Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.COC1C=NC2C(C=1)=CC=CC=2>C(COC)OC>[CH3:2][Sn:3]([CH3:5])([CH3:4])[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1cc2ccccc2nc1Br
Agent: COc1cnc2ccccc2c1
Agent: [Na]
Solvent: COCCOC
Product: COc1cc2ccccc2nc1[Sn](C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3.00 g (131 mmol) of sodium are introduced in a sealed Schlenck-type apparatus under argon inert gas into 3 ml of DMEabs. (=absolute dimethoxyethane). The sodium is cut into very small pieces and, before being added to the reaction solution washed with DMEabs to remove any adhering paraffin. During addition of the sodium to the reaction solution, the DMEabs. slightly foams. The reaction solution is then cooled to -10° C. using an ice/common salt mixture. 0.83 g (4.18 mmol) of trimethyltin chloride is added to this solution. After a reaction time of 2 hours, the reaction solution is colorless, milky and cloudy. After a total of 3 hours, the reaction solution has become milky, cloudy and green. This can be considered as an indication of the formation of sodium trimethylstannate. Excess sodium is removed from the reaction solution under argon via a D-2 Schlenck-type frit. 0.35 g (1.45 mmol) of 2-bromo-3-methoxyquinoline (20) dissolved in 3 ml of DMEabs. is added dropwise to the filtered cloudy green reaction solution. Upon dropwise addition of the educt, the reaction solution spontaneously turns blood red. After a short time, the reaction solution has a brown color. After 30 minutes, the reaction solution finally turns beige. The solution is stirred at -10° C. for a total of 3 hours, during which the color of the reaction solution no longer changes. After the reaction is complete, the product mixture is filtered through a D-4 frit to remove the precipitate. The precipitate is washed with DMEabs. without vacuum, the runoff being dark brown. A colorless solid remains in the frit. Upon evaporation of the filtrate in a rotary evaporator, a dark-brown oil is obtained whose composition is analyzed by 1H-NMR spectroscopy. Explicit purification of the product is omitted due to the sensitivity to hydrolysis. The product content is determined by spectroscopy. The hydrolysis product 3-methoxyquinoline can be detected as a by-product of this reaction. This finding is confirmed by the 1H-NMR experiments described below.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:44][CH2:45][CH:46]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[S:23][C:22]1=[O:21])([CH3:34])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
Acetic acid (0.12 mL, 2.16 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (266 mg, 1.08 mmol) (which was obtained in Example 10), tert-butyl 2-{2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (450 mg, 1.08 mmol) (which was obtained in Example 49), and DMF (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce a yellow solid (480 mg, 68% yield); mp 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.50 (m, 11H), 1.81-1.85 (m, 2H), 2.60-2.80 (m, 4H), 2.85-2.9 (m, 4H), 3.40 (m, 1H), 3.60 (m, 1H), 4.20 (s, 2H), 4.50 (m, 1H), 5.04 (m, 1H), 6.80-6.87 (m, 3H), 7.02 (m, 1H), 7.08 (m, 2H), 7.20 (m, 1H); Anal. Calcd. for C30H40N4O8S2: C, 55.54; H, 6.21; N, 8.64. Found: C, 53.86; H, 6.11; N, 7.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][CH:60]=[C:52]([Cl:51])[CH:53]=2)[CH3:56])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CC(O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(Cl)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 52.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-chloro-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 49%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:33]=[CH:34][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:7]4[CH:8]=3)=[CH:14][CH:15]=2)[N:19]=1)[CH3:32]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)nc1OCC
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)nc1OCC
Yield: 96.3 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (676 mg), phenylboronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40.4 mg), sodium carbonate (339 mg), ethanol (3 ml), water (3 ml) and toluene (15 ml) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (707 mg, yield: 96%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 104–105° C.
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([O:23]C=C)(=[O:22])[CH3:21].[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:26]([O:29][CH:21]([CH3:1])[C:20]([OH:23])=[O:22])(=[O:28])[CH3:27]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)O
Reactant: C=COC(C)=O
Product: CC(=O)OC(C)C(=O)O
Temperature: 150 °C

Procedure:
A 300 ml autoclave is charged with 0.110 g of [(C3H5)PdCl]2 (0.6 mmole Pd), 3.15 g. of Ph3P (12 mmole), 83 ml of acetic acid as solvent, and 37 ml of vinyl acetate (0.4 mole). The autoclave was flushed with nitrogen, pressured to 30 psig with carbon monoxide, and heated to 150° C. After reaching 150° C. one milliliter of water was pumped into the reaction solution from a Jurgenson Gauge and the pressure was raised to 700 psig with carbon monoxide. The reaction began absorbing gas as evidenced by a drop in the autoclave pressure. Therefore the autoclave pressure was maintained at 700 psig by feeding carbon monxide from a high-pressure reservoir. In addition, the water concentration in the reaction solution was maintained by addition of one milliliter of water from the Jurgenson Gauge for every 130 psig pressure drop in the high-pressure reservoir. After the addition of a total of five milliliters of water the reaction had consumed 675 psig of carbon monoxide from the high pressure reservoir. At this time the reaction was terminated. The production of α-acetoxypropionic acid was shown by a nuclear magnetic resonance and gas chromatography of the concentrated reaction solution. Pure α-acetoxypropionic acid was isolated from a subsequent fractional distillation. The mass spectrum of other fractions showed ethylidene diacetate (major), propionic acid (minor), and acrylic acid (minor) to be by-products.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].CO[C:15]1[CH:16]=[CH:17][C:18]2[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[C:21]([C:27]([OH:29])=O)[S:20][C:19]=2[CH:30]=1.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.Cl>O1CCCC1.O>[CH3:1][O:2][C:17]1[C:18]2[C:22]([O:23][CH:24]([CH3:25])[CH3:26])=[C:21]([C:27]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:29])[S:20][C:19]=2[CH:30]=[CH:15][CH:16]=1
Reactant: COc1ccc2c(OC(C)C)c(C(=O)O)sc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2sc(C(=O)Nc3nnn[nH]3)c(OC(C)C)c12
Yield: 60 %

Procedure:
Carbonyldiimidazole (3.8 g, 23 mmoles) is added to a stirred solution of 6-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (5.4 gg, 20 mmoles) in tetrahydrofuran (75 mls) under nitrogen, and the mixture is heated under reflux. After 75 minutes 5-aminotetrazole (1.66 g. 20 mmoles) is added. After an additional three hours under reflux the mixture is stirred into water (350 mls) and acidified with concentrated HCl. The resulting precipitate is filtered off, rinsed with water, and dried. Recrystallization from DMF/methanol gave the pure product (4.0 g): mp=233°-234? C. (dec).
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:3]1.O.[OH-].[NH4+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccnc1-c1cc2cccnc2c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cccnc1-c1cc2cccnc2c(Cl)n1
Temperature: 0 °C

Procedure:
Heat a mixture of 8-oxo-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine (16.4 g, 69.1 mmol) in phosphorus oxychloride (200 mL) on a steam bath for 3 hours. Remove excess phosphorus oxychloride under reduced pressure, cool in an ice-water bath and add ice (100 g) and water (100 mL). Add concentrated ammonium hydroxide to neutralize the solution, while maintaining the temperature below 10° C. Filter the resultant mixture, air dry the solids and triturate with boiling benzene (1 L). Concentrate the mixture, filter and crystallize the isolated solid from benzene to obtain the title compound, mp 130-1° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A crudely purified product (20.7 g) of 6-fluoro-2-methyl-3-nitrobenzoic acid was dissolved in N,N-dimethylformamide (208 mL), and potassium carbonate (28.7 g, 208 mmol) and iodomethane (8.45 mL, 135 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product (21.0 g, yield 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[OH:16])=[N:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(O)c2ccc(Br)cn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78° C. was added n-BuUi (1.05 eq.). The mixture was stirred for 2 h at −78° C. then 4-methoxy-benzaldehyde (1.1 eq.) was added. The final mixture was warmed 0° C., poured in saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 3:2) and stirring in Hex:Et2O afforded the title compound as a white solid after filtration.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCOCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCCCCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
In a 1000 ml pressure resistant flask equipped with a stirrer were charged 100.0 g of ethyl 11-(p-benzyloxyphenoxy)undecanoate synthesized in Synthetic example 1, 3.0 g of a 10% palladium-carbon, 400 ml of 1,4-dioxane and 200 ml of ethanol, and the mixture was heated to 60° C. and under pressurized conditions of an inner vessel pressure at 2.5 kgf/cm2, a hydrogen gas was passed through and the mixture was vigorously stirred for 3 hours. Insolubles were removed by filtration, and the filtrate was concentrated to precipitate crystals. The resulting crystals were washed with cooled n-hexane to obtain 73.4 g of the title compound.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[C:60]([C:63]1[S:64][C:65]2[CH:70]=[CH:69][N:68]=[CH:67][C:66]=2[N:71]=1)([OH:62])=[O:61].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CS(C)=O>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:68]4[CH:69]=[CH:70][C:65]5[S:64][C:63]([C:60]([OH:62])=[O:61])=[N:71][C:66]=5[CH:67]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)c1nc2cnccc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(C(=O)O)nc4c3)CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-carboxythiazolo[4,5-c]pyridine [prepared according to the procedure of Zhur. Obshchei Khim., 26, 613 (1956); C.A., 50, 13906 (1956)] (90 mg, 0.5 mmole) in 2 ml of DMSO was stirred at room temperature for 1.5 hours and diluted with ethyl acetate-ether to give 375 mg of crude quaternary salt, which was treated with 5 ml of TFA and 0.1 ml of anisole at room temperature for 15 minutes. The mixture was evaporated in vacuo and triturated with ether to give 213 mg of crude Iv. The crude product was dissolved into a small volume of phosphate buffer (pH 7.0) and chromatographed on a column of packing (20 ml) in PrepPAK/C18 cartridge. The column was eluted with water (200 ml) and 10% aqueous CH3OH (150 ml) to afford 51 mg (17%) of the title compound (Iv) as an amorphous powder. Mp. 144°~160° C. (dec.). Estimated purity by HPLC: 85%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([NH:11][C:12]1[NH:18][C:17]2[N:19](C(C)=O)[CH:20]=[N:21][C:16]=2[C:14](=O)[N:13]=1)=[O:10].P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[C:9]([NH:11][C:12]1[N:18]=[C:17]2[C:16]([NH:21][CH:20]=[N:19]2)=[C:14]([Cl:27])[N:13]=1)(=[O:10])[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc(=O)c2ncn(C(C)=O)c2[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
60.0 g (0.36 mol) of tetraethylammonium chloride and 20.3 g (0.2 mol) of triethylamine are added to a suspension of 42.6 g (0.18 mol) of 2,9-diacetylguanine in 450 ml of acetonitrile. 165.3 g (1.08 mol) of phosphorus oxychloride are then added at a temperature of the reaction mixture of 0° C. to 5° C. The mixture is stirred at 25° C. for 20 hours and then worked up as in Example 1. 30.9 g of 2-acetamido-6-chloropurine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>CO>[NH2:20][CH2:19][C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To the crude 2-({2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione obtained in Preparative Example 13 were added methanol (15 mL) and hydrazine monohydrate (0.125 mL) at room temperature, followed by stirring at 60° C. for 4.5 hours. The resulting precipitate was removed by filtration and the filtrate was concentrated, and then, the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 5-(aminomethyl)-N-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (105 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([NH2:12])=O)=[C:8]2[C:4]([N:5]=[N:6][S:7]2)=[N:3]1.S(Cl)(Cl)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:10]([C:9]1[N:2]([CH3:1])[N:3]=[C:4]2[C:8]=1[S:7][N:6]=[N:5]2)#[N:12]
Reactant: Cn1nc2nnsc2c1C(N)=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1nc2nnsc2c1C#N
Temperature: 80 °C
Reaction time: 55 h
Yield: 24.6 %

Procedure:
The compound, 5-methylpyrazolo-1,2,3-thiadiazole-6-carboxamide (0.9 g, 4.92 mmol) was slurried in toluene (10 mL) and thionyl chloride (0.5 mL) was added. The mixture was heated to 80° C. and then to 105° C. with no reaction. The mixture was cooled to 70° C. and ethyl acetate (10 mL) was added. The slurry was stirred at 70° to 80° C. for 55 h, cooled and concentrated onto Silica Woelm®TSC and chromatographed on 50 g of the same silica (25% ether-hexane) to give after a 300 mL forerun 0.2 g of 6-cyano-5-methylpyrazolo-1,2,3-thiadiazole as a light yellow solid; mp 111° to 114° C.; 1H-NMR (CDCl3) σ 4.41 (s, 3H); IR (KBr) 2230, 1332, 679 cm-1 ; Mass spec. m/e 165.0109; m/e calcd. for C5H3N5S 165.0109.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[CH2:42][CH2:43][CH:44]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=[C:2]2[NH:1][CH2:44][CH2:43][CH2:42][N:33]2[C:34](=[O:41])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]2=[O:31])=[CH:7][CH:8]=1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc(NCCCN3C(=O)c4ccccc4C3=O)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a slurry of 4-(4-amino-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (150 mg, 0.42 mmol) in 1,2-dichloromethane (10 ml) was added N,N-diisopropylethylamine (250 μl) followed by acetic acid (0.5 ml), 3-(1,3-dioxoisoindolin-2-yl)propanal (140 mg) and sodium triacetoxyborohydride (200 mg). The mixture was stirred at room temperature for 24 hours before being poured into ethyl acetate (100 ml) washed with water (250 ml) and dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow oil which was purified by silica gel chromatography eluting with 40-60% ethyl acetate in hexanes to yield 2-(3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)propyl)isoindoline-1,3-dione 181 as a yellow foam (95 mg). 1H NMR (CDCl3) 400 MHz δ 8.34 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.86-7.83 (m, 3H), 7.8 (d, J=8.8 Hz, 1H), 7.75-7.71 (m, 2H), 7.34 (s, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4 and 8.8 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 5.24 (m, 1H), 4.9 (m, 1H), 4.04 (s, 3H), 3.9 (t, J=6.0 Hz 2H), 3.5 (t, J=6.0 Hz, 2H), 3.11 (d, J=5.2 Hz, 3H), 2.24 (m, 2H), 2.2-2.14 (m, 2H), LCMS m/e 468 (M+H)