Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:35]([CH:38]([CH2:42][O:43][CH3:44])[CH2:39][O:40][CH3:41])[N:36]=[CH:37][C:10]=13)[CH2:2]2.[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:35]([CH:38]([CH2:42][O:43][CH3:44])[CH2:39][O:40][CH3:41])[N:36]=[CH:37][C:10]=13)[CH2:4]2
Reactant: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)OC)cc4)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)O)cc4)cc3)nc21
Temperature: 60 °C

Procedure:
A suspension of methyl 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)benzoate (25 mg) in tetrahydrofuran/methanol/water (2:2:1, 20 mL) was treated with two pellets of sodium hydroxide. The mixture was heated overnight at 60° C. and then acidified with concentrated hydrochloric acid to precipitate a fine solid, which, after collection via Buchner filtration, washing with water, and drying under house vacuum, provided 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)benzoic acid. MS (ES+): 588.3 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Li]CCCC.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28]>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][C:11]([CH:27]([OH:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(C(O)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-ethyl-6-methyl-5-thiophen-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 24, Step 3 (97 mg, 0.442 mmol) in anhydrous THF (1 ml) is cooled to −78° C., and n-BuLi (2.5 M in hexane, 0.4 ml, 1 mmol) is added. The resulting dark green mixture is stirred for 30 min, and then pyridine-2-carbaldehyde (80 mg, 0.746 mmol) is added. The cooling bath is removed after 20 min, and the reaction mixture is slowly warmed to room temperature. After 3 hr, water (5 ml) is added to the mixture, and it is extracted with ethyl acetate. The organic phases are washed and dried, and the residue is purified on silica gel to afford a yellow solid (60 mg). MS: m/e=327 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.65 (s, 1H); 8.51 (d, 1H); 7.85 (d, 1H); 7.61 (d, 1H); 7.29 (m, 1H); 7.21 (s, 1H); 6.88 (m, 2H); 6.43 (d, 1H); 5.88 (d, 1H); 2.38 (q, 2H); 2.24 (s, 3H); 1.06 (t, 3H, J=7.4 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]2)[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=O)(C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:69]1([C:72]2[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=2)[CH2:71][CH2:70]1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:27](=[O:28])[NH:78][C:75]2[CH:76]=[CH:77][C:72]([CH:69]3[CH2:71][CH2:70]3)=[CH:73][CH:74]=2)[N:30]2[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C=Cc1ccc(C(C(=O)O)N2CCC(O)C2)cc1
Reactant: Nc1ccc(C2CC2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(C(=O)Nc2ccc(C3CC3)cc2)N2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-(3-hydroxy-pyrrolidin-1-yl)-acetic acid (200 mg, 0.42 mmol), PyBroP (290 mg, 0.62 mmol) and DIPEA (162 mg, 1.26 mol) in CH2Cl2 (10 mL) was added 4-cyclopropyl-phenylamine (100 mg, 0.75 mmol). This mixture was stirred overnight at room temperature and then diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, and evaporated to obtain a yellow residue. Hydrochloric acid in methanol (1.25 M, 5 mL) was added to the residue, the mixture was stirred for about 3 h, and then NaHCO3 was added to the reaction system. After filtration of solids, the crude mixture was purified by preparative HPLC to obtain 42.3 mg pale-yellow solid. MS: calc'd 497 (MH+), exp 497 (MH+). 1H NMR (d4-MeOD, 400 MHz) 7.70 (m, 5H), 7.45 (m, 2H), 7.21 (m, 1H), 7.04 (m, 3H), 6.88 (m, 2H), 6.76 (m, 1H), 4.35 (m, 1H), 3.98(s, 1H, epimer A), 3.97 (s, 1H, epimer B), 3.00 (m, 1H), 2.56-1.85(m, 6H), 0.94(m, 2H), 0.64 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:19][O:20][CH3:21])[N:11]([CH3:22])[C:10](=[O:23])[C:9]=2[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][C@H:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:21][O:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12]1[N:11]([CH3:22])[C:10](=[O:23])[C:9]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:31])[CH:7]=2)[N:13]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: COCC1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C)c2)c(=O)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COCC1CCCN1c1nc(-c2ccnc(NC(C)c3ccccc3)c2)c(-c2cccc(C)c2)c(=O)n1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 100 mL RBF, was added 6-(2-chloro-pyridin-4-yl)-2-(2-methoxymethyl-pyrrolidin-1-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one (0.3 g, 0.71 mmol), 50 mL toluene, and (S)-α-methyl benzylamine (0.181 mL, 1.42 mmol). The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(OAc)2 (24 mg, 0.106 mmol), BINAP (65 mg, 0.106 mmol) and NaOtBu (0.191 g, 2.0 mmol), the mixture was warmed up to 100° C. and stirred for 3 h under nitrogen. The mixture was cooled down to rt, and vacuumed down all volatile composites. After purified by flash chromatography, the title compound was obtained in 0.18 g as pale yellow solid. MS (ES+): 510 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=O.[CH3:11][Li].O>CCOCC>[CH3:10][C:2]([CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](=[O:5])[CH3:11]
Reactant: CCCCC(C)(C)C(=O)O
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCCCC(C)(C)C(C)=O

Procedure:
A solution of 14.4 g (100 mmol) of 2,2-dimethylhexanoic acid (XXIX) in 100 ml of dry ether was stirred a 0° C. under argon as 130 ml (237 mol) of a solution of methyllithium (1.82 M) in ether was added dropwise. The resultant mixture was stirred with ice-bath cooling for 1 hour and then without cooling overnight. It was then poured into a vigorously stirred 500 ml portion of water in a large beaker. The phases were separated and the aqueous phase was back-extracted twice with ether. The combined extract was dried (MgSO4) and evaporated in vacuo. The residue was distilled at 20 mm to yield 12.7 g of XXX as a colorless oil, bp 125°-130°; Rf (CHCl3) 0.54; nmr 0.9 (3, broad t, J=6.0 Hz), 1.12 (6, s), 1.0-1.8 (6, m) and 2.14 (3, s); ir (film) 8.85, 7.45, 6.80, 5.85, 3.50, 3.41 and 3.38μ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.C(O)C>[CH2:12]([O:19][C:20]([N:3]1[C:2]([NH2:1])=[CH:7][C:6]([NH2:8])=[N:5][CH2:4]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(N)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1=CC(N)=NCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a mixture of 4,6-diaminopyrimidine (4.7 g), ethanol (500 ml) and water (200 ml) was added 1N sodium hydroxide (13.25 ml) while cooling with ice water. After the dropwise addition of 1N hydrochloric acid (26.5 ml) thereto, benzyloxycarbonyl chloride (4.5 g) was dropwise added thereto. After being stirred at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give crystals. The crystals were collected by filtration and recrystallized from chloroform:methanol=5:1 to give 2.4 g of N-benzyloxycarbonyl-4,6-diaminopyrimidine, melting point 194° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[CH:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=O)[NH:25][C:19]=2[CH2:18]1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[S:2])[NH:25][C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CC(C(F)(F)F)C2)Sc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1ccccc1S2
Yield: 70.7 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 8-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (0.295 g, 1 mmol) in pyridine (10 ml). The mixture was heated under reflux for 6 hr and then at room temperature overnight. A further 0.3 g of phosphorous pentasulphide was added and the reaction mixture refluxed for 6 hr and then left at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from toluene then ethanol gave he title compound as fine yellow needles (0.22 g, m.p. 232°-233° C. Rf 0.76, petrol/EtOAc 2:1).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>CCOCC>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([C:9]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)c1ccc(C(C)(C)C)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Temperature: 25 °C

Procedure:
All of the 4-tert-butyl-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide prepared above (174 mmol) was charged into a 500 mL round bottom flask fitted with a stir bar and septum. Established and maintained nitrogen atmosphere. Added 50 mL (685 mmol) of thionyl chloride dropwise over 20 min. Warmed the flask with a heat gun to dissolve some of the resin and initiate the reaction. The reaction mixture solidified. Warmed the flask with a heat gun to dissolve all the solids. Cooled to room temperature. Poured the reaction solution in a thin stream into 500 mL of stirred Et2O. A white precipitate formed. Collected the precipitate by filtration and washed thoroughly with Et2O. Dissolved the collected solids in 300 mL water and neutralized with 25% NaOH. Extracted the yellow aqueous solution with 2×200 mL Et2O. Washed the yellow extracts with 200 brine, dried over MgSO4, and removed the solvent on rotavap to obtain 28.50 g of the title compound as a waxy white solid. MS (ESI) 232 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[C:11]([Cl:37])[C:10]=1[F:38])(C)(C)C.[OH-].[Li+].CO>O1CCCC1>[F:36][C:33]([F:34])([F:35])[C:25]1[CH:24]=[C:23]([S:20]([NH:19][CH:14]2[CH2:15][CH2:16][CH2:17][C:18]3[C:9]([O:8][CH2:7][C:6]([OH:39])=[O:5])=[C:10]([F:38])[C:11]([Cl:37])=[CH:12][C:13]2=3)(=[O:21])=[O:22])[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=1
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred solution of [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (163.4 mg, 0.27 mmol) in tetrahydrofuran (4 mL) were added an aqueous (2 mL) solution of lithium hydroxide (0.036 g, 0.87 mmol) and methanol (1 mL) at room temperature and the resulting reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL) and acidified with dilute hydrochloric acid, which resulted in the formation of a precipitate. The resulting mixture was extracted with ethyl acetate (15 mL×3). The combined organic layers was washed with water (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-200 mesh, 50% ethyl acetate in hexane) gave [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid (130.4 mg, 88%). MS cald. for C20H15ClF7NO5S 549, obsd. 548 (ESI+) [(M−H)+].
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].CN1CCN(S([C:25]2[CH:26]=[CH:27][C:28]([O:45][CH2:46][CH2:47][CH3:48])=[C:29]([C:31]3[NH:39][C:38]4[C:37](=O)[NH:36][C:35](=[O:41])[N:34]([CH2:42][CH2:43][CH3:44])[C:33]=4[N:32]=3)[CH:30]=2)(=O)=O)CC1>N1C=CC=CC=1>[CH2:46]([O:45][C:28]1[CH:27]=[CH:26][CH:25]=[CH:30][C:29]=1[C:31]1[NH:39][C:38]2[C:37]([SH:2])=[N:36][C:35](=[O:41])[N:34]([CH2:42][CH2:43][CH3:44])[C:33]=2[N:32]=1)[CH2:47][CH3:48]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c([nH]1)c(=O)[nH]c(=O)n2CCC
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2c([nH]1)c(S)nc(=O)n2CCC
Yield: 129.2 %

Procedure:
Phosphorus pentasulphide (0.7 g, 3.1 mmol) was added portionwise to a stirred suspension of 8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropurine-2,6-dione (1.5 g, 23.3 mmol) in pyridine (15 mL) and the resulting mixture stirred under reflux for 3 hours, then evaporated under reduced pressure to give crude 8-(2-propoxyphenyl)-3-propyl-6-mercapto-3,7-dihydropurin-2-one (1.38 g) which was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 97 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-aminobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 395 mg of the title compound (97%) as a yellow solid in 99.2% purity by HPLC (Rt: 4.41, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[C:9]=1[NH:20][C:21](=O)[CH3:22].O>C(O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:17](=[O:18])[C:16]3[C:11]([C:10](=[O:19])[C:9]=2[N:20]=[C:21]1[CH3:22])=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: COCCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCn1c(C)nc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.7 %

Procedure:
2 M Sodium hydroxide aqueous solution (0.9 ml) was added to a solution of N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.5 g) in ethanol (10 ml) and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was collected by filtration and washed with ethanol to give 1-(2-methoxyethyl)-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazole (0.58 g) as a light orange powder.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[B-](F)(F)(F)F.CN(C(O[N:27]1[C:32](=[O:33])[CH2:31][CH2:30][C:28]1=[O:29])=[N+](C)C)C>CC#N>[C:28]1(=[O:29])[N:27]([O:12][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[C:32](=[O:33])[CH2:31][CH2:30]1
Reactant: C#CCCCCCCCCC(=O)O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C#CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 10-undecynoic acid (0.40 g, 2.2 mmol) in CH3CN (10 mL) was added O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.99 g, 3.29 mmol). After stirring for 2 min at RT, the reaction was quenched with 1% AcOH and diluted with CHCl3 (150 mL). The organic solution was then extracted with 1% AcOH (10 mL), rinsed with H2O (2×40 mL), then dried over Na2SO4. The solution was then decanted and concentrated. A quantitative yield was assumed and the material was taken on directly to the next step. TLC (10% MeOH/CHCl3) Rf=0.90, UV active.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N+]=[N-])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:9]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 19.2 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (17.75 g., 51 mmoles) was dissolved in 100 ml. methylene chloride. Diphenyldiazomethane (ca. 75 mmoles) was added dropwise with stirring until purple color persisted in the reaction mixture. After an additional 30 minutes of stirring at room temperature, the methylene chloride was evaporated in vacuo. The residue was taken up in a mixture of 100 ml. of water and further processed according to Preparation 4 to yield benzhydryl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [5.03 g.; pnmr (CDCl3 /TMS/delta): includes 2.0 (s, 3H), 3.2 (m, 2H), 4.5 (s, 2H), 6.9-7.6 (m, 11H)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)NC1CCSc2cc(C(=O)O)c(Cl)cc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)NC1CCSc2cc(C(=O)Nc3ccncc3)c(Cl)cc21
Yield: 104.1 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (200 mg), 4-aminopyridine (54.7 mg) and 2-chloro-1-methylpyridinium iodide (178 mg), the objective 4-(tert-butoxycarbonylamino)-6-chloro-N-(4-pyridyl)thiochromane-7-carboxamide (254 mg) was obtained as a colorless amorphous solid.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:9]1[NH:10][NH:11][C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([Cl:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[ClH:27].[ClH:1].[CH2:3]([C:9]1[NH:10][N:11]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=2)[C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC1=Nc2cccnc2NN1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CCCCCCC1=Nc2cccnc2N(C(=O)c2cccnc2)N1

Procedure:
12 g (0.04 mole) of 3-n-hexyl-1,2-dihydropyrido-[3,2-e]-as-triazine dihydrochloride are boiled with an excess of nicotinic chloride. The reaction mixture is cooled and the separated product is filtered off.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31](S(C)(=O)=O)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31]([NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:15]=3)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N4CCNCC4)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(3-amino-phenyl)-piper-azine-1-carboxylic acid tert-butyl ester (from the previous step, 54 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example, 1(e) above, 80 mg, 0.19 mmol). A yellow solid was obtained (60 mg, 62%) after a preparative HPLC (32 mL/min 5-100% MeCN/H2O gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2Cl2 (1:1 v/v) to give the title compound. 1H NMR (400 MHz, CDCl3/CD3OD 10:1 v/v) δ (ppm): 9.26 (br, 1H), 8.49 (s, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.20 (s, 1H), 7.11 (11, 2H), 6.78 (br, 2H), 6.54 (m, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.98 (m, 4H), 2.29 (m, 4H), 2.96 (m, 4H), 2.14 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([NH:9]C(=O)C)[CH2:5][C:4]([CH3:13])=[N:3]1.Cl.[OH-].[Na+]>CO>[NH2:9][N:6]1[CH2:5][C:4]([CH3:13])=[N:3][N:2]([CH3:1])[C:7]1=[O:8]
Reactant: CC(=O)NN1CC(C)=NN(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(C)C(=O)N(N)C1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a slurry of N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (0.34 g, 1.846 mmol) in MeOH (3 mL) is added concentrated HCl (0.25 mL, 2.9 mmol). The mixture is heated to reflux for 3 h. The mixture is then chilled to 0° C., adjusted to pH 12 with 1 M aqueous NaOH (2.9 mL) and concentrated in vacuo. CH3CN is added to the residue with stirring and the mixture is filtered. The filtrate is concentrated in vacuo. CH3CN is added to the residue with stirring and the mixture is filtered. The filtrate is concentrated in vacuo to afford 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (˜100%)). MS: 143 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 4.6-3.6 (broad peak, 2H), 4.02 (s, 2H), 3.29 (s, 3H), 1.95 (s, 3H).