Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][CH2:7][C:8]1[C:9]([CH3:53])=[N:10][C:11]([CH3:52])=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)=[CH:18][CH:17]=1>ClCCl>[CH3:53][C:9]1[C:8]([CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[CH:12]=[C:11]([CH3:52])[N:10]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CN)c(C)n1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCc1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(Example 51A): A solution of ethyl isocyanate (71 mg) and 3-aminomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (628 mg) in dichloromethane (15 ml) was left to stand for 2 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (7:93 v/v), to give 2,6-dimethyl-3-(ethylaminocarbonylamino)methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (602 mg), as a foam: NMR (CDCl3): 1.0(t,3H), 2.5(s,3H), 2.65(s,3H), 3.0-3.1(m,2H), 4.1(br t, 1H), 4.4(d,2H), 4.5(br d, 1H), 5.0(s,2H), 6.6(s,1H), 6.8-7.0(m,6H), 7.1-7.55 (complex m,16H), 7.9(dd,1H).
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13]>>[CH3:10][N:11]([CH3:15])[C:12]([O:2][N:1]=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)=[O:13]
Reactant: CC1=NCCSC1=NO
Reactant: CN(C)C(=O)Cl
Product: CC1=NCCSC1=NOC(=O)N(C)C

Procedure:
2-Oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime is reacted with dimethylcarbamoyl chloride as described in Example 2 to yield 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine O-(dimethylcarbamoyl) oxime, m.p. 64°-65° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:18](=[N:5][CH2:4][C:3]1[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[C:9]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)c1cc(CN)c(O)c(C(C)(C)C)c1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc(CN=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxy-3,5,di-t-butylbenzylamine (prepared by the procedure described by G. E. Stokker, et al.; J. Med. Chem. 1980, 23, 1414; 2.35 g, 10.0 mmol) is prepared in 50 mL methanol. Benzaldehyde (1.06 g, 10.0 mmol) is added, and the resulting solution is stirred for 30 minutes. Product crystallizes upon cooling the solution to −40° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)=[O:13]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC)CC1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of methyl 7-bromo-1-methoxycarbonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), 4-morpholinophenyl borate (0.22 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7](Cl)=[O:8])[CH2:4][CH2:3]1.[CH2:10]([Mg]Br)[CH3:11]>C1COCC1>[C:7]([C@H:5]1[O:6][C:2](=[O:1])[CH2:3][CH2:4]1)(=[O:8])[CH2:10][CH3:11]
Reactant: CC[Mg]Br
Reactant: O=C1CC[C@@H](C(=O)Cl)O1
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1CCC(=O)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of (2S)-5-oxotetrahydrofuran-2-carbonyl chloride (compound 28b, 70 g, 473 mmol) in dry THF (400 mL) was added ethylmagnesium bromide (173 mL, 520 mmol, 3M in THF) slowly at −78° C. under N2. After addition, the reaction mixture was stirred at −78° C. for another 2 hours. The mixture was then quenched with saturated NH4Cl solution and extracted with EtOAc (500 mL) twice. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:7 to 1:3 EtOAc in petroleum ether) to afford 35 g of (5S)-5-propanoyltetrahydrofuran-2-one (compound 28c) as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[OH-].[Na+]>O1CCCC1>[CH3:2][N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[CH:18][C:14]2=[CH:15][CH:16]=[CH:17][N:13]12
Reactant: CN(c1ccncc1[N+](=O)[O-])n1cccc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1c2ccncc2N=Cc2cccn21
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To cold, concentrated hydrochloric acid (200 ml) was added, in the following order, 100 g of stannous chloride dihydrate, 200 ml of tetrahydrofuran, and a solution of 28 g of 1-[N-methyl-N-(3-nitro-4-pyridinyl)amino]pyrrole-2-carboxaldehyde in 150 ml of tetrahydrofuran. Upon completion of the 1-[N-methyl-N-(3-nitro-4-pyridinyl)amino]pyrrole-2-carboxaldehyde addition, the reaction was poured into an aqueous solution of sodium hydroxide (200 g in 1 liter of water), stirred for five minutes, and then extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resultant oil was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to afford 10 g (38%) of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine as an oil, IR(CHCl3) C=N @ 1610 cm-1 ; MS(EI) M+ @ 199(100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C>C1(C)C=CC=CC=1.[Cu].O>[N+:8]([C:4]1[CH:3]=[C:2]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Temperature: 200 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
An intimate mixture of 1-iodo-3-nitrobenzene (24.9 g, 0.1 mol), copper bronze (320 mg, 5 mmol), potassium carbonate (15.2 g, 0.11 mol) and imidazole (15.0 g, 0.22 mol) was heated under a stream of nitrogen at 200° C. for 90 minutes. The reaction was cooled to 100° C., carefully treated with water (750 ml) and the resulting suspension stirred to ambient temperature over 16 hours. Filtration gave a grey-coloured solid which was dissolved in hot toluene (125 ml) and treated with decolourising charcoal (2 g). Filtration and cooling afforded 1-(3-nitrophenyl)-1H-imidazole as pale green needles (13.5 g, 71%). δH (360 MHz, CDCl3) 7.29 (1H, br s), 7.38 (1H, br s), 7.68-7.78 (2H, m), 7.97 (1H, br s), 8.23-8.29 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]=[N+:29]=[N-:30])[C@H:25](OC)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]=[N+:29]=[N-:30])[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CO[C@@H]1O[C@H](COC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: [N-]=[N+]=N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (730 mg, 3.97 mmol) in ACN (15 mL) was added BSA (2.8 mg, 13.8 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, [(2S,4R,5R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]methyl benzoate (compound 33a, crude, 1.1 g, 3.97 mmol) and TMSOTf (4.4 g, 19.5 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 500 mg crude product of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]methyl benzoate (compound 33b) as a yellow solid. MS obsd. (ESI+) [(M+H)+]: 430.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[O:30]>C(#N)C>[Br-:27].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Solvent: CC#N
Product: Cc1ccc(C(=O)C[N+]23CCC(CC2)C(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (95 mg, 0.27 mmol, prepared as in example 4) and 2-bromo-1-p-tolylethanone (62.3 mg, 0.29 mmol) were dissolved in acetonitrile (10 ml) and stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O/EtOAc (1/1) and recovered by suction filtration to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-1-(2-oxo-2-p-tolylethyl)-1-azoniabicyclo[2.2.2]octane bromide (117.6 mg, racemic mixture).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[C:27]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CN(C)c1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-(dimethylamino)phenyl boronic acid according to the procedure described in example 21. MS m/z 280; HRMS: calcd for C19H21NO+H+, 280.16959; found (ESI, [M+H]+), 280.1689.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17]C)=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.B(Br)(Br)[Br:20]>ClCCl>[BrH:20].[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(N)cc(C)cc1-c1ccc(C(=O)O)o1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Cc1cc(N)c(O)c(-c2ccc(C(=O)O)o2)c1
Yield: 54.7 %

Procedure:
5-(3-Amino-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46b (248 mg, 1 mmol) was dissolved in 20 mL of dichloromethane followed by dropwise addition of a solution of boron tribromide in dichloromethane (3 mL, 1 mmol/L). The reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure. The resulting residue was washed with ethyl acetate (50 mL×3) and dried to obtain the title compound 5-(3-amino-2-hydroxy-5-methyl-phenyl)-furan-2-carboxylic acid hydrobromide 46c (172 mg, yield 54.7%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15]2)[CH2:10][CH2:9]1.CCN(CC)CC.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:36]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCN(C2CCNCC2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(C2CCN(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 25.9 %

Procedure:
(RS)-4-(1-Piperidin-4-yl-pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid (53.8 mg, 0.1 mmol), Et3N (50.5 mg, 0.5 mmol), phenylboronic acid (36.6 mg, 0.3 mmol) and copper(II) acetate (36 mg, 0.2 mmol) were suspensed in CH2Cl2 (2 ml). After 3.5 hours stirring at room temperature, the reaction mixture was directly chromatographed over silica gel (CH2Cl2—MeOH 98:2 then 95:5) to provide (RS)-4-[1-(1-phenyl-piperidin-4-yl)-pyrrolidine-3-sulfonyl]-phenol (10 mg, 26%) as a white foam, MS: m/e=387.3 (M+H+).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH3:19]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO>[C:6]([O:8][CH2:9][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:1][CH2:2][CH2:3][CH3:4])=[O:12])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCO
Agent: [Ti]
Solvent: CO
Solvent: CCCCO
Product: CCCCCOC(=O)c1ccc(C(=O)OCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A 2-liter multineck flask with distillation bridge and reflux divider, 20 cm packed column, stirrer, dip tube, dropping funnel, and thermometer was charged with 679 g (3.5 mol) of dimethyl terephthalate (Oxxynova), 1.7 g of tetrabutyl orthotitanate (0.25% by mass based on DMT, DuPont, Tyzor TnBT) and, to start with, 200 g out of a total of 748 g (8.5 mol) of n-pentanol (>99% purity, FLUKA), and this initial charge was heated slowly until the DMT forms a homogeneous mixture with the alcohol, at which point the stirrer was switched on. The reflux divider was set so that the overhead temperature remained at a constant level of approximately 65° C. (the boiling point of methanol). From a liquid-phase temperature of approximately 185° C., the remaining alcohol was slowly run in at a rate such that the temperature in the flask did not fall below 180° C. and a reflux sufficient for the distillation was maintained. The distillate removed was analyzed by GC for the amount of methanol separated off. After a major fraction of the methanol (approximately 90% of the anticipated 7 mol of methanol) had been taken off, a sample was taken from the reaction flask every 30 minutes and analyzed by GC. Transesterification was at an end when the amount of dimethyl ester and mixed ester(methyl pentyl) in total had dropped below 0.3% by mass (approximately 8 to 9 hours).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[N:46]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34](=[O:36])[NH:54][CH2:53][CH2:52][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:4][N:3]=1
Reactant: NCCN1CCCCC1
Reactant: COc1cc(-c2csc3c(/C=C/C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(/C=C/C(=O)NCCN4CCCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A mixture of Example 271 (30.6 mg, 0.044 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), 2-piperidin-1-ylethylamine (14.3 μL, 0.10 mmol), and DMF (1 mL) was treated sequentially with 0.5M (0.09 mL) of HBTU in DMF and 0.5M (0.09 mL) of HOBT in DMF. The reaction was stirred for 24 hours at ambient temperature and partitioned between 1N NaOH and ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (20.4 mg, 0.034 mmol). LCMS m/e 609.2; retention time: 2.93 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
4-[5-(4-Fluoro-phenyl)-3-methyl-3H-imidazol-4-yl]-pyridin-2-ylamine (13 mg, 0.048 mmol) and benzoyl isocynate (8.6 mg, 0.058 mmol) are mixed in DCM (0.5 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (0.5 mL) and potassium carbonate (10 mg, 0.073 mmol). The mixture is then heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is recrystallized in DCM to give 15 mg of the titled product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=O)[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)C.O1CCCC1.[OH:31][CH:32]([C:37]1[CH:38]=[CH:39][C:40]([CH:43]=O)=[N:41][CH:42]=1)[C:33]([OH:36])([CH3:35])[CH3:34].C([N:47](CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[CH3:34][C:33]([OH:36])([CH3:35])[CH:32]([C:37]1[CH:42]=[N:41][C:40]([C:43]2[NH:47][C:12]([CH:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:14]=2)=[CH:39][CH:38]=1)[OH:31]
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(O)C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)nc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.79 g) in a mixed solvent of ethanol (30 mL) and tetrahydrofuran (30 mL) was deaerated, and 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (1.52 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (150 mg) and triethylamine (0.310 mL) were added. The reaction solution was purged with nitrogen, and the mixture was stirred at 70° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in acetic acid (150 mL) was added ammonium acetate (4.28 g), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) to give the title compound (1.79 g, yield 65%) as a colorless amorphous solid. MS: 499 (MH+).
Reaction SMILES: C(OC([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[OH:21])=O)C.N(O[CH2:25]CC(C)C)=O>C(O)(C(F)(F)F)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:25])=[CH:6][S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)c1sc2c(c1O)CCN(C(=O)OCC)CC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCc2scc(OC)c2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step b) (256 mg, 0.69 mmol) was stirred in TFA (2 mL) for 30 minutes. The reaction was concentrated and dissolved in EtOH (5 mL). Isoamyl nitrite (140 μL, 1.04 mmol) and Cu(OAc)2 (188 mg, 1.04 mmol) were added to the solution and the reaction was stirred at room temperature overnight. The reaction was filtered through a silica plug and purified by silica gel chromatography (EtOAc/Hex-gradient) to give 17 mg of the subtitle compound. MS: ESI (positive): 271 (M+H).