Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH2:14][CH3:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:13]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCSc1nc2cc(C)c(C)cc2[nH]1

Procedure:
2-Propylthio-5,6-dimethylbenzimidazole (II) was prepared by the same procedure for I from 0,89 g (0,005 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 0,8 g (0,006 mol) propylbromide in the presence 0,24 g (0,006 mol) sodium hydroxide in a yield of 0,72 g (60%), m.p. 122-123° C. (from mixture ethylacetate with hexane).
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].C(=O)([O-])O.[Na+].[Br:28][CH:29]([CH3:33])[C:30](Br)=[O:31]>C1(C)C=CC=CC=1.O>[C:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[C:2]([NH:1][C:30](=[O:31])[CH:29]([Br:28])[CH3:33])[S:13][C:5]=2[CH2:6]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2Cl)C1
Reactant: CC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Temperature: 60 °C

Procedure:
13.3 g of toluene and 3.66 liters of water were added to 600 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine, to which 301 g of sodium hydrogencarbonate was further added. While heating to 60° C., 301 ml of 2-bromopropionyl bromide was dropped into the solution. Further, 170 g of sodium hydrogencarbonate and 170 ml of 2-bromopropionyl bromide were added in order to complete the reaction. After cooling down to room temperature, 500 g of sodium hydrogencarbonate was added, after which the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate, followed by combination with the organic phase, washing with water and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant solid matter was washed with ether to obtain 800 g of the intended product.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O>>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:35]([C:31]2[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: Cn1ccnc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1ccnc2ccc(F)cc12
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3ccnc4ccc(F)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 6-fluoroquinoline-4-carbaldehyde, followed by, followed by 1-methyl-1H-imidazole-2-carbaldehyde. 462 (M+H).
Reaction SMILES: [CH2:1]([O:17][C:18](=[O:35])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[C:43](Cl)(=[O:47])[C:44]([CH3:46])=[CH2:45].[OH-].[K+]>O1CCCC1>[CH2:1]([O:17][C:18]([CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:43](=[O:47])[C:44]([CH3:46])=[CH2:45])=[CH:23][CH:22]=1)=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(OCCCCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To an ice-cooled solution of 3-[4-(6-hydroxy-hexyloxy)-phenyl]-acrylic acid hexadecyl ester (2.6 g, 5.3 mmol), triethylamine (0.99 ml, 7.4 mmol) and 4 crystals of BHT in tetrahydrofuran (30 ml) was added dropwise methacryloyl chloride (0.68 g, 6.9 mmol). The reaction mixture was allowed to react for 7.5 hours, warming to room temperature. Potassium hydroxide solution (5 wt %, 50 ml) was added and the solution extracted 3×100 ml ethyl acetate. The combined organic layers were washed with 100 ml portions of 1M HCl, water, brine and then dried with magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane, followed by recrystallization from hexane, to give 0.37 g white solid, 95% pure by HPLC. H1 NMR (CDCl3): 7.65 (d, 1H, J=16 Hz), 7.49 (d, 2H, J=8.7 Hz), 6.90 (d, 2H, J=8.8 Hz), 6.33 (d, 1H, J=15.8 Hz), 6.12 (m, 1H), 5.57 (m, 1H), 4.19 (m, 4H), 4.00 (m, 2H), 1.96 (m, 3H), 1.8-1.4 (m, 8H), 1.28 (s, 32H), 0.90 (vt, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:28](=[O:30])[CH3:29])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1.[NH2:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:42][C@@H:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][OH:46])[C:5]([CH2:21][C:22]2[CH:38]=[CH:37][C:25]([CH2:26][N:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:28](=[O:30])[CH3:29])=[CH:24][C:23]=2[O:39][CH3:40])=[C:4]([CH3:41])[N:3]=1
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)C(C)=O
Reactant: CCC[C@H](N)CCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)C(C)=O)cc1OC
Yield: 23.8 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (25 mg) and (S)-3-aminohexan-1-ol (15 mg). The sub-title compound (5.1 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.93 (1H, d), 6.72-6.67 (2H, m), 4.82 (2H, br s), 4.65 (1H, d), 4.56 (2H, s), 4.18-4.08 (3H, m), 3.99 (2H, s), 3.88 (3H, s), 3.65 (2H, s), 3.48-3.42 (1H, m), 3.32-3.26 (1H, m), 2.33 (3H, s), 2.17 (3H, s), 1.84-1.74 (1H, m), 1.46-1.35 (1H, m), 1.23 (3H, t), 1.16-0.97 (4H, m), 0.73 (3H, t); LC-MS: m/z=502.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[SH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>CC(O)C>[SH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: Nc1ccccc1S
Solvent: CC(C)O
Product: Sc1ccccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
340.5 g (3 moles) 2-chloropyridine are added dropwise to a boiling solution of 375 g (3 moles) 2-mercaptoaniline in 1.8 liters 2-propanol with agitation and under an atmosphere of protective gas within 15 min. After termination of the addition, the mixture is agitated for 5 hours at boiling temperature. The mixture is then allowed to cool to room temperature, and the precipitated yellowish product is filtered off and washed twice with 50 ml 2-propanol per wash. After drying in a vacuum, 592 g (86% of theory), 2-(2-mercapto-phenylamino) pyridine is obtained as colorless to yellowish crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(OC(C)C)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: Nc1ncc(Cl)cc1/C=C/C(=O)N1CCOCC1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and morpholine as a yellow solid following crystallisation from isopropyl alcohol and trituration with diisopropyl ether:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:4][N:3]=1.[OH-:15].[K+].C(Br)(Br)Br.[OH-].[K+].[CH:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1.C1([CH2:31][OH:32])CC1>O1CCOCC1>[CH:23]1([CH2:26][O:27][CH:11]([C:10]2[CH:13]=[CH:14][C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)=[CH:8][CH:9]=2)[C:31]([OH:32])=[O:15])[CH2:25][CH2:24]1
Reactant: OCC1CC1
Reactant: Cc1nnc(-c2ccc(C=O)cc2)o1
Reactant: [OH-]
Agent: [K+]
Solvent: BrC(Br)Br
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccc(C(OCC3CC3)C(=O)O)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (5.3 g, 27.7 mmol) in cyclopropylmethanol (25 mL) and anhydrous dioxane (25 mL) at 0° C. (bath temperature) was added several drops of a solution of KOH (7.77 g, 138.5 mmol) in cyclopropylmethanol (35 mL). Bromoform (3.1 mL, 35.2 mmol) was added, then the remaining KOH/cyclopropylmethanol solution was added over a period of 20 min. After stirring for 30 min, the reaction mixture was allowed to warm slowly to room temperature overnight then concentrated to dryness. After dissolving in a minimum amount of H2O, the residue was acidified to pH 1 with concentrated HCl. The aqueous mixture was extracted with EtOAc several times with the addition of brine to the aqueous layer during extraction. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 2-(cyclopropylmethoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid as a semisolid which was then recyrstallized from Et2O (0.5 g, 7% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(F)c2)CC1
Yield: 100.5 %

Procedure:
The solution of 4-(3-fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 6.4 mmol) in ethyl acetate (20 mL) in the presence of 10% palladium on carbon was shaken under the hydrogen with a pressure of 50 psi at room temperature for 2 hr. The reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layer was collected, concentrated, and dried to give 4-(4-amino-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.90 g, crude) as a light red solid, which was directly used in the next step reaction without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:10])[C:7](O)=[O:8].[NH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:5][CH:6]([F:10])[C:7]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH3:16])=[O:8]
Reactant: O=C(O)C(F)F
Reactant: CCOC(N)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)NC(=O)C(F)F
Temperature: 25 °C
Yield: 93.3 %

Procedure:
During a thirty minute period 65.4 g (0.55 mole) of thionyl chloride was added dropwise to 50.0 g (0.52 mole) of difluoroacetic acid with stirring, while maintaining a reaction temperature of 20°-25° C. After complete addition the mixture was stirred at room temperature for 1.5 hours and 46.4 g (0.52 mole) of urethane was added. The resultant mixture was heated at reflux for approximately three hours then allowed to cool to room temperature and stir for approximately 18 hours. The reaction mixture was again heated at 77° C. for two hours. Unreacted materials were removed from the reaction mixture by evaporation under reduced pressure leaving 81.1 g of ethyl difluoroacetylcarbamate as a semi-solid residue.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([C:10]#N)=[CH:8][N:7]=[CH:6][CH:5]=1.CO.C([O-])(O)=[O:15].[Na+]>Cl.C(Cl)(Cl)Cl>[C:10]1(=[O:15])[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[CH2:3][CH2:2][O:1]1
Reactant: N#Cc1cnccc1CCO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1OCCc2ccncc21
Yield: 67.75 %

Procedure:
4-(2-Hydroxyethyl)nicotinonitrile (I-65b: 1.1 g) in concentrated HCl (30 mL) was refluxed overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure and the crude residue was dissolved in water. The resulting reaction mass was basified with saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 750 mg of the product (67.75% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]([NH:24][C:25](=NC(OC)=O)SC)=[O:23].CC(O)=O>CO.[Pd]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=3)[CH:14]=[CH:15][C:16]=2[N:17]=[C:25]1[NH:24][C:22](=[O:23])[O:21][CH3:20]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CNc1cc(Oc2ccc(N)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2ccc(Oc3ccc(N)cc3)cc2n1C
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 84.7 %

Procedure:
After hydrogenation of 4-(3-methylamino-4-nitrophenoxy)aniline (Intermediate 8G-519.2 mg, 2.0 mmol) with 5% Pd—C in MeOH (20 mL), 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0 mmol) and AcOH (2.0 mL) was added then stirred at 85° C. for 5.5 hrs. After cooling, the mixture was added 2N HClaq. (25 mL) then stirred at 65° C. for 2 hrs. The mixture was passed through celite pad to remove catalyst and the solvent was removed by evaporation. The residue was extracted with ethyl acetate. The organic layer was washed with NH4OH(aq). and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (529.1 mg, 85%): MS m/e 313 (M+1).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([O:17][CH3:18])=[O:16].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([O:17][CH3:18])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: COC(=O)C1CCCCCC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -5 °C

Procedure:
Methyl 2,2-di(tertiary-butylperoxy)-1-cycloheptanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (12.21 g, 0.1250 mol) to 99% methyl 2-oxo-1-cycloheptanecarboxylate (8.600 g, 0.0500 mol) at room temperature in a three necked 125-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (7.540 g, 0.0600 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for ninety minutes with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed by gas chromatography. The purity was found to be 17%. This product was not purified due to low conversion of product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([C:22]1[NH:32][C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:21].O[CH:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[C:45]#[N:46])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[CH2:20]([C:22]1[N:32]([CH:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43]4[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=4[C:45]#[N:46])=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:21]
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2O
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triphenylphosphine (393 mg, 1.5 mmol) in toluene was slowly added diethylazadicarboxylate (261 mg, 1.5 mmol). After 1 hour, this solution was added to a mixture of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (350 mg, 2.0 mmol) and 2-(1-hydroxy-indan-5-yl)-benzonitrile (246 mmol, 1.01 mmol). The reaction mixture was stirred for 17 hours at room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes. The residue was dissolved in CHCl3, hexanes were added to precipitate out a white solid. The mixture was filtered and the filtrate was concentrated in vacuo to give a yellow oil which solidified upon standing.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)([O-])=O.C(OCC)(=O)C.O>[Fe].C(O)(=O)C>[O:15]1[C:14]2[CH:18]=[CH:19][C:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:12][C:13]=2[O:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCO2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccccc1Nc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
13.6 g (244 mmol) of iron powder and 10.5 g (40 mmol) of N-(2-nitrophenyl)benzo[d][1,3]dioxol-5-ylamine were added to a solvent mixture of ethyl acetate (130 ml), water (65 mL) and acetic acid (15 mL), and the mixture was stirred for 1 hour at 70° C. The reaction solution was cooled to room temperature, and the waste was separated by filtration using a filter aid. The organic layer of the filtrate was batched off, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 9.2 g (yield: 99%) of N-(benzo[d][1,3]dioxol-5-yl)benzene-1,2-diamine as white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)=[CH:10][CH:9]=1>>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCCSc1ccc(O)cc1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Oc1ccc(SCCCCCN2CCOCC2)cc1

Procedure:
Lithium aluminum hydride reduction of the amide was accomplished according to the procedure of Example 5, giving 26.1 g of the 4-(5-(4-hydroxyphenylthio)pentyl)morpholine as a white solid. Recrystallization from ethanol gave the product as white crystals, mp 168°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Yield: 124.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.05 g), aminoguanidine hydrochloride (0.021 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (5 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 147) (0.04 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:27])[F:28])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCOC2)cc1
Yield: 23.4 %

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 200 mg (0.77 mmoles) of the product obtained in Stage 1 of Example 2 and 3 ml of butanol and using 0.130 ml of 4-(trifluoromethoxy)-benzenamine (0.96 mmoles) in place of the benzylamine. In this way 72 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([NH:22][C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:20][CH:19]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>ClCCCl>[CH:37]1([C:40]([N:22]2[C:21]3[C:26](=[CH:27][C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)=[CH:19][CH:20]=3)[N:25]([C:28]([O:30][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[CH2:24][C@@H:23]2[CH3:36])=[O:41])[CH2:39][CH2:38]1
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
N,N-Diisopropylethylamine (0.148 mL 0.846 mmol) was added to a solution of (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.062 g, 0.169 mmol) and cyclopropanecarbonyl chloride (0.077 mL, 0.846 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-cyclopentyl 4-(cyclopropanecarbonyl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.056 g, 76%) as a an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71-0.91 (m, 3 H), 0.93-1.12 (m, 8 H), 1.48-1.99 (m, 9 H), 3.42-3.55 (m, 1 H), 3.75 (tt, J=7.33, 3.81 Hz, 1 H), 3.93 (br dd, J=12.75, 6.30 Hz, 1 H), 4.86-4.98 (m, 1 H), 5.14 (td, J=5.50, 2.79 Hz, 1 H), 7.29-7.44 (m, 2 H), 7.76 (s, 1 H), 7.91 (s, 1 H), 8.17 (s, 1 H). MS (ESI, pos. ion) m/z 435 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([NH2:18])[CH:4]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[C:7]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Solvent: c1ccncc1
Product: CN(C)c1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
N1,N1-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (324 mg, 1.24 mol) was dissolved in 11 mL pyridine. The mixture was submitted to three vacuum-argon cycles and was cooled at 0° C. with an ice bath. Methanesulfonyl chloride (110 μl, 1.42 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized in hexane to obtain a solid that was filtered off and dried in the oven to give 365 mg (87% yield) of the final compound as a mixture of boronic acid and boronate ester. Purity 100%.