Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10](CC2C=CC(OC)=CC=2OC)[CH2:9][C:8]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:7]=2[C:6]1=[O:31])=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:7]=2[C:6]=1[OH:31])=[O:4]
Reactant: COC(=O)C1C(=O)c2oc(-c3ccccc3)nc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Reaction time: 5 h
Yield: 29.7 %

Procedure:
5-(2,4-Dimethoxy-benzyl)-7-oxo-2-phenyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (1.05 g, 2.49 mmol), was dissolved in 17 mL of anhydrous dichloromethane. To the solution was added 272 μL of thionyl chloride, and the reaction was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 0.20 g of the title compound as a white solid. MS: (−) m/z 269.1 (M−1).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([OH:35])=[O:34])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([OH:35])=[O:34])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN(C)C)CS[C@H]12)c1csnn1
Yield: 26.6 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (350 mg.) and 7-amino-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (600 mg.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (230 mg.).
Reaction SMILES: [C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([SH:17])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1>C(O)C>[C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([S:17][CH2:35][C:36]4[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(S)n2C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C#N)cc1)n2C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 1.30 g (3.4 mmol) of 1-methyl-2-mercaptobenzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, 0.52 g (3.74 mmol) of potassium carbonate and 0.66 g (3.4 mmol) of 4-bromomethylbenzonitrile were dissolved in 40 mL of absolute ethanol, stirred for 4 hours at 60° C. and 16 hours at room temperature. Then the solvent was distilled off in vacuo, the crude product was taken up in 30 mL of methylene chloride, washed with 40 mL of water and dried with sodium sulfate. After filtration and distillation of the solvent, the desired compound was obtained as a beige-white solid. Yield: 1.8 g (100% of theory); Rf value: 0.64 (silica gel; ethyl acetate).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16](O)=O)[CH2:11][CH2:12][C:13](O)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[CH2:19](N(CC)CC)C.C(Br)C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH:10]1([NH:9][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH2:19][CH2:16]1
Reactant: CCN(CC)CC
Reactant: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C1CCC(NC2CCCCC2)CC1
Reaction time: 60 h
Yield: 64.5 %

Procedure:
A solution of 108.8 g (420 mmol) of N-heptanoyl-D-glutamic acid and 50.6 g (500 mmol) of triethylamine in 135 ml of dimethylformamide was treated with 85.7 g (500 mmol) of benzyl bromide and stirred under nitrogen atmosphere for 60 hours. The reaction was poured onto one liter of ethyl acetate and washed successively with two 500 ml portions each of dilute hydrochloric acid and water. The ethyl acetate was then washed with 500 ml of 1N sodium hydroxide. The basic aqueous layer was acidified with dilute acid and extracted with four 500 ml portions of ethyl acetate. The combined ethyl acetate extracts were treated with excess dicyclohexylamine and stirred 18 hours. The suspension was filtered, slurried in fresh ethyl acetate (400 ml) for two hours, refiltered and dried under vacuum to give 49.1 g of dicyclohexylamine salt. The resulting salt (14.0 g) was stirred in dilute hydrochloric acid, filtered and washed with ethyl acetate. The aqueous filtrate was extracted twice with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 7.9 g (86% from salt) of the title ester: mp 76°-79° C.; IR (Nujol) 3300, 2700-3100, 1730, 1700, 1645 cm-1 ; NMR (CDCl3) delta 7.35 (s, 5H), 5.20 (s, 2H), 4.70 (m, 1H), 1.85-2.50 (m, 6H), 1.55-1.70 (m, 2H), 1.10-1.40 (m, 6H), 0.75 (t, 3H); [alpha]D =27.6 (C=0.6, MeOH).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:17]=[C:18]([NH2:20])[S:19][CH:2]=2)=[C:6]([CH3:16])[CH:7]=1)([CH3:15])[CH3:14]
Reactant: NC(N)=S
Reactant: Cc1cc(OC(C)C)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OC(C)C)cc(C)c1-c1csc(N)n1
Yield: 72 %

Procedure:
A mixture of 2-bromo-1-(4-isopropoxy-2,6-dimethylphenyl)ethanone (5.18 g, 18.2 mmol) and thiourea (1.38 g, 18.2 mmol) in 95% EtOH (26 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isopropoxy-2,6-dimethylphenyl)thiazol-2-amine (3.44 g) as yellow solids in 72.2% yield: 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 2 H), 6.26 (s, 1 H), 4.97 (bs, 2 H), 4.54 (m, 1 H), 2.13 (s, 6 H), 1.32 (d, J=6.1 Hz, 6 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C.O>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Yield: 15.2 %

Procedure:
To a stirred solution of 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.25 mmol) in ethanol (10 ml) was added 1N NaOH (1.26 ml, 1.26 mmol) solution at RT. The reaction mixture was refluxed for 24 h. The volatiles were removed under vacuum to afford a crude residue which was diluted with water. The aqueous layer was washed with ethyl acetate to remove non-polar impurities and then the pH was adjusted to 4-3 with 10% citric acid under cooling. Then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude residue which was purified via Prep-HPLC followed by Prep-TLC to obtain pure 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid as pale yellow solid (14 mg, 15%). LC-MS: 369 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(F)cc1N
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
5-Fluoro-2-methylaniline (10.0 g, 79.9 mmol, 1 equiv) was dissolved In toluene (50 mL) and placed in a cool water bath. Acetic anhydride (11.3 mL, 120 mmol, 1.5 equiv) was added slowly. After 15 minutes, a white precipitate had formed. The solid was collected by filtration and washed with toluene several times, affording 10.93 g (82%) of the title compound as a white crystalline solid. MS (ES+) m/e 213 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O>CO.N1CCCCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:3]2[C:4]3[O:8]/[C:7](=[CH:26]\[C:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=5)[NH:30][CH:29]=4)/[C:6](=[O:9])[C:5]=3[CH:10]=[CH:11][C:2]=2[OH:1])[CH2:18][CH2:17]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 782.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.060 g, 0.017 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with methyl 3-formyl-1H-indole-6-carboxylate (0.040 g, 0.019 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (93:7)) to obtain methyl (Z)-3-[(7-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-6-hydroxy-3-oxobenzofuran-2(3H)-ylidene)methyl]-1H-indole-6-carboxylate (0.071 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22].Cl.O>CN(C)C=O>[Cl:18][C:19]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:32])[CH:28]=[CH:27][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22]
Reactant: NNC(=O)c1ccc(C(=O)NCCO)c(Cl)c1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCO)c(Cl)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (40 mg, 0.14 mmol) and 2-chloro-4-hydrazinocarbonyl-N-(2-hydroxyethyl)benzamide (43 mg, 0.17 mmol) prepared in Reference Synthetic Example 8 in dimethylformamide (0.7 mL), concentrated hydrochloric acid (12 μL, 0.14 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 1 day and stirred with 2-chloro-4-hydrazinocarbonyl-N-(2-hydroxyethyl)benzamide (18 mg, 0.07 mmol) for 1 day. After addition of water, the resulting crystals were recovered by filtration and dried. Chloroform was added, and the resulting crystals were recovered by filtration to give the desired product (yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(C)c4)nc23)ccn1
Yield: 48.2 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (97 mg, 48%). MS (ISP) 403.5 [(M+H)+]; mp 240° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25]OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C.O>[C:11]([O:15][C:16](=[O:17])[NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([CH2:25][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[N:4]2)[CH2:23][CH2:24]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1n[nH]c(C)c1C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3,4,5-trimethyl-1H-pyrazole (84 mg, 0.761 mmol) in dry acetonitrile (4 mL) at room temp is added sodium hydride (33 mg of a 60% dispersion on mineral oil, 0.83 mmol). The mixture is stirred at room temp for 10 minutes and then treated with a solution of trans-trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (step 1) (250 mg, 0.692 mmol) in dry acetonitrile (3 mL). The reaction mixture is stirred at room temp for 17 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with brine (20 mL), dried (MgSO4), filtered and evaporated to give the title compound as a colourless oil. This is used in the next step without further purification; MS m/z 322.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@@H:25]3[CH3:37])=[CH:20][CH:19]=2)[C:5](=[O:16])[N:6](COCC[Si](C)(C)C)[N:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]3[CH3:37])=[CH:22][N:23]=2)[C:5](=[O:16])[NH:6][N:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn(COCC[Si](C)(C)C)c2=O)nc1
Agent: Cl
Solvent: CO
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)n[nH]c2=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50-mL round-bottomed flask was charged with 253b (551 mg, 1.0 mmol), concentrated HCl (2 mL), and methanol (10 mL). The mixture was stirred at room temperature overnight. It was then concentrated under reduced pressure to afford 253c, which was used directly in the next step without further purification. MS-ESI: [M+H]+ 321.1
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:18]2[C:17](=[O:19])[NH:16][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH2:28][CH3:29])=[N:14][C:13]=2[N:12]([CH2:30][CH2:31][CH3:32])[N:11]=1>>[Br:1][C:24]1[CH:23]=[CH:22][C:21]([O:26][CH2:27][CH2:28][CH3:29])=[C:20]([C:15]2[NH:16][C:17](=[O:19])[C:18]3[C:10]([CH3:9])=[N:11][N:12]([CH2:30][CH2:31][CH3:32])[C:13]=3[N:14]=2)[CH:25]=1
Reactant: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Product: CCCOc1ccc(Br)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from N-bromosuccinimide (4.9 g, 0.0276 mol) and 3-methyl-6-(2-n-propoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidin-4-one (Example 18; 3.0 g, 0.0092 mol), following the procedure of Example 6, and was obtained as yellow crystals (1.11 g, 30%), m.p. 157-159° C., after crystallisation from ethyl acetate. Found: C,53.14; H,5.17; N,13.76. C18H21BrN4O2 requires C,53.34; H,5.22; N,13.82%.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:30][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: NCc1cccs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3cccs3)(CC1)CC2
Yield: 75.4 %

Procedure:
In a similar manner to Example 92, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-thienylmethylamine (38.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-thienylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (48.8 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7][OH:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (5.0 g, 18.3 mmol) and MnO2 (2.4 g, 27.5 mmol) in chloroform (110 mL) are heated to reflux for 48 hrs, cooled to room temperature, filtered through celite. Concentration yields 5 gram of the title compound.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: Sc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,6-dinitrobenzonitrile (2.0 g, 10.36 mmol) and K2CO3 (1.43 g, 10.36 mmol) in 5 mL of anhydrous DMF was added PhSH (1.14 ml in 5 mL of DMF) dropwise under nitrogen at 0° C. After the completion of addition, the reaction mixture was stirred at 0° C. for 0.5 hr. Then the reaction mixture was poured into 50 mL of water, the resultant precipitation was collected by filtration, washed with water and dried in the air to give the title product.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[F:37][C:17]1[CH:18]=[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:20]([F:22])=[CH:21][C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:14])=[O:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2cnc(Cl)cc2-c2cccnc2)cc1F
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: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cccnc2)cc1F
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
10 mg (0.03 mmol) of tert-butyl((4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.5 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
Chromium trioxide (951 mg, 9.51 mmole; dried in vacuo over phosphorous pentoxide) was added to a stirred solution of 1.49 g (18.88 mmole) of dry pyridine in 25 ml of dry methylene chloride. The deep red solution was stirred for 15 minutes at room temperature. A solution of (trans)-3-(6-phenyl-1,3,5-hexatriynyl)oxiranemethanol (300 mg, 1.35 mmole; see Example 3) in 5 ml of dry methylene chloride was then added in one portion. A tarry, black deposit separated immediately. After stirring for 20 minutes at room temperature, the solution was decanted and filtered through a pad of silica gel. Several portions of ether were then passed through the silica gel. Solvent was removed from the combined filtrates and the residue was chromatographed on silica gel (ether-hexane) to afford 130 mg of the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3].O.[OH-].[Li+].Cl>CO.O>[N:1]([CH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([OH:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: COC(=O)c1c(CN=[N+]=[N-])c(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(azidomethyl)-2-phenylquinoline-4-carboxylate (2b) (1781 mg, 5.0 mmol) in methanol (50 mL) was added the solution of lithium hydroxide monohydrate (674 mg, 28.1 mmol) in 25 mL water. The reaction mixture was stirred at reflux for 4 h and the residue was acidified with 1N HCl to pH 2. The volume of reaction mixture was reduced under reduced pressure. The resulting aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was separated and washed with brine (20 ml) and dried over sodium sulfate and then concentrated in vacuo. Crystallization from ethyl acetate/hexane to afford the title compound (1200 mg, 66%) as an off white solid. MS APCI, m/z=305 (M+1). LCMS: 1.09 min.