Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH:6]=[CH2:7])[CH2:3][CH:4]=O.[NH3:9].C1(C)C(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=CC=1>CO>[CH3:1][C:2]([CH3:8])([CH:6]=[CH2:7])[CH2:3][C:4]1[N:9]=[CH:19][NH:20][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: N
Reactant: C=CC(C)(C)CC=O
Solvent: CO
Product: C=CC(C)(C)Cc1c[nH]cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
At 30 C, 3,3-dimethylpent-4-enal (126 g, 0.34 mol) was added over 20 minutes to an ambient temperature, saturated solution of ammonia in methanol (2.7 L). After stirring at 40° C. for 30 minutes, toluenesulfonylmethyl isocyanide (67 g, 0.4 mol) was added. After stirring at reflux overnight, the reaction mixture was concentrated, dissolved in ether and poured into 2N ammonium hydroxide (1500 mL) and stirred. The aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford 4-(2,2-dimethylbut-3-en-1-yl)-1H-imidazole which was used in the subsequent step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]4[NH:27][C:26]5[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:25]=5[N:24]=4)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:33](=[O:36])([O-])[O-].[K+].[K+].[OH-:39].[Na+].OO>CS(C)=O.C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:25]2[N:24]=[C:23]([C:18]3[C:17]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]([C:8]5[CH:7]=[CH:6][C:3]([C:4]([NH2:5])=[O:39])=[C:2]([NH:5][CH:4]([CH2:33][OH:36])[CH2:3][CH3:2])[CH:9]=5)[C:22]=4[CH:21]=[CH:20][CH:19]=3)[NH:27][C:26]=2[CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)cc1F
Reactant: [OH-]
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CCC(CO)Nc1cc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)ccc1C(N)=O

Procedure:
The process is carried out as in stage 3 of Example 3, but using 300 mg of 2-fluoro-4-[4-(6-fluoro-1H-benzimidazol-2-yl)carbazol-9-yl]benzonitrile, obtained according to stage 2 of Example 3, 296 mg of potassium carbonate and 1.273 g of 3(R,S)-aminopropanol in 3 ml of dimethyl sulphoxide. 1.357 ml of a 1M aqueous solution of sodium hydroxide, 1.313 ml of a 30% aqueous solution of hydrogen peroxide and 7 ml of ethanol are then added to the reaction medium. After treatment as in stage 3 of Example 3, then purification by flash chromatography on silica gel, elution being carried out with a mixture of dichloromethane and ethanol (95/5 by volume), followed by crystallization from 10 ml of diisopropyl ether, 165 mg of 4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]-2-(4-hydroxybutan-3(R,S)-ylamino)benzamide are thus obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([CH2:7][CH2:8]N)[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C([N:12](CC)CC)C.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].Cl>CO>[F:17][C:18]([F:25])([F:24])[C:19]([NH:12][CH:3]([CH2:2][CH2:1][CH2:7][CH3:8])[C:4]([OH:6])=[O:5])=[O:20]
Reactant: NCCCCCC(=O)O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: CCCCC(NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Yield: 41.5 %

Procedure:
ω-aminocaproic acid (2.59 g, 19.7 mol) was dissolved in 100 mL methanol, and triethylamine (4.2 mL, 29.9 mmol) and ethyl trifluoroacetate (3.5 mL, 29.5 mmol) were added and agitated for a day and night at room temperature. The reaction solution was poured into 1% by weight hydrochloric acid (100 mL), and extracted once with methylene chloride. The methylene chloride layer was washed once with water and once with a saturated aqueous sodium chloride solution, and then dried and concentrated with anhydrous sodium sulfate to obtain 2.78 g of a crude product.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.O[N:16]=[C:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.N>>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[O:13][N:24]=[C:17]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:16]=3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: FC1(F)Oc2ccc(-c3nc(-c4cccnc4)no3)cc2O1

Procedure:
The title compound was prepared according to Method C using 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=8.1, 4.8, 1.0 Hz, 1 H), 7.73 (d, J=8.5 Hz, 1 H), 8.14 (dd, J=8.5, 1.7 Hz, 1 H), 8.25 (d, J=1.7 Hz, 1 H), 8.44 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.25 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 304 (M+H)+.
Reaction SMILES: [ClH:1].N[C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14].Cl.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: Cl
Reactant: Nc1ccc2c(c1C(=O)O)OCCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Cl)ccc2c1OCCO2
Reaction time: 1 h
Yield: 74.4 %

Procedure:
58 g of 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride and 116 ml of water were introduced in a 500 ml balloon flask provided with a stirrer, a thermometer and a dropping funnel. 28 ml of hydrochloric acid (d=1.18) were added and the mixture was cooled to a temperature of from 0°-5° C. A solution of 17.5 g of sodium nitrite in 38 ml of water was added at a temperature within the 0°-5° C. range. The mixture was stirred for one hour. 20 g of cuprous chloride and 75 ml of hydrochloric acid were added. The mixture was allowed to stand overnight and then filtered. The solid was washed with water, dried at 50° C. and purified by treatment with carbon black in alkaline solution (200 ml of water and 25 ml of 36° Be' caustic soda lye) and then 25 ml of hydrochloric acid was added. 40 g of 6 -chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P. 162° C.; yield: 74%).
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.COCCOC>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>[C:1]([C:3]1[C:4]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=2[Cl:29])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1I
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: COCCOC
Product: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 99.7 %

Procedure:
A mixture of ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 0.000679 mol), 2,4-dichlorophenylboronic acid (262 mg, 0.00137 mol), tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.000044 mol) and sodium carbonate (220 mg, 0.0021 mol) in water (3 mL, 0.1 mol) and 1,2-dimethoxyethane (10 mL, 0.1 mol) was flushed with argon and then irradiated in microwave at 140° C. for 12 min. The reaction mixture was filtered and concentrated in vacuum to afford ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 99%). LCMS: (FA) ES+ 443.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:30][NH2:31]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([NH:30][NH2:31])=[O:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NN
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.061 g, 2.16 mmol) was dissolved in THF (5 mL) then 1,1′-carbonyldiimidazole (0.390 g, 2.38 mmol) was added and the reaction was heated to 70° C. for 40 minutes. The reaction was then cooled to 0° C. and hydrazine monohydrate (0.220 mL, 4.32 mmol) was added. The reaction was then allowed to slowly warm to room temperature and stirred overnight. Standard aqueous workup afforded the title compound, which was brought to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1
Product: Cc1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 14 h
Yield: 92.4 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (5.114 g) was added to 4-chloro-3-nitrotoluene (3.434 g) and the mixture was stirred for 14 hours at 125° C. The reaction mixture, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.93 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=1:0-10:1), thereby yielding the entitled compound (4.39 g) as reddish orange oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl-].[Na+]>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14](=[N:1][OH:3])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)c1cc(I)ccc1F
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1cc(I)ccc1F
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
Employing the method utilized by Fray (Fray, J. M., Cooper, K., Parry, M. J., Richardson, K., Steele, J. J. Med. Chem. 1995, 38, 3514-3523), a solution of sodium nitrite (0.52 g) in water (3 mL) is added dropwise to a solution of ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate (Preparation 15, 2.4 g) in glacial acetic acid (3 mL) at 5° C. with stirring. After 1.5 h, the mixture is poured into saturated aqueous sodium chloride and extracted with dichloromethane. The organic extracts are washed with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated in vacuo to give a sticky oil which is flash chromatographed on silica gel (230-400 mesh, 10 g) eluting with 20% ethyl acetate and hexane to give, after concentration of product fractions, 1.31 g of the title compound as a yellow liquid (˜3/1 ratio of oxime isomers). Physical characteristics: MS (ESI+) m/z 366 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[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:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:21]([O:23]CC3C=CC(OC)=CC=3)=[O:22])=[C:14](/[CH:17]=[CH:18]\[CH2:19]Cl)[CH2:15][S:16][C@H:11]12)=[O:8].[I-].[Na+].[CH3:62][N:63]([CH2:65][C:66]1[S:70][CH:69]=[N:68][C:67]=1[CH3:71])[CH3:64]>>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][F:1])/[C:7]([NH:9][C@@H:10]2[C:33](=[O:34])[N:12]3[C:13]([C:21]([O-:23])=[O:22])=[C:14](/[CH:17]=[CH:18]/[CH2:19][N+:63]([CH3:64])([CH3:62])[CH2:65][C:66]4[S:70][CH:69]=[N:68][C:67]=4[CH3:71])[CH2:15][S:16][C@H:11]23)=[O:8])[N:36]=1
Reactant: Cc1ncsc1CN(C)C
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OCCF)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ncsc1C[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3csc(N)n3)[C@H]2SC1
Yield: 32.3 %

Procedure:
p-methoxybenzyl 7β[(Z)-2-fluoroethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate (1.3 g), sodium iodide(0.68 g) and 5-dimethylaminomethyl-4-methylthiazole(0.27 g) were reacted in the same manner as described in Example 1 to obtain the target product (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C)C=O.O>[CH3:25][N:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)N1CCOCC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(CCCCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[5-(N-t-butoxycarbonylamino)valeryl]morpholine (1.656 g) in dry N,N-dimethylformamide (20 ml) were added sodium hydride (60% dispersion in mineral oil: 347 mg) and methyl iodide (2.462 g) at 0°-5° C. under nitrogen atmosphere. After being stirred for 6 hours at room temperature, the reaction mixture was added to ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with 0.5N hydrochloric acid (200 ml), water (200 ml), aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 4-[5-(N-methyl-N-t-butoxycarbonylamino)valeryl]morpholine (1.093 g) as an oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]([C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]4[N:49]=[CH:50][N:51]=[C:25]34)[CH2:20][CH2:19]2)=[CH:16][N:15]=[CH:14]1>C(OCC)(=O)C>[O:13]1[C:17]([C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]4[N:49]=[CH:50][N:51]=[C:25]34)[CH2:20][CH2:19]2)=[CH:16][N:15]=[CH:14]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogen carbonate (0.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.95 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.098 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C(#N)C>[OH2:19].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18](=[S:22])[NH2:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: CC#N
Product: NC(=S)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Reaction time: 5 h
Yield: 29.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide (3.44 g, 0.012 mole) and phosphorus pentasulfide (1.47 g, 0.0033 mole) in 150 ml of dry acetonitrile (dried over molecular sieves) was heated at reflux for 3 hr. The reaction mixture was filtered and washed with boiling acetonitrile. The solid residue in the flask was treated with boiling methanol and filtered. The methanol and acetonitrile filtrates were combined and evaporated to dryness. The residue was treated with acetone and filtered through a silica gel filter funnel. The filtrate was treated with Florisil®, filtered, and evaporated to dryness. The residue was treated with acetone, applied to a silica gel column (7×15 cm), and eluted with acetone. The appropriate fractions were combined and evaporated. The residue was dissolved in hot methanol, treated with activated charcoal, and filtered through a Celite pad. The filtrate was concentrated to initiate crystallization. The mixture was diluted with water and ice, then filtered to collect the precipitate which was washed with water. The solid was dried under high vacuum overnight at room temperature, then at 55° C. for 5 hr. to give 0.31 g product (8.3%), mp 226°-29° C. with decomposition.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[OH2:27]>>[CH3:5][S:6]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][CH:8]=1)(=[NH:1])=[O:27]
Reactant: CSc1ccc(-n2cnnn2)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)c1ccc(-n2cnnn2)cc1

Procedure:
Sodium azide (2.6 g.) was added at 35°-45° C. over 11/2 hours to a stirred mixture of 1.78 g. (0.01 mol) of 1-[p-(methylthio)phenyl]-1H-tetrazole and 6 ml. of concentrated sulfuric acid. After 4 additional hours of stirring the chloroform was poured off, the remaining paste diluted with water, filtered, and the filtrate adjusted to pH 8.5 and chilled. White crystals, m.p. 180°-181° C. were isolated.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=1[CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:3][C:4]2[N:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][C:5]=2[CH3:12])[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ncn(C(C)C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2c(C)ncn2C(C)C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1-(propan-2-yl)-1H-imidazole hydrochloride (824 g, 3.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (970 mg, 7.0 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in acetone (30 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-8% MeOH/DCM), affording 6-methyl-2-({[4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}-sulfanyl)pyrimidin-4-ol (215 mg, 28% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.36 (d, 3H, J=6.7 Hz), 2.09 (s, 3H), 2.19 (s, 3H), 4.31 (m, 1H), 4.45 (s, 2H), 6.00 (s, 1H), 7.66 (s, 1H); M+ 279. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH3:10])[C:6]=2[C:11]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:12][C:11]2[C:2](=[CH:3][CH:4]=[C:5]3[N:9]=[N:8][N:7]([CH3:10])[C:6]3=2)[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Cn1nnc2ccc(N)c(N)c21
Agent: Cl
Solvent: O
Product: Cn1nnc2ccc3nc(O)c(O)nc3c21

Procedure:
A solution of 6,7-diamino-1-methylbenzotriazole (1.63 g, 10 mmol) and oxalic acid dihydrate (2.0 g, 16 mmol) in 50 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h. The mixture was cooled on ice and the precipitate was collected by filtration, washed with water and ethanol affording 1.94 g (89%) of the title compound: m.p.>300° C.: IR (KBr): 3520-2400, 1700 cm-1 ; 1H-NMR (DMSO-d6): 4.63 (s, 3H, CH3), 6.70 (d, J=9 Hz, 1H; ArH), 7.60 (d, J=9 Hz, 1H, ArH), 11.3 (very broad s, 1H, OH), 12.1 (broad s, 1H, OH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:41][C:42]1[C:43]([C:56]([NH2:58])=[O:57])=[N:44][N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[C:46]=1[CH2:47][CH3:48]>C(OCC)(=O)C>[C:56]([C:43]1[C:42]([NH:41][C:6](=[O:7])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:46]([CH2:47][CH3:48])[N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[N:44]=1)(=[O:57])[NH2:58]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Reactant: CCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (0.875 Kg, 2.55 mol) was charged followed by ethyl acetate (7L, 8 ml/g) to the reaction vessel and 2 ml/g was distilled off at atmospheric pressure to ensure the reaction system was dry. The slurry was cooled to room temperature under a nitrogen atmosphere and carbonyldiimidazole (0.43 Kg, 2.65 mol) added in one portion. The slurry was heated to 35° C. and held for half an hour. The reaction was further heated to 45-50° C. and held for a further half hour. The reaction was then heated to reflux, stirring at reflux for one hour. On confirmation of complete imidazolide formation the reaction was cooled to 45-50° C. under nitrogen and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (0.59 Kg, 2.42 mol) charged in one portion before returning to reflux and a further 1 ml/g was distilled off at atmospheric pressure. The reaction was stirred at reflux for 16 hours with crystallisation of product occurring after 4 hours. The reaction was cooled to 10-15° C. and granulated for one hour. The reaction slurry was filtered and washed (ethyl acetate) which was dried under vacuum at 50° C. to afford the title compound (1.252 Kg, 90.7%) as a white solid. Mpt 178-179° C. ? (CDCl3): 1.04 (3H, t), 1.06 (3H, t), 1.59 (3H, t), 240 (2H, q), 2.50 (4H, q), 2.90 (4H, q), 3.08 (4H, m), 2.78 (2H, q), 5.35 (1H, s) 5.48 (2H, s), 6.68 (1H, s), 6.92 (1H, d), 7.22 (IH, m), 7.65 (1H, m), 8.58 (1H, d), 8.64 (1H, d), 8.83 (1H, d). m/z (Found:571 [M+H]+, 100%. C26H34N8O5S requires 571.67).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]=[O:15].[OH-].[Ca+2].[OH-]>>[CH2:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[OH:15]
Reactant: C=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Ca+2]
Agent: [OH-]
Product: OCn1c2ccccc2c2ccccc21

Procedure:
105 parts of carbazole, 145 parts of formalin (40% W/V formaldehyde in water) and 265 parts of IMS were thoroughly mixed and then 10 parts of calcium hydroxide added. The mixture was heated with stirring at a temperature of 56° to 58° C. for an hour and thereafter filtered to remove unreacted carbazole and the calcium hydroxide. As the IMS cooled, the product N-methylol carbazole crystallised out of solution. The white crystals were separated by filtration and dried under vacuum at 50° C. for 2 hours. The crystals were identified by proton NMR and IR spectroscopy as NMC, m.p. 127°-129° C., and contained less than 1% carbazole according to gel permeation chromatography, which was used with a U.V. detector. (λ=254 mm).