Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([O:32]CC)=O)=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH:47][CH3:48]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([N:47]([CH3:48])[CH3:46])=[O:32])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (256 mg) and 2.2 ml of dimethylamine were dissolved in 2.2 ml of tetrahydrofuran, and the solution was sealed in a tube and subjected to 39 hours of reaction at 60° C. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/ethanol=1/1) to give 230 mg of amorphous 2-[(2S)-2-[[(2RS)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.C[O-].[Na+].[CH3:15][O:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C@H:18]1[CH2:29][C:30](=[O:33])[CH2:31]Br>CO>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:31][C:30](=[O:33])[CH2:29][C@H:18]3[C@H:17]([O:16][CH3:15])[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cc(Cl)sc12
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere in a flame dried flask and with magnetic stirring, a solution of 0.80 g (0.0043 mole) of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one, 3.52 ml of 1.22N sodium methoxide in methanol, and 20 ml of methanol was treated with 1.86 g (0.0056 mole) of allyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate. The reaction mixture was stirred overnight at room temperature, and was then evaporated under reduced pressure. The residue was taken up in 25 ml of 0.1N aqueous sodium hydroxide, and the resulting solution was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated to afford a solid material which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 2 cm×height 25 cm); the eluant was 7% ethanol in chloroform; after a forerun of 125 ml, 25 ml fractions were taken. Fractions 13-20 were combined and evaporated to furnish the title compound: yield 0.56 g (27%); 1H-nmr (CDCl3) delta ppm 1.2-2.1 (multiplet, 4H, OCHCH2CH2CH2N), 2.7-3.1 (multiplet, peaks, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3H, OCH3), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad double, 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.3 (triplet with fine splitting, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.2 (singlet, 1H, thieno H), 8.0 (broad singlet, 1H, N=CH--N).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[F:15][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.2 %

Procedure:
To a nitrogen sparged flask containing 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (34.0 g, 152 mmol), 2-methylsulfonylphenylboronic acid (38.0 g, 190 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (2.39 g, 3.0 mmol) were added sparged THF (300 mL) and K3PO4(aq) (608 mL, 0.5 M). The mixture was stirred for 15 hours at rt and then concentrated under reduced pressure to remove the THF. The remaining portion was treated with toluene (325 mL) and THF (25 mL). The biphasic slurry was stirred for 20 h at rt and then filtered and the isolated solid washed with water (150 mL) and toluene (150 mL). The filter cake was dried to provide the title compound (47.1 g, 90%). MS (ESI): mass calcd. for C17H14FN3O2S, 343.08; m/z found, 344.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J=2.4, 1.5, 1H), 8.12 (dd, J=7.9, 1.4, 1H), 8.04 (d, J=1.5, 1H), 7.93 (m, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.48 (dd, J=7.6, 1.4, 1H), 7.37 (dd, J=12.3, 1.7, 1H), 7.32 (dd, J=8.1, 1.7, 1H), 6.76 (s, 2H), 2.95 (s, 3H).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[N:10]1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:11]3[CH:12]=[CH:13][N:9]([CH3:8])[N:10]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cn1ccc(CN)n1
Agent: NCc1cocn1
Product: Cn1ccc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)n1
Yield: 30 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1-methyl-1H-pyrazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)isonicotinamide was obtained as a colorless solid in 30% yield: mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.37 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.27-7.22 (m, 3H), 7.03-6.91 (m, 3H), 6.19 (d, J=2.1 Hz, 1H), 4.60 (d, J=5.1 Hz, 2H), 4.41 (s, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.84 (s, 3H), 3.34 (t, J=8.1 Hz, 2H); MS (ES+) m/z 408.8 (M+1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:59][O:60][CH3:61])[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]\[CH2:39]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:64]>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:59][O:60][CH3:61])[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]/[CH2:39][OH:64])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CO)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a mixture of diphenylmethyl 7-[2-(2-tritylaminothia-zol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-chloropropen-1-yl]-3-cephem-4-carboxylate (IIa) (715 mg, 0.825 mmol) in DMSO (9 ml) and water (2.5 ml) was added silver nitrate (700 mg) under cooling and the mixture was stirred for 6 hours at room temperature. The mixture was poured into water (50 ml) and extracted with CHCl3 (300 ml). The organic phase was washed with water and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel (Merck kieselgel 60, 20 g) by successively eluting with 0.5% MeOH/CHCl3, 1% MeOH/CHCl3 and 3% MeOH/CHCl3. The eluate was monitored by TLC and the fractions containing the desired product were combined. Evaporation under reduced pressure gave 452 mg (65% yield) of the title product as an amorphous powder.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[NH:11][CH:10]=[C:9]([CH2:12][N+](C)(C)C)[CH:8]=1)=[O:6])[CH3:3].[C-:17]#[N:18].[Na+]>C(O)C>[C:17]([CH2:12][C:9]1[CH:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[NH:11][CH:10]=1)#[N:18]
Reactant: CCOC(=O)c1cc(C[N+](C)(C)C)c[nH]1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(CC#N)c[nH]1

Procedure:
A solution of the product obtained in Step E and sodium cyanide (0.225 g) in ethanol is heated at reflux for 72 hours. After evaporation to dryness, the residue is taken up in a mixture of CH2Cl2/water. The aqueous phase is extracted three times with CH2Cl2. The organic phases are combined. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness to yield the title product which is used directly in the next Step.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].Cl>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: Cl
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C
Yield: 140 %

Procedure:
A solution of 19.2 g. of acetonine in 70 g. of acetone was added with 7 g. of methanol. Then, 0.9 g. of dry gaseous hydrogen chloride was introduced therein and absorbed. The solution was sealed and heated at 60°C. for 10 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 140%.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]([NH2:5])[N:7]=2)[CH:10]=1
Reactant: O=C(Nc1nc2ccc(F)cn2c1-c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 100 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide (compound k, 0.190 g, 0.0006 mol) was dissolved in methanol (8.0 mL) and water (2 ml). To this was added potassium carbonate (0.2 g, 0.002 mol). The reaction was heated in the microwave at 100° C. for 45 min. The solvent concentrated and residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was dried (magnesium sulfate) then chromatographed on silica (55:40:5, DCM:acetonitrle:MeOH) to give 6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine Rf 0.40, (55:40:5, DCM:acetonitrle:MeOH); MS m/z 228 (M+H).
Reaction SMILES: Cl.C(N)(=N)C.[O-]CC.[Na+].ClC1C=CC=CC=1C(C(=CN(C)C)C(OCC)=O)=O.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38]([C:47]2C=CC=CC=2)[N:37]=1>C(O)C>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38]([CH3:47])[N:37]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Agent: CC(=N)N
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Agent: CC[O-]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1-c1ccccc1Cl
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a stirred solution of 2.09 g of acetoamidine hydrochloride in 50 cc of ethanol was added 1.50 g of sodium ethoxide at room temperature and the mixture was stirred for 10 minutes. The resulting suspension was added to 6.1 g of compound D in 50 cc of ethanol and the resulting mixture was heated under reflux for 6 hours. Thereafter, 4.5 g of compound F was obtained in the same manner as for compound E. Yield: 73.7%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([O:11][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To a solution of 1-benzyl-3-tritylglycerol (17.5 g, 0.41 mol) in anhydrous dichloromethane (200 mL) at 0° C. was added triethylamine (8 mL, 0.58 mol) followed by methanesulfonyl chloride (4.1 mL, 0.54 mol). The reaction was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The reaction mixture was washed with 1N hydrochloric acid (30 mL), dried (Na2SO4), filtered and concentrated. Crystallisation using diisopropyl ether gave the title compound (15.2 g, 72%) as a solid. m/z not found, r.t.=4.41 mins. NMR (400 MHz; CDCl3) δ7.43-7.41 (6H, m), 7.38-7.23 (14H, m), 4.90-4.83 (1H, m), 4.52 (2H, m), 3.75-3.63 (2H, m), 3.41-3.33 (2H, m), 3.02 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Yield: 97 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum, and the partitioned between water (75 mL) and methylene chloride (75 mL) and the aqueous phase was extracted with methylene chloride (2×75 mL). The combined organic phases were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 5.30 g, in 97% yield: 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.70-6.79 (m, 2H), 8.09 (t, J=9.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[CH:9]=[CH2:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:9]=[CH2:10]
Reactant: C1=COCCC1
Reactant: C=CC(O)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CC(OC1CCCCO1)c1ccccc1Br

Procedure:
To 1-(2-bromophenyl)prop-2-en-1-ol) (31.0 g; 0.145 mol) in 150 ml of dry THF (tetrahydrofuran) was added 20 ml of 3,4-dihydro-2H-pyran and then 1 ml of POCl3 and the mixture stirred over the weekend at room temperature. The reaction mixture was neutralized with saturated NaHCO3 and concentrated down. The resulting material was partitioned between water and diethyl ether and the aqueous layer extracted again with diethyl ether. The organics were combined and washed with water and then brine and dried over K2CO3 and concentrated. The crude subtitle compound was chromatographed by HPLC using a solvent gradient from pure hexane to 5% ethyl acetate in hexane to afford the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(-c5ccccc5C(F)(F)F)c4)n3n2)cc(OC)c1OC
Temperature: 150 °C
Yield: 27.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (50 mg, 0.106 mmol), 2-trifluoromethylphenyl boronic acid (30.3 mg, 0.159 mmol), potassium carbonate (44.1 mg, 0.318 mmol), and Combiphos catalyst POPd1 ((dihydrogen di-κ-chlorotetrakis(di-tert-butylphosphinito-κP)dipalladate(2-)) (5.0 mg, 0.005 mmol) was added 1,4-dioxane (1.8 mL) and distilled water (0.2 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 150° C. for a total time of 1 hour. After cooling to room temperature, poured reaction mixture into dichloromethane (50 mL) and washed with distilled water (3×25 mL) and brine (1×25 mL). Dried over MgSO4, filtered and removed solent under reduced pressure to give a gold oil. Dissolved oil in dichloromethane and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (20:80 to 70:30) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[2′-(trifluoromethyl)-1,1′-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amine (0.0154 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.59 (d, J=7.90 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (dd, J=7.9, 7.1 Hz, 1H), 7.62 (dd, J=7.3, 7.5 Hz, 1H), 7.54 (dd, J=7.7, 7.9 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.05 (s, 2H), 3.67 (s, 6H), 3.61 (s, 3H), 2.51 (s, 3H). MS m/z 536 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1>ClCCl>[Cl:3][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]1[C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=[C:6]([CH3:5])[C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Yield: 86.8 %

Procedure:
Thionyl chloride (10.72 mL, 147 mmol) was added dropwise to a mixture of 5-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]pentan-1-ol (34.0 g, 98 mmol) and dichloromethane (250 mL). The reaction mixture was heated at reflux for 2 hours and then it was placed in an ice bath and quenched with water. The reaction mixture was concentrated under reduced pressure. The residue was combined with water (300 mL). Solid sodium bicarbonate was slowly added to pH 10; then the mixture was extracted with ethyl acetate (250 mL). The extract was washed sequentially with saturated sodium bicarbonate (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 30.96 g of N-(5-chloropentyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:31])[CH:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:19]([CH:21]=[CH2:22])[CH:20]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:31])[C:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:19]([CH:21]=[CH2:22])[CH:20]=1)=[CH2:11])[CH3:7]
Reactant: C=Cc1cc(CC(C(=O)O)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Agent: C=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=Cc1cc(CC(=C)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Diethylamine (0.85 ml, 8.80 mmol) was added dropwise to a mixture of 2-(6-tert-butoxycarbonylamino-5-vinyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (3.05 g, 8.37 mmol) and 37% aq. solution of formaldehyde (0.71 g, 8.80 mmol) in CH2Cl2 (2 ml) at 0° C. The mixture was stirred for 3 h at room temperature and then poured onto ice-water and extracted with dichloromethane. The organic layer was washed with 5% NaHCO3 and dried. Flash chromatography (1% methanol in CH2Cl2) yielded 2-(6-tert-butoxycarbonylamino-5-vinyl-pyridin-3-ylmethyl)- acrylic acid ethyl ester (1.70 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=1)[C:5]([OH:7])=O.Cl.[F:19][C:20]([F:32])([F:31])[CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=1)[C:5]([NH:30][CH2:29][C:26]1[CH:27]=[N:28][C:23]([O:22][CH2:21][C:20]([F:32])([F:19])[F:31])=[CH:24][CH:25]=1)=[O:7]
Reactant: Cc1cc(C(=O)O)cc(NC(=O)C(C)(C)C)n1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Cc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)cc(NC(=O)C(C)(C)C)n1

Procedure:
The title compound is prepared from 2-methyl-6-pivalamidoisonicotinic acid (30 mg, 0.06 mmol, Step-1) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (15 mg, 0.06 mmol) by the similar manner in Example 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=O)[C:20]3[CH:23]=[CH:24][C:25]([N+:27]([O-])=O)=[CH:26][C:19]=3[S:18]2(=O)=O)[CH2:9][CH2:8]1.Cl[Sn]Cl.O>Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2)[CH2:11][CH2:12]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc2c(c1)SN(CCCCN1CCN(c3ncccn3)CC1)C2
Reaction time: 0.5 h
Yield: 71 %

Procedure:
0.03 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-nitro-1,2-benzoisothiazol-3(2H)one 1,1-dioxide is dissolved in 50 ml of concentrated hydrochloric acid, and a solution of 0.13 mol of SnCl2.2 H2O in 100 ml of concentrated hydrochloric acid is added After the exothermic reaction is complete, the mixture is stirred for 30 minutes. The mixture is poured onto ice, filtered and the crystals are washed with water. After treatment with dilute sodium hydroxide solution, the base is extracted by shaking with methylene chloride, the solvent is evaporated off and the product is obtained as colourless crystals. Yield 71 % of theory; melting point: 150°-151° C.