Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[O:20][C:21]2[N:22]=[C:23]([CH3:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1.O>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[O:20][C:21]2[N:22]=[C:23]([CH3:29])[N:24]([CH2:8][CH2:9][CH3:10])[C:25](=[O:28])[C:26]=2[N:27]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[O:20][C:21]2[N:22]=[C:23]([CH3:29])[N:24]=[C:25]([O:28][CH2:8][CH2:9][CH3:10])[C:26]=2[N:27]=1
Reactant: Cc1nc2oc(-c3cc(F)ccc3Cl)nc2c(=O)[nH]1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(C)nc2oc(-c3cc(F)ccc3Cl)nc12
Product: CCCn1c(C)nc2oc(-c3cc(F)ccc3Cl)nc2c1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
26.2 g of potassium carbonate and 6.4 g of 1-bromo-propane were added to a solution of 15 g of 2-(2-chloro-5-fluoro-phenyl)-5-methyl-6H-oxazolo[5,4-d]pyrimidin-7-one in 150 ml of dimethylformamide. The suspension was stirred at 60° C. for 72 h. After cooling, the mixture was poured onto 300 ml of water. The precipitate was filtered off by suction. The obtained mixture of regioisomers was separated by silica gel chromatography (method SC1). Besides 3.3 g of 2-(2-chloro-5-fluoro-phenyl)-5-methyl-6-propyl-6H-oxazolo[5,4-d]pyrimidin-7-one, 3.2 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Temperature: 80 °C

Procedure:
To a solution of 7-chloro-3-iodo-imidazo[1,2-a]pyridine (5.0 g, 17.8 mmol) in DME (350 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (7.36 g, 21.4 mmol), 2M Na2CO3 (71.6 ml, 35.8 mmol) [reaction degassed by bubbling N2 through] followed by tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was triturated with CH2Cl2 to afford the desired product as a beige solid. MS: [M+H]+ 389
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]=[CH:23][N:24]([CH3:26])[CH3:25])(=[O:21])=[O:20])[CH:13]=2)=[O:11])=[C:8]([Cl:29])[C:7]=1[Cl:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]=[CH:23][N:24]([CH3:26])[CH3:25])(=[O:20])=[O:21])[CH:13]=2)=[O:11])=[C:8]([Cl:29])[C:7]=1[Cl:30])[CH:2]=[CH2:3]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)c(Cl)c2Cl)ccc1Cl
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.6 g (40 mmol) of allyl bromide are added dropwise, with magnetic stirring, to a mixture of 13.1 g (30 mmol) of 4-hydroxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone, 5.0 g (36 mmol) of ground potassium carbonate and 50 ml of dry dimethylformamide at room temperature, and the mixture is stirred for about 8 hours. The pale yellow suspension is then stirred in portions into a mixture of 400 ml of ice-water and 100 ml of 2N hydrochloric acid, and the precipitate is filtered off. Colorless crystals, melting point 141°-142° C. (from acetone/ethanol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.FC(F)(F)C([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=O>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH:20]2[CH2:21][CH2:22][NH:18][C:19]2=[O:23])=[CH:6][CH:5]=1
Reactant: O=C1CCCN1C(=O)C(F)(F)F
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: O=C1NCCC1Cc1ccc(OC(F)(F)F)cc1
Yield: 53 %

Procedure:
Following the procedure as described in Preparation 5, making variations as required to use 4-(trifluoromethoxy)benzaldehyde in place of 4-fluorobenzaldehyde to react with 1-(2,2,2-trifluoroacetyl)pyrrolidin-2-one, the title compound was obtained as a white solid in 53% yield: 1H NMR (300 MHz, CDCl3) δ 7.24-7.06 (m, 4H), 3.71-3.50 (m, 2H), 3.34-3.02 (m, 3H), 2.19-2.00 (m, 1H), 1.83-1.70 (m, 1H); MS (ES+) m/z 260.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)=[O:4].[NH2:15][CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1>>[O:14]=[C:12]([NH:15][CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1)[CH2:11][N:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: COC(=O)C1CCN(CC(=O)O)CC1
Product: COC(=O)C1CCN(CC(=O)NCc2nc3c(c(=O)[nH]2)COCC3)CC1
Yield: 39.7 %

Procedure:
The title compound (1.2 g) was prepared according the general procedure of Example 1 from 2-(4-(methoxycarbonyl)piperidin-1-yl)acetic acid (2.2 g, 11 mmol) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.5 g, 8.3 mmol). MS m/z 365.3 (M+1), retention time=1.46 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[C:17]=1[O:26][CH3:27].[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:26][CH3:27])[C:18]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OC
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
6-Amino-2-chloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (0.2 g, 0.9 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (0.29 g, 1.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (65 mg, 0.1 mmol), and cesium fluoride (0.28 g, 1.9 mmol) were combined in 1 mL of 1,2-dimethoxyethane and 1 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min and 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (162 mg, 51.1% yield): mp 155-158° C.; 1H NMR (CDCl3): δ 7.58 (dd, 1H), 7.20 (dd, 1H), 5.56 (br s, 2H) 4.00 (s, 3H), 3.99 (d, 3H), 3.94 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28]#[N:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([OH:33])(C)C>[OH-].[K+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](=[O:33])[NH2:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3c2CCCC3)CC1
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(N)=O)c3c2CCCC3)CC1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
4-(4-Cyano-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (545 mg, 1.30 mmol) was dissolved in a mixture of isopropanol (2 ml) and 2N KOH (4 mL). The reaction was stirred for 5 days at 80° C. The isopropanol was removed in vacuo and the residue was diluted with H2O (20 mL). The mixture was charged to a separatory funnel and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to a white solid that was triturated with dichloromethane to afford 4-(4-carbamoyl-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester F-29 as a white solid. Wt.: 340 mg (60%). 1H NMR (300 MHz, D-DMSO) δ 7.81 (m, 2H), 7.72 (d, 1H), 7.52 (s, 1H), 7.23 (d, 1H), 3.72 (m, 2H), 3.09 (m, 3H), 2.81 (m, 2H), 2.71 (m, 2H), 1.70 (m, 4H), 1.55 (m, 2H), 1.36 (s, 9H), 1.25 (m, 2H); LC/MS m/z 436 (M−H)−. The aqueous extract was acidified to pH 2 with IN HC1 and extracted twice with dichloromethane. The combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration in vacuo afforded 4-(4-carboxy-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Wt.: 76 mg (13%). 1H NMR (300 MHz, d6-DMSO) δ 7.72 (d, 1H), 7.33 (s, 1H), 7.23 (d, 1H), 3.72 (m, 2H), 3.09 (m, 3H), 2.81 (m, 2H), 2.71 (m, 2H), 1.70 (m, 4H), 1.55 (m, 2H), 1.36 (s, 9H), 1.25 (m, 2H); LC/MS m/z 437 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20](OC)[O:21]C)[C:11]3=[O:25])[CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20]=[O:21])[C:11]3=[O:25])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21
Temperature: 0 °C

Procedure:
A suspension of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)-1′-(2,2-dimethoxyethyl) spiro[cyclopropane-1,3′-indolin]-2′-one (1 g) in water (1 mL) was cooled to 0° C. and treated with a mixture of DCM and TFA (1:1, 6 mL) for 2 hours. The reaction mixture was poured into saturated aq. NaHCO3 solution and extracted with DCM (3×6 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure. The crude product was used for next step directly without any further purification. LC/MS m/e calcd. for C18H14ClNO2: 311, observed (M+H)+: 312.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]O)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:3])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cc(OCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.76 ml (24.16 mmol) of thionyl chloride are added to 2 g (9.29 mmol) of [4-(benzyloxy)pyridin-2-yl]methanol [described in J. Org. Chem., (1996), 61(8), 2624] in 46 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue obtained is taken up in a saturated aqueous sodium carbonate solution and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. 2.1 g of a brown oil are collected. Mass spectrometry (ES+ Mode): MH+=234
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH2:21][CH:22]2[CH2:24][CH:23]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:2]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:41][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:42][C:37]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:3]=[CH:2][C:1]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:6][CH:5]=4)[C:9]([O:20][CH2:21][CH:22]4[CH2:24][CH:23]4[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:10][C:11]=3[C:16]=2[F:17])=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
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: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 120 °C

Procedure:
A solution of Ethyl 2-({[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}methyl)cyclo-propanecarboxylate (0.0440 g, 0.748 mmol), biphenylboronic acid (0.163 g, 0.823 mmol), and Pd(PPh3)4 (0.035 g, 0.030 mmol) in 7.5 mL of DMF was treated with a 1 M solution of K2CO3 (1.50 mL). The resulting yellow solution was heated at 120° C. for 45 min., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (0% then 0-20% then 20-30% EtOAc/hexanes) afforded the title compound as a white solid. LCMS: calculated for C39H32F2N2O3 614.68, observed m/e 615.1 (M+H)+ (Rt 2.78/4 min).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.CO.Cl.[O-:16][C:17]#[N:18].[K+]>O>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: CNC1CCCc2ccccc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C(N)=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.05 grams (0.05 mole) of 1,2,3,4-tetrahydro-N-methyl-1-naphthylamine in 10 ml. of methanol is added a solution of 4.2 ml. of 12N hydrochloric acid (0.05 mole) in 35 ml. of water. The mixture is cooled in an ice-water bath while a solution of 4.46 grams (0.055 mole) of potassium cyanate in 15 ml. is added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 45 minutes and then at 70°C. to 75°C. for 30 minutes. The mixture is cooled to 25°C., and the solid product filtered off, washed with water and then with cold ethyl acetate. The dried product weighs 7.1 grams and has melting point 160°-163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Analysis Calculated for C 12 H16N2O: C, 70.56; H, 7.90; N, 13,72. Found: C, 70.60; H, 7.94; N, 13.75.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([F:28])[CH:12]=3)=[CH:6][N:5]2[CH:29]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.O.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:30]1([C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:13]([F:28])[CH:12]=4)=[CH:6][N:5]3[CH:29]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of benzyl {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-fluorophenyl}carbamate (12.1 g, 30.9 mmol) in N,N-dimethylacetamide (84.7 mL) was added cyclopropanecarbonyl chloride (3.36 mL, 37.0 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.7 g, 68%) as a thin-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:27][CH2:26]3)[C:20](OC)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:24][CH:25]([CH2:26][NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:27][C:20]3=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Nc1ccccc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in aniline (0.17 mL, 1.92 mmol) is added magnesium perchlorate (2 mg, 0.009 mmol) and the resulting mixture is heated for 4 h at 80° C. The resulting mixture is cooled to room temperature, and then the mixture is diluted with water, and extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (7:3) to give the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH:8]=[C:9](SC)SC>C(O)C>[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH:8]=[C:9]1[NH:1][CH2:2][CH2:3][S:4]1
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Reactant: NCCS
Solvent: CCO
Product: O=C(C=C1NCCS1)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.5 %

Procedure:
A solution of 36 mg (0.46 mmol) of 2-aminoethanethiol dissolved in 10 mL of ethanol was added to 100 mg (0.46 mmol) of 1,1,1-trifluoro-4,4-bis(methylthio)-3-buten-2-one obtained by the method described in Comparative Example 4, and the mixture was refluxed under heating for 6 hours, then stirred at room temperature for 13 hours. Following reaction completion, the ethanol was distilled off under reduced pressure, after which the condensate was dissolved in ethyl acetate and washed once with water. The washed product was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure, giving 73 mg (yield, 81%) of 1,1,1-trifluoro-3-(thiazolidin-2-ylidene)propan-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH:12]3[O:14][CH:9]([CH2:10][CH:11]3O)[CH2:8]2)=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=[N:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>C(Cl)Cl.CN(C=O)C>[N:31]([CH:11]1[CH2:10][CH:9]2[O:14][CH:12]1[CH2:13][N:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17])[CH2:8]2)=[N+:32]=[N-:33]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CC2CC(O)C(C1)O2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CC2CC(N=[N+]=[N-])C(C1)O2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-(2-Methyl-4-nitro-pyrazol-3-yl)-8-oxa-3-azabicyclo[3.2.1]octan-6-ol (500 mg, 1.96 mmoL) was dissolved in DCM (15 mL) and triethylamine (0.41 mL, 2.95 mmol) was added. After cooling to 0° C., methanesulfonyl chloride (0.19 mL, 2.45 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred for 18 hr. The mixture was diluted with DCM (10 mL), quenched with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give a light brown solid. This solid (450 mg, 1.35 mmol) was dissolved in DMF (20 mL), sodium azide (450 mg, 6.8 mmol) was added and the mixture heated at 150° C. for 18 hr, behind a blast shield. The mixture was allowed to cool to room temperature, the mixture partitioned between water (20 mL) and EtOAc (20 mL) and the aqueous layer extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (10-50%, EtOAc/isohexane) gave 6-azido-3-(2-methyl-4-nitro-pyrazol-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane as brown gum (25 mg, 68% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.65 (d, J=7.4 Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=8.0, 3.2 Hz, 1H), 3.82 (s, 3H), 3.75-3.70 (m, 2H), 2.83-2.73 (m, 1H), 2.64-2.49 (m, 2H), 2.20 (ddd, J=13.4, 7.3, 3.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S.[OH2:12]>[Cu]>[OH:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O
Agent: [Cu]
Agent: S
Product: O=C(O)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To 10.1 g (0.05 mol) of 5-bromonicotinic acid was added 10 g of NaOh dissolved in 63 mL of water, 3.1 g of coppersulfate pentahydrate and 0.42 g of copper (0). The reaction mixture was vigorously stirred and heated under reflux for 30 hours. After cooling the mixture to room temperature, 4.8 g of Na2S.H2O was added and stirring was pursued overnight. The reaction mixture was heated to 70° C. and treated with H2S gas until disappearance of the white precipitate (3 h). After cooling to room temperature, the mixture was filtered and the pH of the filtrate was adjusted to 5.2 with concentrated hydrochloric acid. The precipitate was filtered and the pH of the % filtrate was adjusted to 4.6 with concentrated hydrochloric acid. The white precipitate was then filtered, washed with water and dried under reduced pressure giving 4.3 g (yield: 62%) of product of molecular formula C7H5NO3. Aspect: white powder.