Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:8]([NH2:7])[CH2:9][O:10][CH3:11])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:15]=2[CH:23]=1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester (419 mg, 1 mmol) in DCM (6 mL) was added TFA (3 mL) and the mixture was stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification: yellow oil (135 mg, 47%). LCMS (Method B): RT 1.71 min [M+H]+ 287.01.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:28]2[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: FCCNCC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A suspension of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU, 100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (40 mg), mp 138°-142° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[CH3:19])=[CH:5][C:4]=1[N+:20]([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[C:4]([NH2:20])[C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[C:11]([CH3:19])[CH:12]=1
Reactant: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(Oc2ccc(N)cc2C)cc1N

Procedure:
To a solution of N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (1.90 g, 6.27 mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added 10% Pd/C (0.342 g, 0.321 mmol). After shaking under 50 psi of hydrogen for 1 hour, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product as clear oil.
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.C([O-])(=O)C.[Na+:48]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:48]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate (13 g) was added and charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:35]([C:32]3[CH:33]=[CH:34][C:29]([N:28]([CH3:27])[CH3:37])=[CH:30][CH:31]=3)[CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNc1ccc(N(C)C)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(N(C)C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in dry dimethylformamide (75 ml) was cooled in an ice bath and oxalyl chloride (2.2 g, 0.0172 mole) was added dropwise, with stirring, under nitrogen. The reaction mixture was stirred at room temperature for 3.5 hours and then N,N,N'-trimethyl-1,4-benzenediamine (2.9 g, 0.0193 mole) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen overnight, poured into 400 ml of ice water and made basic with triethylamine (6 ml). The resulting white solid was collected by filtration, dissolved in hot isopropyl alcohol, treated with charcoal, and filtered while hot. Water was added to the cloud point an upon cooling, a solid precipitated. The gray solid was collected by filtration and rinsed with water to yield 6.6 g (92%) of product. A 1.0-g sample was dried under high vacuum to give 0.6 g of title compound, mp 152°-155° C.
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]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=2)=[CH:4][N:3]=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>>[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]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])[CH:33]=2)=[CH:4][N:3]=1
Reactant: CCNCC
Reactant: COc1cc(-c2csc3c(-c4cccc(C=O)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: CCN(CC)Cc1cccc(-c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)c1

Procedure:
The title compound was prepared using N-{4-[4-amino-7-(3-formylphenyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, N,N-diethylamine, and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.02 (d, 1H), 7.92 (s, 1H), 7.71 (d, 1H), 7.67 (s, 1H), 7.64 (m, 2H), 7.60 (s, 1H), 7.52 (m, 1H), 7.47 (t, 1H), 7.35 (m, 1H), 7.32 (m, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 7.12 (m, 1H), 5.62 (br, 2H), 4.05 (s, 3H), 3.92 (s, 3H), 3.62 (s, 2H), 2.53 (qt, 4H), 1.02 (t, 6H); MS: (MH)+ 590.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: Cc1ncccc1Oc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-3-phenoxy-pyridine (0.501 g, 2.70 mmol) (Butler, D E et al. J. Med. Chem 1981, 24, 346-350) in CH2Cl2 (2.7 mL) was added 3-chloroperoxybenzoic acid (0.698 g, 4.05 mmol) and the solution stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (30 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated to give 2-methyl-3-phenoxy-pyridine 1-oxide as a brown oil, which was used without further purification. 1H NMR (CDCl3) δ 2.54 (s, 3H), 6.77 (d, 1H), 6.97-7.06 (m, 3H), 7.16-7.21 (m, 1H), 7.34-7.41 (m, 2H), 8.11 (m, 1H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])[CH2:11][CH2:12][CH3:13].C(OCCOCCO)CCC>>[CH2:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: CCCCOCCOCCOCCO
Solvent: CCCCOCCOCCO
Product: CCCCCCCCOCCOCCOCCOCCCC

Procedure:
The procedure followed that of Reference Example 4, except for use of n-octyl bromide and triethylene glycol n-butyl ether instead of butyl bromide and diethylene glycol butyl ether, respectively. Triethylene glycol n-butyl n-octyl ether (abbreviated as “TEG-BO” hereafter) was obtained by distillation (b.p.: 140-145° C. at 70 Pa). TEG-BO has a corresponding boiling point of about 350° C. under normal pressure. The solubility of glycolide in this compound at 25° C. was 2.0%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]([F:15])([F:14])[F:13])[N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[NH:11][NH:10]1
Reactant: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of intermediate 64, 3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5 mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide (1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamide was removed in vacuo. The residue was extracted with CH2Cl2, washed with water, then dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, 1:1 CH2Cl2/pentane) to provide 140 mg (Yield 82%) of the title compound as a solid; 1H NMR (300 MHz, CDCl3) δ ppm: 4.80 (2 H, s) 7.09-7.21 (2 H, m) 7.32 (1 H, t, J=7.9 Hz) 7.41-7.49 (2 H, m) 7.66-7.71 (2 H, m) 7.81-7.85 (2 H, m); LC/MS m/z 346 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a stirring solution of 4-iodophenol (100 g, 0.5 mol) and K2CO3 (70 g, 0.5 mol) in DMF (400 mL) was added 1,4 dibromobutane (100 mL, 0.84 mol) over a period of 1 hr. The solution was stirred overnight at room temperature under Ar. H2O (1000 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer was then washed with 1000 mL of brine, dried over MgSO4, concentrated to gave a white solid (100 g); 1H NMR (CD3Cl): δ 2.15-1.87 (m, 6H), 3.50-3.20 (m, 4H), 3.94 (t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: S(O[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])(C1C=CC(C)=CC=1)(=O)=O.[S-:21][C:22]#[N:23].[K+]>CN(C)C=O>[S:21]([CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:16])=[O:17])[C:22]#[N:23]
Reactant: N#C[S-]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CSC#N)CS(N)(=O)=O
Yield: 21.7 %

Procedure:
A solution of 6.2 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide and 3.75 g of potassium thiocyanate in 30 ml of dimethylformamide was stirred at 130°-140° C. for 6 hours, and then concentrated to dryness. A mixture of dichloromethane and methanol (9:1) was added to the residue, followed by filtration to remove insoluble material. The filtrate was concentrated and the residue was subjected to a column chromatography, eluting with chloroform-ethyl acetate (2:1). The relevant fractions were concentrated to obtain 0.87 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide as yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:22]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:31])[C:8]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(c1ncccc1C)CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1c(C)ccc[n+]1[O-])CC(C)(C)O2
Yield: 26.3 %

Procedure:
101 mg of 6-acetyl-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 91 mg of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic extract was dried over sodium sulphate and evaporated to give an oil. This oil was triturated with t-butyl methyl ether to give a solid which, after recrystallization from ethyl acetate/t-butyl methyl ether, gave 28 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 154°-156° C.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=1>O1CCCC1>[C:2]1(=[CH:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C1CCCC1)c1cccnc1
Temperature: 5 °C
Reaction time: 1.33 h
Yield: 61.8 %

Procedure:
A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran (1000 ml) at 2° C. was treated with vigorous stirring under an atmosphere of argon, with potassium t-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5° C. for 80 minutes and then treated with pyridine-3-carbaldehyde (58.9 g, 0.55 mol) during a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then at 20° C. for 18 hours. The tetrahydrofuran was removed in vacuo (30° C.; 14 mmHg) and the residue extracted with pentane (2×500 ml). After treatment with decolourising charcoal (5 g), the mixture was filtered through a plug of flash silica gel (Merck 70-230 mesh; 13 cm×2 cm diameter). The filtrate was concentrated in vacuo (30° C., 14 mmHg; then 20° C., 0.01 mmHg) to afford 3-cyclopentylidenemethylpyridine (54 g, 0.34 mol) as an orange oil which was used without further purification;
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1I.Cl>CN1CCCC1=O>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[S:1][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[OH:13])[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(O)c(I)c1
Reactant: O=[N+]([O-])c1ccc(CO)c(S)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(O)c(Sc2cc([N+](=O)[O-])ccc2CO)c1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of 2-mercapto-4-nitrobenzyl alcohol 9.49 g, 18.86 mmoles), 4-hydroxy-3-iodo-benzoic acid (4.67 g, 17.69 mmoles), red cuprous oxide (1.35 g, 9.44 mmoles) and 1-methyl-2-pyrrolidinone (40 ml) was heated under a N2 atmosphere. The mixture became a thick slurry at 90° but at 130° had become a dark red solution. After 1/2 hour at 140° TLC showed that the reaction was finished. The mixture was poured onto 2N HCl (200 ml) and after stirring for a few minutes it was extracted 4× with EtOAc. The EtOAc extracts were washed with water, then extracted 4× with 1N NaOH. The aqueous extracts were washed once with EtOAc then acidified and the resulting solid filtered, washed with water and dried to yield 4.65 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH3:23])[CH:6]=[CH:5]2.[Se](=O)=[O:25]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:23]=[O:25])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C

Procedure:
6-Fluoro-2-methyl-8-(triisopropylsilyloxy)quinoline (1.76 g, 5.29 mmol) was dissolved in dioxane (58 mL) and water (0.49 mL). The reaction was treated with selenium dioxide (0.76 g, 6.8 mmol) and the mixture was heated to reflux for 13 hours. The mixture was cooled and filtered through GF/F paper. The filtered solids were washed with Et2O then all the filtrates were concentrated in vacuo. The crude mixture was chromatographed on silica gel, eluting with a gradient of 1-5% Et2O/hexanes, (0.515 g). 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 8.18 (d, J =8.7 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 1H), 7.06-7.00 (m, 1H), 1.52-1.41 (m, 3H), 1.16 (d, 18H).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([NH:7][C:8]2([C:21]([NH2:23])=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH:25](OCC)(OCC)OCC>>[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]2([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=3)[CH:25]=[N:23][C:21]2=[O:22])[CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)cc1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)cc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
4-(p-tolyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (1.62 g) was dissolved in 10 ml triethyl orthoformate and stirred at 150° C. for 15 hours. After cooling to room temperature, the reaction mixture was filtered and the light brown powder washed with ether to yield 8-benzyl-1-p-tolyl-1,3,8-triazaspiro[4,5]dec-2-en-4-one (0.99 g). M.p. 208-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.N1C=CC=CC=1.[O:27]=[P:28](Cl)([Cl:30])[Cl:29]>C(Cl)Cl>[CH2:11]([O:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][P:28]([Cl:30])([Cl:29])=[O:27])=[CH:3][C:4]=1[O:19][CH3:20])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(N)ccc1NC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NP(=O)(Cl)Cl)ccc1NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of benzyl N-(4-amino-2-methoxyphenyl)carbamate (IV; X=PhCH2OCONH, R1 =OCH3) (20 g, 73.5 mM) in CH2Cl2 (25 mL) was added over 5 min to a stirred, icecold, mixture of dry pyridine (25 mL) and POCl3 (100 mL), and the resulting mixture was stirred below 5° C. for a further 2 h. Precipitation with petroleum ether (500 mL) at -10° C. for 15 h gave crude solid product, which was isolated by decantation and washed with two portions of petroleum ether.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([NH:24][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)C1CCCC1
Product: Cc1nc(NC(=O)C2CCCC2)sc1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopentanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 38% yield; 1H NMR (CDCl3, 300 MHz) δ 9.56 (s, br, 1H), 7.35-7.24 (m, 5H), 5.92 (s, br, 1H), 4.56 (d, J=5.7 Hz, 2H), 2.81-2.69 (m, 1H), 2.62 (s, 3H), 1.97-1.72 (m, 8H); MS (ES+) m/z 344.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([N:20]3[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[N:21]3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[F:26][C:25]([F:28])([F:27])[C:24]1[N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2]([C:41]4[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=4)=[CH:3][CH:4]=3)[N:19]=2)[N:21]=[CH:22][C:23]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a flask containing the title compound from Example 2 Step A (40.0 mg, 0.073 mmol) were added 4-trifluoromethylphenyl boronic acid (21.0 mg, 0.110 mmol) and dichlorobis(triphenylphosphine)palladium(II) (2.6 mg, 0.004 mmol). Degassed acetonitrile (0.5 mL) and sodium carbonate (0.183 mL, 1.0 M aqueous, 0.183 mmol) were added, and the reaction mixture was stirred at 70° C. After 1.5 h, the reaction mixture was allowed to cool to ambient temperature, then was filtered through a short plug of silica gel, eluting with DCM. The Suzuki product was used in the subsequent step without further purification: LCMS m/z 612.2 [M+H]+.