Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][CH3:12])=[N:7][C:6]=2[C:5]([N+:13]([O-])=O)=[C:4]([F:16])[CH:3]=1.[Cl:17][C:18]1[C:26]2[O:25][C:24]([CH2:27][CH3:28])=[N:23][C:22]=2[CH:21]=[C:20]([F:29])[CH:19]=1.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36]>>[NH2:13][C:5]1[C:6]2[N:7]=[C:8]([CH2:11][CH3:12])[O:9][C:10]=2[C:2]([Cl:1])=[CH:3][C:4]=1[F:16].[Cl:17][C:18]1[C:26]2[O:25][C:24]([CH2:27][CH3:28])=[N:23][C:22]=2[CH:21]=[C:20]([F:29])[C:19]=1[N+:35]([O-:37])=[O:36]
Reactant: CCc1nc2cc(F)cc(Cl)c2o1
Reactant: CCc1nc2c([N+](=O)[O-])c(F)cc(Cl)c2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1nc2c(N)c(F)cc(Cl)c2o1
Product: CCc1nc2cc(F)c([N+](=O)[O-])c(Cl)c2o1
Reaction time: 2 h

Procedure:
Step 4 Preparation of 7-Chloro-2-ethyl-5-fluoro-4-nitrobenzoxazole as an Intermediate 7-Chloro-2-ethyl-5-fluorobenzoxazole (0.9 g) was slowly added to a mixture of sulfuric acid (9 ml) and nitric acid (0.6 ml) at −40° C. The dryice-acetone bath was removed and the mixture stirred for 2 hours. Ice-water was added and the mixture was extracted with ether. The organic phase was dried over anhydrous sodium sulfate and concentrated to an oil under reduced pressure. The residue was purified by column chromatography on silica gel using 5% ether in hexane. The desired product was obtained as a white solid [0.35 g, 1H-NMR (CDCl3, 300 MHz): 1.48(3H, t, J=7.6 Hz), 3.07(2H, q, J=7.6 Hz), 7.27(1H, d, J=10.5 Hz) ppm], along with a by-product, 7-chloro-2-ethyl-5-fluoro-6-nitrobenzoxazole (0.49 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)Cl>[Br:22][C:6]1[CH:5]=[C:4]2[C:9](=[N:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: c1cnc2c(c1)CCN2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Brc1cnc2c(c1)CCN2
Temperature: 25 °C

Procedure:
The bromination may be carried out by any of the procedures known for such a reaction. The bromination may be carried out, for example, by mixing 7-azaindoline, p-toluene sulphonic acid monohydrate and 1,3-dibromo-5,5-dimethylhydantoin in methylene chloride and stirring the mixture at for example ambient temperature for a period of time, for example 3 hours. Extraction and purification gives 5-bromo-7-azaindoline.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]1[CH3:18].[Br:24]Br>C(O)(=O)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][N:5]1[C:6]([CH3:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[C:9]([Br:24])=[C:10]1[CH3:11]
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)cc1=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-ethoxycarbonyl-4-pyridone (2.43 g, 7.6 mmol) was dissolved in glacial acetic acid (25 mL) and treated with bromine (490 μL, 9.5 mmol). The resulting mixture was stirred at room temperature for 8 hours and poured into ice/water. The product was extracted with dichloromethane, and the extracts were washed with 10% aqueous NaHCO3, 5% aqueous Na2S2O3 and brine. The organics were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was triturated with diethyl ether to give the product as a white solid (1.32 g, 3.3 mmol, 43%). 1H NMR (CDCl3, 300 MHz): 7.41-7.31 (m, 1H), 7.00-6.92 (m, 2H), 5.31 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 2.66 (s, 3H), 2.37 (s, 3H), 1.37 (t, J=6.9 Hz, 3H); LRMS m/z 400.1 (M+−1), 402.1 (M++1).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].CN(C)[CH:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH:15]=O>CO>[O:4]=[C:3]1[C:2]([C:1]([NH2:7])=[O:6])=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)=[CH:13][NH:5]1
Reactant: NC(=O)CC(N)=O
Reactant: CN(C)C=C(C=O)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O

Procedure:
To a solution of 1.1 g. of malonamide and 1.1 g. of sodium methoxide in 50 ml. of methanol is added 2.43 g. of 3-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]-2-propenal. The resulting mixture is heated at reflux temperature for 12 hours. The mixture is cooled, concentrated and acidified with hydrochloric acid to yield 800 mg. of the product of the Example as a yellow solid m.p. 276.5°-278.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:42])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13].[O-]CC.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([N:11]=[N+:12]=[N-:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1cc(C)cc(C=O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc(C)cc(C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g of 3,5-dimethylbenzaldehyde and 19.3 g of ethyl azidoacetate is added, at −10° C. under dry nitrogen, to a mixture of 25 ml of ethanol and 50 ml of a 21% solution of sodium ethoxide in ethanol. The mixture is left stirring for 1 hour at −10° C. and for fourteen and a half hours at +5° C. It is poured into 100 ml of water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in ether and this solution is dried over MgSO4 and then evaporated to give the product, which is used without further purification in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15](C(O)=O)=[N:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+].CCOCC>O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-c2cn3ccncc3n2)cc1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
A mixture of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylic acid (Preparation #C.1, 18.9 g, 66.1 mmol) and 1M of hydrogen chloride in water (500 mL) was heated to about 100° C. for about 2 h. The reaction mixture was cooled to ambient temperature and solid Na2CO3 (50.0 g) was added cautiously portion-wise to raise the pH to about 8-9. The resulting brown solid was collected washing with water (4×80 mL). The product in the filtrate was extracted with EtOAc (3×200 mL). In addition the solid was dissolved in EtOAc (1 L) and filtered from insoluble material. The combined organic extracts were washed with water (3×200 mL) and brine (150 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown solid. The solid was stirred with Et2O (8×150 mL); the insoluble solid was filtered each time until no product remained in the insoluble material. The Et2O was evaporated to yield a brown solid, which was dissolved in EtOAc (25 mL) and purified by silica chromatography using the EtOAc as eluent to yield an orange/brown solid (5.12 g, 34.8%): LC/MS (Table 1, Method g) Rt=2.10 min; MS m/z: 214.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([O:26][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@@H](O)CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](COS(C)(=O)=O)OS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((S)-2,3-dihydroxypropylthio)propanoate (1 eq) was stirred in dry DCM (0.1M) in an ice bath (0° C.) under an atmosphere of N2. Pyridine (8.0 eq) was then carefully added at 0° C. Methanesulfonyl chloride (4.0 eq) and DMAP (0.1 eq) were added with the reaction slowly warming to room temperature, then stirred overnight. The crude reaction mixture was then loaded directly onto a silica column and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 100% Hex, 0-20% EtOAc/Hex, 20-50% EtOAc/Hex, 100% EtOAc to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[O:30][CH3:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:19]([O:30][CH3:31])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][C:23]3=[O:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)CCCC2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)C(=O)CCC2
Yield: 53.3 %

Procedure:
To a solution of methyl 7-(4-fluorophenyl)-7-(2-methoxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.4 g) in benzene (12 ml) was added a mixture of pyridinium chlorochromate (1 g) and cerite (1.8 g) and the mixture was refluxed for 5 hours. After cooling, insoluble materials were filtered off and the filtrate was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-(6-methoxy-7,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-5naphthyl)-heptanoate (0.22 g) (Compound 59). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: S(C1C=CC=CC=1)([O-])(=O)=O.[CH3:11][S:12]([CH2:15][C:16]([OH:18])=O)(=[O:14])=[O:13].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([C:47]2([C:64]([F:67])([F:66])[F:65])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:63][NH:62][CH2:61]3)[O:56][CH2:55]4)[CH2:48]2)[CH:42]=[C:43]([Cl:46])[C:44]=1[F:45]>C(OCC)(=O)C>[Cl:46][C:43]1[CH:42]=[C:41]([C:47]2([C:64]([F:65])([F:67])[F:66])[O:51][N:50]=[C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57]3([CH2:61][N:62]([C:16](=[O:18])[CH2:15][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:63]3)[O:56][CH2:55]4)[CH2:48]2)[CH:40]=[C:39]([Cl:38])[C:44]=1[F:45]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)COC43CNC3)=NO2)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)([O-])c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 35 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Alternatively, the besylate salt of the chiral 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]can be coupled with methanesulfonylacetic acid using n-propylphosphonic anhydride via a simplified one-pot process instead of the CDI two-pot method. Triethylamine (0.825 g, 1.3 eq.) was added drop-wise over 1 minute at about 18-22° C. to methanesulfonylacetic acid (0.615 g, 1.3 eq.) and chiral-5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran] (Preparation 8, 2.1 g, 3.39 mmol) in 9.3 mL ethyl acetate (EtOAc). The addition funnel was rinsed with 0.5 mL EtOAc and the resulting mixture stirred for a minimum of 2 hours and cooled to <10° C. To this mixture, 50% n-propylphosphonic anhydride in EtOAc (4.313 g, 2.0 eq) was added drop-wise over 15 minutes at <10° C. The addition funnel was then rinsed with 1.5 mL EtOAc. The reaction mixture was warmed to 35° C. and stirred overnight. (HPLC >97% with <1% starting material). To the reaction was added 1.0 g Celite filter aid and filtered through a 1 g celite plug in a 15 mL coarse frit glass funnel and rinsed with 4 mL EtOAc (2×). In process chiral HPLC was 98.8% S-enantiomer and 1.2% R-enantiomer; HPLC >97%. Filtrate was washed with 4 mL water (3×), 4 mL 10% NH4Cl, 4 mL water and the organic layer concentrated to the amorphous S form of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone (foam, 70-80% yield). 1H NMR, 600 MHz (d6-CDCl3) δ ppm: 7.65 (m, 5H), 5.19 (br s, 2H), 4.70 (m, 2H), 4.48 (d, 1H), 4.38 (d, 1H), 4.12 (d, 1H), 3.90 (d, 2H), 3.72 (d, 1H), 3.23 (s, 3H); m/z (CI) 581 [M+H].
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]1[O:12][C:11]2[CH:10]=[CH:9][C:8]([NH2:13])=[C:7]([NH2:14])[C:6]=2O1.[OH2:15]>C(O)C>[NH2:1][C:2]1[NH:13][C:8]2[CH:9]=[C:10]3[O:15][CH2:4][O:12][C:11]3=[CH:6][C:7]=2[N:14]=1
Reactant: N#CBr
Reactant: Nc1ccc2c(c1N)OCO2
Reactant: O
Solvent: CCO
Product: Nc1nc2cc3c(cc2[nH]1)OCO3

Procedure:
Cyanogen bromide (3.4 g.) in water (60 ml.) was added to 3,4-methylenedioxy-o-phenylenediamine (3.8 g.) in ethanol (60 ml.) to give 2-amino-5,6-methylenedioxybenzimidazole (4.4 g.) m.p. 230°-243° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.O=S(Cl)Cl.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C(Cl)Cl.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3(O)CCCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: COCCN
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCNC1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-cyclohexyl)-phenyl]-amide (as prepared in Example 1, 42.0 mg, 0.100 mmol) in 1.5 mL of DCM at −15° C. was added SOCl2 (22.0 μL, 0.300 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled to −15° C. To the reaction was then added 2-methoxyethylamine (70.0 μL, 0.800 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was diluted with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-5% MeOH/DCM) to afford the title compound (21.7 mg, 46%) as a white solid. 1H-NMR (1:1 CDCl3/CD3OD; 400 MHz): δ 8.40 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.44 (m, 1H), 7.32 (br s, 1H), 5.81 (m, 1H), 3.48 (t, 2H, J=5.1 Hz), 3.27 (s, 3H), 2.60 (t, 2H, J=5.1 Hz), 2.35-2.45 (m, 2H), 2.28-2.35 (m, 2H), 2.09-2.15 (m, 2H), 1.87-1.98 (m, 2H), 1.68-1.78 (m, 2H), 1.61 (t, 2H, J=6.3 Hz), 1.34-1.60 (m, 4H), 1.12 (s, 6H). Mass spectrum (APCI-neg, m/z): Calcd. for C28H37N5O2, 474.3 (M−H). found 474.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([N:11]2[CH2:15][CH2:14][S:13][C:12]2=[S:16])=[O:10])=[CH:7][C:6]([C:17]([N:19]2CCS[C:20]2=S)=[O:18])=[CH:5][C:4]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][C:28]1=[S:32])=[O:26].CN.C(O)(C)C.CO>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:25]([N:27]2[CH2:31][CH2:30][S:29][C:28]2=[S:32])=[O:26])=[CH:5][C:6]([C:17]([NH:19][CH3:20])=[O:18])=[CH:7][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][S:13][C:12]1=[S:16])=[O:10]
Reactant: COc1c(C(=O)N2CCSC2=S)cc(C(=O)N2CCSC2=S)cc1C(=O)N1CCSC1=S
Agent: CN
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: CNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a slurry of the trithiazolide 5 (27.1 g, 0.05 mol) in dichloromethane (600 mL), a mixture of 2 mL methylamine solution (40% wt in water, d=0.902) and isopropanol (30 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in methylene chloride). The desired product was obtained as a thick, yellow oil, yield 7.5 g (71% based on the methylamine). 12.8 g of unreacted starting trithiazolide was recovered during the separation.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38]([N:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([N:9]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=3)[CH2:10]2)[CH2:15]1)=[O:39]
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 27) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C20H17F4N7O, 447.40; m/z found 448.0 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C([N:13]([CH2:16][CH3:17])[CH2:14]C)C.N1CCC1.P(Cl)(Cl)([Cl:24])=O>>[N:13]1([C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:24])=[CH:3][CH:4]=2)=[O:10])[CH2:14][CH2:17][CH2:16]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(O)nn1
Agent: C1CNC1
Product: O=C(c1ccc(Cl)nn1)N1CCC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Phosphorus oxychloride (50 mL) was added to 6-hydroxypyridazine-3-carboxylic acid (9.82 g, 70.05 mmol) and the resulting solution heated to reflux. After 45 mins the solution was allowed to cool and the excess of phosphorus oxychloride was removed under reduced pressure. THF (50 mL) was added to the black residue and the resulting solution cooled to 0° C. Triethylamine (9.77 mL, 70.05 mmol) and azetidine (4.0 g, 70.05 mmol) were added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The volatiles were removed under reduced pressure and water (50 mL) added, then the residue was adjusted to pH8 using sodium hydroxide solution. The aqueous layer was extracted five times with ethyl acetate, the combined organics dried (MgSO4) and the solvent removed to give the crude product as a dark oil. A sample was purified by preparative HPLC, eluting with 5-95% acetonitrile in water (+0.2% TFA), and gave the title compound as a colorless solid (135 mg).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(-c3ccc(F)cc3)n2n1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a stirred mixture of 3-bromo-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.275 mmol), 4-fluorophenylboronic acid (0.412 mmol), Na2CO3 (0.825 mmol) in 2-propanol (6 mL) and water (2 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0275 g). The reaction mixture is heated at 80° C. for 6 hours, cooled, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 0.092 g (88%) of the title compound as a yellow solid: Rf 0.47 (1:1 EtOAc:hexanes); LCMS (m/z)=379.4 [M+H]+, tR=3.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Br)(Br)(Br)(Br)[Br:22]>>[Br:22][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrP(Br)(Br)(Br)Br
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)c(Cl)c1
Product: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
To 15.0 g. (0.0476 moles) of ethyl 3-chloro-4-cyclohexylphenylglycolate there is added slowly with stirring at 40°-50° C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate.
Reaction SMILES: [C:1]1([N:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CCCCCC>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN(CC(=O)O)c1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN(c2ccccc2)CC(=O)O1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Into a 2-liter round-bottom flask was put 62.8 g of N-phenyliminodiacetic acid under nitrogen gas stream to dissolve with 500 ml of toluene. To the solution was added 32.0 g of acetic anhydride, and the mixture was refluxed by heating with stirring. After lapse of one our, the mixture was cooled to room temperature and 3 liters of hexane was added thereto with stirring to deposit. The deposit was collected by filtration to obtain 52.0 g of N-phenyliminodiacetic acid anhydride.