Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=N[O:36][C:37]([N:41]([CH3:43])[CH3:42])=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:37]([N:41]1[CH2:42][CH2:13][N:12]([C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH2:8][CH2:43]1)=[O:36])[CH3:2]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 15.4 g (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 24.4 ml NEM and 15.6 g TOTU in 80 ml DMF 7.5 g piperazine-1-carboxylic acid ethyl ester were added at RT and stirred for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous LiCl (4 w/w) and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 23.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[S:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH2:28][CH2:29][S:25][CH2:26]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CSCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCSC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, thiazolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.51 minutes; C19H16Cl2N4O2S (435.33); mass spectrum: (M+H)+=435.1.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[F:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:1]([OH:2])[C@H:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)c2ccc(F)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate (67)(367.3 mg, 1.843 mmol) in THF (9.2 mL, 0.2 M) under nitrogen atmosphere cooled to 0° C. and degassed with N2 was added dropwise a THF solution of (3-chloro-4-fluorophenyl)magnesium bromide (4056 μL, 2.028 mmol) and the solution stirred at 0° C. for 3 h. The reaction was then quenched by addition of water (3 mL) THF was removed by rotovap, and the mixture was extracted with EtOAc (2×30 mL). The combined organics were washed with water (2×30 mL) and brine (1×30 mL). The organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by chromatography eluting a DCM/acetone gradient (2 to 45% acetone) to afford 364 mg (60%) of 69a/69b as an approximate 1:1 mixture of diastereomers as a clear oil which was used without additional purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([OH:31])([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([CH2:15]2)[CH:13]1[C:18]([NH2:20])=[O:19])=[O:11].[C:32]([O:36][C:37]([NH:39][CH:40]([CH:51]([CH3:53])[CH3:52])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](O)=[O:49])=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:32]([O:36][C:37](=[O:38])[NH:39][CH:40]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](=[O:49])[NH:8][CH:9]([CH:21]1[CH:22]2[CH2:23][CH:24]3[CH2:25][C:26]([OH:31])([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([CH2:15]2)[CH:13]1[C:18](=[O:19])[NH2:20])=[O:11])=[O:42])[CH:51]([CH3:53])[CH3:52])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)O
Reactant: NC(=O)C1C2CC2CN1C(=O)C(N)C1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC(C(=O)N1CC2CC2C1C(N)=O)C1C2CC3CC1CC(O)(C3)C2
Reaction time: 0.17 h

Procedure:
To the stirred solution 1.7 gm (0.00380 moles) of 3-[2-Amino-2-(5-hydroxy-adamantan-2-yl)-acetyl]-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid amide trifluoro acetic acid of formula 35 and 1.19 gm (0.00380 moles) of 1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (Formula 26) in THF was added into HoBT (0.6 gm) and DIPEA (1.3 ml) at room temperature and stirred for 10 minutes. To this stirred solution EDC.HCl (0.94 gm) and DIPEA (1.10 ml) were added at 0° C. and the reaction mixture was stirred over night at room temperature. THF was evaporated and residue was taken into EtOAC. The EtOAC layer was washed with 1N HCl and aq. NaHCO3 solution, dried and concentrated in vacuum to get crude product. The crude product was purified by silica gel column chromatography to get pure (1-{2-[2-(2-Carbamoyl-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(5-hydroxy-adamantan-2-yl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (Formula 36). (Yield: 1.7 gm)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH2:15])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9]2/[CH:10]([N:15]3[CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:12][CH2:13][CH2:14]/2)=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Cc1ccc(C=C2CCCCC2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(/C=C2\CCCCC2N2CCC2)cc1

Procedure:
A mixture of N-[2-[(4-methylphenyl)methylene]cyclohexyl]amine, from step C above, 0.64 g (3.2 mmol) with 1.28 g (6.4 mmol) of 1,3-dibromopropane and 0.88 g (6.4 mmol) of potassium carbonate in 20 ml of ethanol was refluxed 18 hr, evaporated and the residue was taken up in a water/diethyl ether mixture. The aqueous layer was separated and saturated with solid potassium hydroxide and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. The residue, 0.67 g, was chromatographed using a HPLC Merck C silica gel column using a 3% methanol in chloroform solution containing 0.5% ammonium hydroxide mixture as eluent. Elution with 620 ml of this eluting mixture gave mixtures of products containing the N-allyl derivative of the starting N-[2-[(4-methylphenyl)methylene]cyclohexyl]amine. Elution of the column contents with 5% methanol in chloroform containing 0.5% ammonium hydroxide (240 ml) gave no product. The next 540 ml gave 180 mg of (±)-(E)-1-[2-[(4-methylphenyl)methylene]cyclohexyl]-azetidine. GC analyses (3% SE 30) 100% at 4.99 min, UV λmax(ε)247(15,300). HR mass spectrum Found 241.1844, Calcd. for C17H23N 241.1830. The NMR spectrum was also consistent for this named product.
Reaction SMILES: C(S[CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])C.[Cl:48]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:48][CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]
Reactant: ClCl
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)OC1COCOC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=S)OC2COCOC2)C1Cl)OCc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1.25 h

Procedure:
A solution of 6.90 g of p-nitrobenzyl 2-(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-(1,3-dioxan-5-yl-oxythiocarbonyl)-acetate in 110 ml methylene chloride was cooled to -20° C. under a nitrogen atmosphere. A solution of chlorine in carbon tetrachloride (98 ml of 0.1M solution) was then added. The reaction mixture was stirred at -20° C. for 75 min., then allowed to warm to 0° C. and was washed successively with 75 ml saturated aqueous sodium bicarbonate solution (5° C.), 75 ml H2O (5° C.) and 75 ml saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo yielding 5.97 g of crude title compound. The NMR spectraum in deuterochloroform shows absorptions at 1.5 (d, 3H); 3.4 (m, 1H); 3.8-4.14 (c, 5H); 4.75 (s, 2H); 4.98-5.5 (c, 6 H); 5.8-6.2 (c, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.O.[C].[Pd]>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)NC1CCNC1
Yield: 97.9 %

Procedure:
To a solution of the above 3-acetylamino-1-benzylpyrrolidine (4.0 g) in ethanol (30 ml) was added 10% palladium-carbon (0.8 g) in water (1 ml). The mixture was shaken at room temperature for 22 hours under hydrogen pressure of 55 p.s.i. using Parr hydrogenator. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and dried over anydrous magnesium sulfate, followed by distilling off the solvent to give 3-acetylaminopyrrolidine (2.3 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][NH2:25]>>[ClH:1].[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)cc(-c3ccc(C)cc3)nc2c1
Reactant: NCC(O)CN
Product: COc1ccc2c(NCC(O)CN)cc(-c3ccc(C)cc3)nc2c1
Product: Cl

Procedure:
The title compound, MS: m/e=337 (M+), was prepared from 4-chloro-7-methoxy-2-p-tolyl-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: BrC1C=CC(C)=C([NH:8][C:9]([C:11]2[N:12]=[CH:13][N:14]3[C:19]=2C(=O)[N:17]2[CH:21]=[N:22][C:23]([C:24]([NH:26][C:27]4[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=4[CH3:34])=[O:25])=[C:16]2[C:15]3=[O:35])=O)C=1.[CH2:37]1COCC1.CC1N=C(N)NC=1C>CN(C=O)C>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([CH3:34])=[C:27]([NH:26][C:24]([C:23]2[N:22]=[CH:21][NH:17][C:16]=2[C:15]([NH:14][C:13]2[NH:8][C:9]([CH3:37])=[C:11]([CH3:19])[N:12]=2)=[O:35])=[O:25])[CH:32]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(Br)cc1NC(=O)c1ncn2c(=O)c3c(C(=O)Nc4cc(Br)ccc4C)ncn3c(=O)c12
Agent: Cc1nc(N)[nH]c1C
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc(C)c(C)[nH]1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
A dry round bottomed flask was charged with N1,N6-bis(5-bromo-2-methylphenyl)-5,10-dioxo-5,10-dihydrodiimidazo[1,5-a:1′,5′-d]pyrazine-1,6-dicarboxamide (490 mg, 0.8 mmol) and anhydrous THF (15 ml). To this suspension was added 4,5-dimethyl-1H-imidazol-2-amine (196 mg, 1.76 mmol) in anhydrous DMF (2 ml). The reaction mixture was then stirred at 53° C. for 16 hours. The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The crude material was treated with methanol and 1M hydrochloric acid. Saturated potassium carbonate solution was then added to neutralize the mixture. The resulting solid was filtered off, washed with 1M hydrochloric acid, saturated potassium carbonate solution and dichloromethane. Purification by reverse phase HPLC (aqueous ammonium acetate/acetonitrile) gave 32 mg of N4-(5-bromo-2-methylphenyl)-N5-(4,5-dimethyl-1H-imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): 7.97 (d, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 2.29 (s, 3H), 2.04 (s, 6H); MS (EI): 418.5 (MO.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.I[C:19]1[NH:23][C:22]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)=[N:21][C:20]=1[CH3:29].IC1NC(C)=NC=1C.[CH3:38][C:39]1[CH:48]=[C:47]([CH3:49])[C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][C:40]=1[C:41]([O:43]C)=[O:42].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH3:38][C:39]1[CH:48]=[C:47]([CH3:49])[C:46]([C:19]2[NH:23][C:22]([CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)=[N:21][C:20]=2[CH3:29])=[CH:45][C:40]=1[C:41]([OH:43])=[O:42]
Reactant: Cc1nc(C2CCOC2)[nH]c1I
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3CCOC3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole (compound 171.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:36]=[C:37]([N:43]1[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]1)[C:38](OCC)=[O:39])C>O>[F:11][C:12]1([F:16])[CH2:15][N:14]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:38](=[O:39])[C:37]([N:43]4[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]4)=[CH:36][NH:9]3)[CH:7]=2)[CH2:13]1
Reactant: NNc1cc(Cl)ncn1
Reactant: FC1(F)CNC1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CC(F)(F)C4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 120 mg (0.8 mmol) of the compound from Example 11A, 129 mg (1.0 mmol) of 3,3-difluoroazetidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 32 μl (47 mg, 0.4 mmol) of trifluoroacetic acid and 194 mg (0.8 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 32 mg (11% of theory)
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#N)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.S(=O)(=O)(O)[OH:15].[OH2:19]>[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]([OH:15])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(-n2ccnn2)cc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-n2ccnn2)cc1
Yield: 81 %

Procedure:
4-(1H-1,2,3-triazol-1-yl)benzonitrile (200 mg, 1.175 mmol, prepared as described in WO 2006/067462 PCT/GB2005/005007 Page 57) in sulfuric acid (3 mL, 0.00 μmol)(50%, 3 ml) was refluxed at 120° C. for 4 h. Cooled down, diluted with water and adjusted pH to 4 with NaOH and Na2CO3, then extracted with ethyl acetate. After the solvent was removed, a white solid was obtained 4-(1H-1,2,3-triazol-1-yl)benzoic acid (180 mg, 0.952 mmol, 81% yield). 1H-NMR (DMSO-d6, 500 MHz): δ8.80 (1H, s), 8.13 (2H, d, J=8.55 Hz), 8.01 (2H, d, J=8.55 Hz), 7.98 (1H, s).
Reaction SMILES: N1C=CC=C[C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]N=1)=[O:8].[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].CC([O-])(C)C.[K+].CO>C1COCC1>[C:7]([OH:17])(=[O:8])/[CH:9]=[CH:14]/[CH2:13][CH2:12][CH3:11].[C:16]([OH:18])(=[O:17])/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH3:2]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC/C=C/C(=O)O
Product: CCC/C=C\C(=O)O
Yield: 88.6 %

Procedure:
Prepared as above from 150.0 mg (0.35 mmol) of the pyridyl ketone, 308.2 mg (0.70 mmol) of (4-carboxybutyl)triphenylphosphonium bromide, and 1.4 mL (1.4 mmol) of 1.0 M t-BuOK in 1.5 mL of THF at 0° C. for 1.5 hr. Flash chromatography followed by preparative HPLC with MeOH--AcOH--CH2Cl2 (3.5:1.5:95) furnished 107.9 mg 60.2%) of (E)-hexenoic acid and 35.4 mg (19.8%) of (Z)-hexenoic acid (E/Z=3:1). The title (E)-isomer was characterized as follows: mp 86-90° C.; 1H NMR (CDCl3) δ 8.55 (br s, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.21 (m, 1H), 7.12 (distorted t, J=~5.1 Hz, 1H), 6.19 (t, J=7.5 Hz, 1H), 3.44 (dt, J=7.0, 6.7, Hz, 2H), 2.34 (t J=7.1 Hz, 2H), 2.25 (dt, J=7.4, 7.3 Hz, 2H), 1.68-0.82 (m, 19H); FDMS 516 (M+1). Anal. (C31H37N3O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[C:5]([CH3:12])[CH:4]=1.[CH3:13][N:14]([CH:16](OC)OC)[CH3:15].C(Cl)Cl.CO.C([O-])(=O)C.[NH4+:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:16]([N:14]([CH3:15])[CH3:13])=[NH:30])=[O:8])=[C:5]([CH3:12])[CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(C(N)=O)c(C)c1
Reactant: COC(OC)N(C)C
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(=N)N(C)C)c(C)c1
Temperature: 25 °C

Procedure:
1G (296.15 g, 1.794 mol) was dissolved in THF (1.5 L) in a flask equipped with a mechanical stirrer and distillation head to give a thick slurry. DMF-DMA (263 mL, 1.1 eq) was added in one portion and slowly heated to gentle reflux. After 30 min at reflux, the reaction mixture became a homogeneous solution. The reaction was maintained at reflux for 1.5 h, and checked by HPLC and TLC (10:1 CH2Cl2/MeOH). At atmospheric pressure, 1150 mL THF was distilled out and replaced with 1500 mL heptane (Note that if the solution is not quite saturated, remaining THF should be removed by distillation). The remaining solution was cooled slowly to rt overnight with stirring, seeded at 68° C. Rapid crystallization was observed. The resulting slurry was cooled to 0° C., filtered and washed with heptanes (500 mL) and dried under vacuum at rt for 48 h. 384.6 g (97.4%) of 1H was isolated as a light tan crystalline solid. HPLC-MS using a neutral buffer ammonium acetate buffer system showed only a single peak, with the expected mass.
Reaction SMILES: [NH2:1][C@@:2]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:19][CH:18]=1)([C:13]([F:16])([F:15])[F:14])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.[N:46]1[N:47](CC(O)=O)[N:48]=[N:49][CH:50]=1.C1C[O:58][CH2:57][CH2:56]1>>[NH:46]1[C:50]([CH2:56][C:57]([NH:1][C:2]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:19][CH:18]=2)([CH2:3][C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[C:13]([F:16])([F:15])[F:14])=[O:58])=[N:49][N:48]=[N:47]1
Reactant: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: O=C(O)Cn1ncnn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1ccc(C(=O)CC(NC(=O)Cc2nnn[nH]2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a solution of Intermediate 2F (789 mg, 1.82 mmol) in anhydrous THF (9 ml) at 0° C. was added DCC (1.13 g, 5.46 mmol). 2-Tetrazole acetic acid (700 mg, 5.46 mmol) was added dropwise as a suspension in anhydrous THF (8 mL). The reaction was stirred at 0° C. for 1 h and then at rt overnight. The reaction was filtered and solids were rinsed with THF. The filtrate was diluted with EtOAc (40 mL), washed with sat'd Na2CO3 and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide Intermediate 2G (1.5 g, 152%) as a reddish brown solid. Intermediate 2G. was used in the next step without further purification. LCMS Anal. Calc'd for C24H23F6N5O3 543.46, found [M+H] 543.9.
Reaction SMILES: [C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:19]1[CH2:24][CH2:23][CH:22]=[CH:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=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:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:22]3[CH2:23][CH2:24][O:19][C:20](=[O:25])[CH2:21]3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1C=CCCO1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(C3CCOC(=O)C3)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0 g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1 g), tetrakis(triphenylphosphine)palladium(0) and triethylamine (2.2 g) in dimethylformamide (5 ml) was stirred at about 95° C. in a sealed vessel under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the layers separated, and the organic layer washed with sodium bicarbonate solution, then dried, and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v) to give the title compound as a brown oil, 1.2 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[S:7]([O:10]S(C(F)(F)F)(=O)=O)(=[O:9])=[O:8].FC(F)(F)S([O-])(=O)=O.O=[N+]=O.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([F:55])([F:54])[S+:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:43]2[CH:50]=[CH:51][CH:52]=[CH:53][C:42]1=2>[N+](C)([O-])=O>[F:5][C:6]([F:19])([F:18])[S:7]([O-:10])(=[O:9])=[O:8].[N+:1]([C:51]1[CH:52]=[CH:53][C:42]2[S+:41]([C:40]([F:54])([F:39])[F:55])[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[C:43]=2[CH:50]=1)([O-:4])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=[N+]=O
Solvent: C[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc2c(c1)c1ccccc1[s+]2C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
A mixture of 0.058 ml (1.3 mmol) of 94% nitric acid and 0.266 ml (1.58 mmol) of trifluoromethanesulfonic anhydride was stirred at room temperature for 1.5 hours to prepare nitronium trifluoromethanesulfonate, and then 2 ml of nitromethane and 502 mg (1 mmol) of S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate was added to the mixture. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration to give 339 mg (76%) of 2-nitro-S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate as pale yellow crystals. The properties of the product are summarized in Table 1.