Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH:35]([C:37]([O:39]CC)=[O:38])[CH3:36])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:51])([F:50])[F:52])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH:35]([C:37]([OH:39])=[O:38])[CH3:36])[CH2:31][CH2:30]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1
Reactant: CCOC(=O)C(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 2.4 mg (0.10 mmol) LiOH in 0.8 mL water was added to 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(1-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture was shaken for 2 h at RT and for 4 h at 50° C. It was then purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].N1CCCCC1>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]2[S:12][C:13](=[O:18])[NH:14][C:15]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Yield: 59.2 %

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g), 1,3-thiazolidine-2,4-dione (11.70 g), piperidine (1.70 g) and ethanol (300 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated. The obtained residue was washed with ethanol to give 5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione as yellow crystals (14.8 g, yield 59%). Recrystallization thereof from acetone-hexane gave pale-yellow prism crystals. melting point: 272-273° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:11]([CH3:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:21][N:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:14]=[C:10]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cn1cc(-c2ccccc2)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cn1cc(-c2ccccc2)nc1Nc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A slurry of 4-aminophenol (0.227 g, 2.08 mmol), 2-chloro-1-methyl-4-phenyl-1H-imidazole (0.400 g, 2.08 mmol), and p-toluenesulfonic acid monohydrate (0.395 g, 2.08 mmol) was heated in 2.5 mL 2-BuOH in a sealed tube to about 110° C. for 24 h. The temperature was increased to about 120° C. and the solution was heated for 24 h. The reaction was cooled and partitioned between 50 mL pH7 buffer and DCM. The aqueous layer was extracted with DCM (3×), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting brown oil was purified by silica gel chromatography (0-100% 90/10 DCM/MeOH in DCM) to give 4-(1-methyl-4-phenyl-1H-imidazol-2-ylamino)phenol as a tan solid. MS m/z=266 [M+H]+. Calc'd for C16H15N3O: 265.3.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:32])[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[NH:23][C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][CH:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)[CH2:30][CH2:31]1
Reactant: c1ccc2c(c1)CC(OCC1CO1)C2
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reaction time: 24 h

Procedure:
To a solution of 6 (0.43 g, 2.3 mmol) in ethanol(4 ml) was added 5 (0.405 g, 1.64 mmol). The solution was heated to reflux and stirred for 24 h. Upon completion the solution was concentrated in vacuo and purified using Prep TLC (10:1, DCM:MeOH) to yield 7. Mass Spectrum (M+1)=438.36.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.P(Br)(Br)[Br:15].P(Br)(Br)(Br)=O.[OH-].[Na+]>>[Br:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=[C:2]([NH2:1])[CH:11]=1
Reactant: Nc1cc(O)c2cc(Cl)ccc2n1
Reactant: BrP(Br)Br
Agent: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)c2cc(Cl)ccc2n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
2-Amino-6-chloro-4-hydroxyquinoline (CAS 64319-84-2, 6.0 g, 31 mmol) were added portionswise to phosphorus tribromide (25 g, 92 mmol). Phosphorus oxybromide (10 g, 37 mmol) were added and the mixture was stirred at 150° C. for 16 h. The mixture was poured into 300 mL ice water and the pH was adjusted to 11 by addition of 32% sodium hydroxide solution. The solid was filtered off and washed with water and cyclohexane. 4-Bromo-6-chloro-quinolin-2-ylamine was obtained as a yellow solid (7.8 g, 98%), MS: m/e=258.9 (M+H+).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31].C(=O)([O-])O.[Na+]>COC(C)(C)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([CH:32]2[CH2:37][CH2:36][C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33]2)=[CH:26][C:25]=1[F:24]
Reactant: O=C1CCC(c2ccc(F)c(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=C1CCC(c2ccc(F)c(F)c2)CC1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
4.1 g of potassium t-butylate were added in an inert gas atmosphere to a suspension of 12.2 g of dry methoxymethyltriphenylphosphonium chloride in 125 ml of t-butyl methyl ether and the orange-red suspension was stirred for 30 minutes. A solution of 5.00 g of 4-(3,4-difluorophenyl)cyclohexanone in 75 ml of t-butyl methyl ether was added dropwise at 0°-5° C. within 1 hour. The reaction mixture was stirred at 0°-5° C. for a further 1 hour and at room temperature for 2.5 hours and then treated with 50 ml of saturated sodium hydrogen carbonate solution. The organic phase was washed with water and concentrated. The residue was taken up in 200 ml of hexane and 100 ml of 80 percent aqueous methanol. The hexane phase was washed with two 40 ml portions of 80 percent methanol, dried over sodium sulphate and concentrated. There were obtained 5.6 g of 1,2-difluoro-4-[ 4-(methoxymethylidene)cyclohexyl]benzene.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C@@H:35]1[NH:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH3:34][C@@H:35]1[N:40]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:39][CH2:38][NH:37][C:36]1=[O:41]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: C[C@@H]1NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 130 °C

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with (S)-3-methylpiperazin-2-one (21.59 mg, 0.189 mmol, Fluka, St. Louis, Mo.) potassium carbonate (78 mg, 0.568 mmol, Sigma-Aldrich, St. Louis, Mo., St. Louis, Mo.) and acetonitrile (1.26 mL). This mixture was heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by silica gel chromatography (10-100% EtOAc in hexanes) and then by reverse-phase HPLC purification (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give (3S)-3-methyl-4-(((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)-2-piperazinone as a mixture of two diastereomers.
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:26](C(OC(C)(C)C)=O)=[N:27]C(OC(C)(C)C)=O.[ClH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCCC1.O>[ClH:42].[ClH:42].[CH:1]1([NH:26][NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: OC1CCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NNC1CCCC1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
Cyclopentanol (6.127 kg, 71.1 moles) and triphenylphosphine (18.667 kg, 71.25 moles) were dissolved in tetrahydrofuran (40 gal) in a clean and dry, nitrogen purged 100 gallon tank and the reaction mixture was cooled to 5° C. A solution of di-t-butyl azodicarboxylate (14.9 kg, 64.7 moles) in tetrahydrofuran (36 L) was added over about 2 hours keeping the temperature <6° C. The reaction was allowed to stir for 5 hours as the temperature was allowed to slowly increase to 20-25° C. 6N HCl (26.5 L) was added to the reaction which was at 20° C. The reaction was allowed to stir 24 hours at 20-25° C. at which point the starting material had reacted. Water (10 gal, 37.85 L) was added and the tetrahydrofuran was removed by vacuum distillation. During the concentration, triphenylphosphine oxide precipitated and an additional 20 gal (75.7 L) of water was added. The reaction was cooled and methylene chloride (30 gal, 113.6 L) was added. The layers were separated and the aqueous was extracted twice more with methylene chloride (10 gal, 37.85 L) The aqueous was distilled to remove water. As the volume was reduced, isopropanol (3×20 gal (75.7 L)) was added to azeotrope the residual water. The resulting slurry was filtered and the solids were vacuum oven dried to give 7.682 kg (68.6% of theoretical) over multiple crops. This material was characterized to be the dihydrochloride salt; mp 189-194° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl[C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=1.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23]>C(COC)OC.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>[CH:22]([C:25]1[CH:30]=[C:29]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CCCc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: CC(C)c1cccc(B(O)O)c1
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: COCCOC
Solvent: O
Product: CCCc1cc(-c2cccc(C(C)C)c2)nc(S(C)(=O)=O)n1
Yield: 23.9 %

Procedure:
Potassium carbonate (0.850 g, 6 mmol), water (1 ml) and tetrakis(triphenylphosphine)palladium (0.695 g, 0.6 mmol) were successively added under a nitrogen atmosphere, to a mixture of 4-chloro-2-methanesulfonyl-6-propyl-pyrimidine (1.17 g, 5 mmol) and 3-isopropyl-phenylboronic acid (0.984 g, 6 mmol) in dimethoxyethane (40 mL). The mixture was refluxed for 18 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 7/3) to afford a yellow oil which crystallised in pentane. After filtration, 4-(3-isopropyl-phenyl)-2-methanesulfonyl-6-propyl-pyrimidine (0.380 g) was obtained as an off white solid (mp=82° C.).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:24][CH3:25].C(OCC)(=O)C>O1CCCC1>[CH3:25][N:24]1[C:15]2[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:22]=[CH:23][C:14]=2[NH:13][C:1]1=[O:2]
Reactant: CNc1cc(C(=O)OC)ccc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Add carbonyl diimidazole (567 mg, 3.50 mmol) to a solution of methyl 4-amino-3-(methylamino)benzoate (586 mg. 3.19 mmol) in tetrahydrofuran (20 mL) at room temperature. Stir the yellow solution at room temperature for 16 hours. Add carbonyl diimidazole (500 mg, 0.96). Stir at room temperature for 4 hours. Add ethyl acetate (75 mL). Wash with 10% citric acid (5 mL), 1N sodium hydroxide (5 mL), and brine (5 mL). Dry the organics over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield a crude yellow solid (690 mg, 100%). Triturate this crude solid with ethyl acetate (10 mL). Filter the precipitate and dry under high vacuum to yield methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (422 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.46 (s, 3H), 3.92 (s, 3H), 7.12 (d, J=8.21 Hz, 1H), 7.68 (s, 1H), 7.84 (dd, J=8.31, 1.47 Hz, 1H), 9.87-10.03 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:14][C@@H:13]([CH2:15][OH:16])[C:12]([CH3:18])([CH3:17])[CH2:11][O:10]2)=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:16][CH2:15][C@H:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][O:10][C@@H:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:14]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc([C@@H]2OCC(C)(C)[C@H](CO)O2)cc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2OCC(C)(C)[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound obtained in Step B (3.59 g, 14.24 mmol) and TEA (1.98 ml, 14.24 mmol) in DCM (50 ml), 4-Nitrobenzoyl chloride (2.64 g, 14.24 mmol) was added and the reaction was stirred overnight at r.t. The organic phase was washed with a solution of NaH2PO4 5% and brine, dried (MgSO4) and evaporated under reduced pressure. The crude was crystallized from EtOAc at 0° C. adding n-hexane. The product was obtained as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)(=O)=O.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:28]([NH:35][C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1nccc2nc(NCc3ccccc3)c3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate (127 mg, 0.253 mmol) in THF (2531 μl), benzylamine (111 μl, 1.013 mmol) was added. The reaction mixture was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. Aqueous sodium hydrogen carbonate (saturated) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford N-benzyl-1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-amine as a brown oil. LRMS (APCI) calc'd for (C22H23N4O) [M+H]+, 359.2; found 359.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CC(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.10 g, 0.28 mmol) and triethylamine (0.1 mL, 0.66 mmol) were combined in CH2Cl2 (2 mL). Isovaleryl chloride (0.04 mL, 0.33 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([O-:29])=O)[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:91](=[O:92])[N:60]2[C:61]([C:75]([O:77]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:76])=[C:62](/[CH:65]=[C:66]3/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/3)[CH2:63][S:64][C@H:59]12>CN(C=O)C.C(OCC)(=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([NH:57][C@@H:58]2[C:91](=[O:92])[N:60]3[C:61]([C:75]([OH:77])=[O:76])=[C:62](/[CH:65]=[C:66]4/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/4)[CH2:63][S:64][C@H:59]23)=[O:29])[N:25]=1
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium 2-(2-tritylaminothiazol-4-yl)-2-Z-trityloxyiminoacetate (0.759 g), in dry DMF (5 mls) was cooled to ca -50° C. under argon. This solution was treated with methanesulphonyl chloride (0.085 mls) and allowed to warm to -15° C. A solution of diphenylmethyl 7β-amino-3-(Z-2,5-dihydro-4-methoxy-3-methyl-2-oxofuran-5-ylidenemethyl)ceph-3-em-4-carboxylate, (0.46 g) in dry DMF (5 mls) was added, and the solution allowed to reach room temperature over 1 h. The solution was diluted with ethl acetate and washed with water, brine and then dried. After removal of solvent the residue was flash chromatographed on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow foam, (0.375 g, 36%), νmax 3380, 1770(br), 1725, 1685, 1630, 1505(br), 1440, 1370 and 1345cm-1 ; δH (CDCl3) 2.07 (3H,s), 3.74 and 3.96 (2H,ABq, J18.3Hz, sharpens on D2O shake), 5.08 (1H, m, sharpens to d, J5.0Hz on D2O shake), 6.12 (1H, br.m, sharpens to d, J5.0Hz on D2O shake), 6.43 (1H, br.s, sharpens on D2O shake), 6.74 (1H, s), 6.78 (1H, br.s, exch.), 6.98 (1H, s) and 7.20 to 7.55 (40H, m, arom-H); [mass spectrum: +ve ion (NOBA, Na+) MNa+, 1180].
Reaction SMILES: CC(S([NH:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=O)(C)C.C(Cl)(Cl)Cl.[N-:45]=[N+]=[N-].[Na+].CS(O)(=O)=O>O>[NH2:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][NH:45][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC4(CC3)OCCO4)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
To the product of Step 2 (100 mg, 0.13 mmol) was added chloroform (630 μL), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 μL, 1.51 mmol). The mixture was heated to 65° C. for 1.5 h., cooled to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The fractions containing the desired product were diluted with ethyl acetate and free based with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M+H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.7, 1H), 7.16 (s, 1H), 2.39-2.08 (m, 9H), 1.30-0.99 (m, 4H). rhSYK activity=+++
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[C:14]1([N:24]=[C:25]=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:25]([NH:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:26]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc2ccccc12
Reaction time: 2 h

Procedure:
A solution of 2-imino-1-methylpyrrolidine (obtained from 6.91 g., 0.051 mole, hydrochloride salt) in benzene is dried over potassium carbonate and filtered. A solution of 1-naphthyl isocyanate (8.45 g., 0.05 mole) in benzene is added by filtration. The mixture is stirred for 11/2 hr. at room temperature and the precipitate separated by filtration. Recrystallization from acetone affords the product, 1-(1-methyl-2-pyrrolidinylidene)-3-(1-naphthyl)urea, m.p. 148°-149° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (8.72 g, 28.3 mmol) and phosphoryl chloride (80 mL) according to the general procedure I. Obtained as a light brown solid (9.13 g, 98%). MS (EI) 326.0 [(M)+]; mp 71.5° C.