J=7 Hz, 3H), 1.28–1.47 (m, 4H), 1.62–1.80 (m, 4H), 2.63–2.75 (m, 4H), 3.63 (s, 3H), 5.27 (s, 2H), 7.13–7.18 (m, 2H), 7.25–7.35 (m, 3H), 7.37–7.44 (m, 1H), 7.48–7.55 (m, 1H), 7.80–7.85 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].Cl.[NH2:22][C@@H:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:24][OH:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][C@H:23]([NH:22][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:24][OH:25]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reactant: N[C@H](CO)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@@H]2C[C@@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (33.7 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC followed by preparative TLC to give the title product (6 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24-1.29 (m, 2H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 2H), 2.77-2.82 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.7, 6.4 Hz, 1H), 3.87 (d, J=4.0 Hz, 2H), 4.34-4.42 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.41 (dd, J=5.1, 1.1 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([I:18])=[N:13][C:14]([I:17])=[CH:15][CH:16]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[I:18][C:12]1[C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:15]=[C:14]([I:17])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(I)nc1I
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCOc1ccc(I)nc1I

Procedure:
To a solution of 4-2 (2.18 g, 4.45 mmol) in dichloromethane (5.0 mL) at room temperature under Ar was added 4.0 M HCl-dioxane solution (25 mL). A white precipitate formed immediately. After two hours the reaction was concentrated and dried to yield a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.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>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([O:20][CH3:21])[CH:3]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:10]=2)[C:6]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:7]1)[CH3:12]
Reactant: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(Br)cc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(-c3ccccc3)cc21
Temperature: 100 °C
Yield: 80.5 %

Procedure:
To a sealable vessel was added 36-3 (100 mg, 0.28 mmol), phenylboronic acid (1042 mg, 0.86 mmol), Pd(PPh3)4 (66 mg, 10 mol %), and potassium carbonate (117 mg, 0.85 mmol). Dioxane (1.5 mL) was added and the reaction heated at 100° C. two days. The reaction mixture was diluted with ethyl acetate, filtered through celite and concentrated. The resulting residue was purified on silica gel column chromatography eluting with hexanes/ethylacetate (50-100%) to afford 79 mg of 36-4. LCMS: calc 350.2 and found: 351.1 [MH]+.
Reaction SMILES: BrN1C(=O)CCC1=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[S:13](=[O:22])(=[O:21])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[N:11]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)Cl>ClC(Cl)C.CN(C=O)C>[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:19][C:14]=2[S:13](=[O:22])(=[O:21])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[N:11]1
Reactant: C1COCCN1
Reactant: COC(=O)C1=NN(C)c2ccc(C)cc2S1(=O)=O
Agent: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1=NN(C)c2ccc(CN3CCOCC3)cc2S1(=O)=O
Reaction time: 0.42 h
Yield: 58.2 %

Procedure:
N-Bromosuccinimide (0.239 g) and methyl 1,6-dimethyl-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 40, 0.30 g) are dissolved in dichloroethane (100 mL). The solution is exposed to light from a 650 W sunlamp with stirring for 25 minutes. The solvent is evaporated and the crude solid obtained is dissolved in DMF (8 mL). Morpholine (0.43 g) is added and the mixture is stirred for 3 hours. The mixture is poured into CH2Cl2 (200 mL) and washed with water (3×200mL). The organic layer is dried with Na2SO4, filtered and the solvent evaporated. The crude solid is chromatographed with MeOH/CH2Cl2 (1-5%) to obtain 0.23 g (59%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 254 (M+H).