Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([C:7](Cl)=[O:8])[CH2:6][O:5][N:4]=[CH:3]1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[C:21](#N)C>>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:2]2[CH:3]=[N:4][O:5][C:6]=2[CH3:21])=[O:8])=[CH:14][CH:13]=1
Reactant: CC1(C(=O)Cl)C=NOC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC#N
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
A solution of 0.05 mol of 4-methylisoxazole-4-carbonyl chloride (7.3 g) in 20 ml of acetonitrile is added dropwise, at room temperature, to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g) in 150 ml of acetonitrile. After stirring for 20 minutes, the precipitated 4-trifluoromethylaniline hydrochloride is filtered off with suction and washed twice with 20 ml of acetonitrile on each occasion, and the combined filtrates are concentrated under reduced pressure. Yield: 12.8 g of white, crystalline N-(4-trifluoromethylphenyl)-5-methylisoxa-zole-4-catboxamide (leflunomide).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:29][C:30]1O[C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:47][CH2:48]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-:66].[Na+]>C(O)C>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:37]=[CH:36][C:35]([C:33]2[O:66][C:30]([CH3:29])=[C:31]([CH2:47][CH2:48][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:17]=[CH:18][C:19]([CH:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)=[CH:20][CH:21]=4)([CH3:14])[C:4]([OH:3])=[O:28])=[CH:12][CH:11]=3)[N:32]=2)=[CH:40][CH:39]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(C3CCCCC3)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 29, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 2H, J=8.60 Hz), 7.66–7.62 (m, 4H), 7.48–7.44 (m, 2H), 7.39–7.36 (m, 1H), 7.19 (d, 3H, J=8.60 Hz), 7.07 (d, 2H, J=8.60 Hz), 6.83 (q, 3H, J=3.52 Hz), 4.13 (t, 2H, J=6.65 Hz), 3.24 (d, 1H, J=13.30 Hz), 3.12 (d, 1H, J=13.30 Hz), 2.99 (t, 2H, J=66.5 Hz), 2.38 (s, 3H), 1.82–1.69 (m, 4H), 1.41 (s, 3H), 1.37–1.22 (m, 6H). MS (ES+) m/z mass calcd for C40H42NO5 616.31, found 616.3.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14]Br)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].O.[C-:17]#[N:18].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: [C-]#N
Reactant: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)n1ccc2ccc(CC#N)cc21
Temperature: 25 °C
Reaction time: 216 h
Yield: 95.1 %

Procedure:
N-methanesulfonyl-6-bromomethylindole (280 mg, 0.97 mmol, from above) was dissolved in 1 ml of dioxane. Water (1 mL) was added followed by NaCN (52 mg, 1.07 mmol). The mixture was stirred for 9 days at room temperature. The reaction mixture was diluted with 30 ml of ethyl acetate and washed with 10 ml water. The aqueous layer was washed with 30 ml ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash column chromatography (silica gel, 40% ethyl acetate/hexane) to give 216 mg of the desired N-methanesulfonyl-6-cyanomethylindole (95% yield).
Reaction SMILES: [C:1]([C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[N:5][C:6]([CH:26]2[CH2:28][CH2:27]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=O)=[CH:11][CH:10]=1)#[N:2].[OH2:37].[NH2:38][NH2:39]>C(O)CC>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][C:6]([CH:26]3[CH2:28][CH2:27]3)=[CH:7][C:8]=2[C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:37])=[CH:13][CH:14]=2)[NH:39][N:38]=1
Reactant: O
Reactant: NN
Reactant: N#Cc1c(-c2ccc(NC(=O)Nc3ccccc3F)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Solvent: CCCO
Product: Nc1n[nH]c2nc(C3CC3)cc(-c3ccc(NC(=O)Nc4ccccc4F)cc3)c12
Yield: 26 %

Procedure:
In analogy to the GP 5, reaction of 175 mg trifluoromethanesulphonic acid 3-cyano-6-cyclopropyl-4-{4-[3-(2-fluoro-phenyl)-ureido]-phenyl}-pyridin-2-yl ester (0.336 mmol) with 62 μl 80% hydrazine hydrate in 1-propanol yielded 35 mg product (0.087 mmol, 26% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH:12]1[CH2:17][NH:16][CH:15]([CH3:18])[CH2:14][NH:13]1.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:13]1[CH2:14][CH:15]([CH3:18])[NH:16][CH2:17][CH:12]1[CH3:11]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1CNC(C)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccc(Cl)c(Cl)c2)C(C)CN1

Procedure:
A solution of 1,2-dichloro-4-chloromethyl-benzene (1.1 ml 7.89 mmol) in DMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) dissolved in DMF (25 ml). The reaction was stirred over night, poured into a mixture of EtOAc and sodium carbonate (5%). The water phase was washed twice with EtOAc and the combined organic phase once with brine, and dried over sodium sulfate. After evaporation the crude was dissolved in methanol. The dibensylated piperazine does not dissolve. The filtrate was filtered through a short silica column, using methanol as eluant and evaporated to give the pure product. Yield 812 mg, 38%
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[N:40]=[C:41]([CH2:44][O:45][CH3:46])[S:42][CH:43]=2)[C:34]1=[O:47])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:49](=O)[CH2:50][CH:51]([CH3:53])[CH3:52].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[N:40]=[C:41]([CH2:44][O:45][CH3:46])[S:42][CH:43]=2)[C:34]1=[O:47])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7]
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CNNC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(COC)n2)C1=O
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CCC(C)C)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(COC)n2)C1=O
Yield: 36 %

Procedure:
A solution of Example 280A (20 mg, 0.029 mmol) in 1,2-dichloroethane (0.3 mL) was treated with isovaleraldehyde (6.2 μL, 2 equivalents), acetic acid (3.3 μL, 2 equivalents), and sodium triacetoxyborohydride (18.5 mg, 3 equivalents) at 25° C. for 16 hrs. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and the solvents were evaporated. The residue was purified by HPLC reverse phase chromatography using water (0.1% TFA):acetonitrile (95:5) to acetonitrile (100%) to give 8 mg (36%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78 (dd, J=13.79, 6.43 Hz, 12H), 0.91 (m, 9H), 1.25 (m, 3H), 1.62 (m, 1H), 1.77 (d, J=8.82 Hz, 1H), 2.58 (m, 3H), 2.69 (m, 4H), 2.79 (m, 2H), 3.09 (m, 3H), 3.37 (s, 3H), 3.81 (m, 2H), 3.95 (m, 2H), 4.10 (s, 1H), 4.36 (m, 2H), 4.66 (s, 1H), 7.06 (m, 5H), 7.20 (m, 1H), 7.44 (m, 1H), 8.96 (s, 2H), 9.17 (s, 1H), 9.48 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].O=[C:19]1C2CCCCC=2C(=O)N1CO>>[CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]([CH3:11])[CH3:19])=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: O=C1C2=C(CCCC2)C(=O)N1CO
Agent: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O
Product: CC(C)OC(=O)C=CC1C(C(=O)[O-])C1(C)C

Procedure:
Using the procedure of Example 9, (1R, cis, ΔZ) 2,2-dimethyl-3-(3-isopropoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid and (1,3,4,5,6,7-hexahydro-1,3-dioxo-2H-isoindol-2-yl)-methanol were reacted to obtain (1,3,4,5,6,7-hexahydro-1,3-dioxo-2H-isoindol-2-yl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-isopropoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a melting point of 94° C. and a specific rotation of [α]D20 =-22.5°±2° (c=0.5% in CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>FC(F)(F)C(O)=O>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CCc1cccs1)N1CCc2cc(O)ccc2C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 14 (2.83 g) in trifluoroacetic acid (30 mL) at 0° C. was added dropwise trimethylacetyl chloride (1.4 mL) and the reaction allowed to warm to room temperature. After 4 hours, the reaction was quenched with water and concentrated, the residue was dissolved in CH2Cl2, washed with brine, dried (MgSO4), filtered and concentrated. Chromatography of the residue on silica gel (elution with 50% ethyl acetate/hexanes) provided 3.8 g of desired product.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[CH2:15][CH:16]=1
Reactant: Clc1cccc(CBr)c1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Product: Clc1cccc(CN2CC=C(c3cc4ccccc4s3)CC2)c1
Yield: 14.9 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 3-chlorobenzyl bromide (0.2 ml, 1.5 mmol) as exemplified in Example 1. The crude product was triturated with methanol to give the title compound as a pale yellow solid (50 mg, 15%); (Found: C, 69.05; H, 5.03; N, 4.07. C20H18ClNS. 0.5H2O requires C, 68.85; H, 5.49; N, 4.01%). δH (CDCl3), 2.65 (2H, m, NCH2CH2), 2.73 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.62 (2H, s, NCH2Ar), 6.19 (1H, m, NCH2 CH), 7.12 (1H, s, ArH), 7.28 (5H, m, ArH), 7.39 (1H, s, ArH), 7.67 (1H, d of d, J 6.2Hz, J 1.9Hz, ArH), 7.73 (1H, d of d, J 8.4Hz, J 1.8Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].CC(=CC)C.[Cl:12][C:13]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][C:24]([CH2:28][CH3:29])=[C:23]2[CH:30]=[O:31])=[O:16].Cl([O-])=[O:38].[Na+]>C(O)(C)(C)C.O>[C:30]([C:23]1[C:22]2[C:27](=[C:18]([NH:17][C:15](=[O:16])[C:14]3[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:13]=3[Cl:12])[CH:19]=[CH:20][CH:21]=2)[N:26]=[CH:25][C:24]=1[CH2:28][CH3:29])([OH:38])=[O:31]
Reactant: [O-][Cl+][O-]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(=O)O
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of sodium dihydrogenphosphate (395 mg) and 2-methyl-2-butene (578 mg) in tert-butanol (6 ml) and water (1.5 ml) was added 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-formylquinoline (615 mg) at ambient temperature, and to the mixture was portionwise added sodium chlorite (298 mg) at the same temperature. The mixture was stirred for 3 hours at the same temperature. The mixture was quenched by diluted hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate-n-hexane to give 4-carboxy-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (404 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([F:19])([F:18])[CH2:4][CH2:5][CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O.[N-:22]=[N+]=[N-].[Na+].[CH3:26][C:27]([O:30][C:31]([O:33]C(OC(C)(C)C)=O)=O)([CH3:29])[CH3:28]>CO.O.[Pd]>[C:27]([O:30][C:31](=[O:33])[NH:22][CH2:6][CH2:5][CH2:4][C:3]([F:18])([F:19])[C:2]([F:1])([F:20])[F:21])([CH3:29])([CH3:28])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
1,1,1,2,2-Pentafluoro-5-p-toluenesulfonyloxypentane (4.00 mg, 12.0 mmol) was dissolved in methanol (40 ml), NaN3 (936 mg, 14.4 mmol) dissolved in water (10 ml) was added thereto, and the mixture was stirred overnight at 60° C. After the reaction was completed, the reaction mixture was extracted with chloroform and washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (40 ml), (Boc)2O (2.62 g, 12.0 mmol) and Pd—C (800 mg) were added thereto, and then the mixture was stirred overnight under hydrogen. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 4,4,5,5,5-pentafluoropentylcarbamic acid t-butylester (1.12 g, yield 50%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[CH3:25][NH2:26]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[N:26][CH3:25])#[N:2]
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Reactant: CN
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1cc2ccc(CN(C)C)cc2o1
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (8.8 g., 0.024 mole) and methylamine (31 g.) in ethanol (90 ml.) is allowed to stand at room temperature for 3 hours. The solvent is evaporated at reduced pressure. The residual oil gradually crystallizes, m.p. 62°-65° C. Two crystallizations of this product from acetonitrile-ether gives 7.0 g, (84%) of N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-methylguanidine as white needles, m.p. 115.5°-117.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[N:20]2)[CH2:15][CH2:14]1)=[O:11].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@@H:16]([N:19]2[CH:23]=[C:22]([C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:25])[N:21]=[N:20]2)[CH2:17][CH2:18]1)=[O:11]
Reactant: C1CCNCC1
Reactant: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)O)nn2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)N3CCCCC3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution under Ar of 1-{cis-4-[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-cyclohexyl}-1H-[1,2,3]triazole-4-carboxylic acid (100 mg) in DMF (4 ml) were added piperidine (22 mg), TBTU (93 mg) and DIPEA (0.13 ml). The solution was stirred 1 h at RT before partitioning it between EtOAc (50 ml) and H2O (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2 to CH2Cl2 5% MeOH) afforded the product (112 mg, 95%). Off-white solid. MS 448.1 (100, [M+H]+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:21][NH2:22])([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]([CH2:21][NH:22][C:2](=[O:3])[O:4][CH2:5][CH3:6])([OH:20])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 14.75 g of ethyl chloroformate in 125 ml of dichloromethane is added, at 0° C., to a solution of 30 g of 1-benzyl-4-aminomethyl-piperidin-4-ol and 13.8 g of triethylamine in 250 ml of dichloromethane. After 10 minutes' contact, the reaction mixture is washed with 0.1N sodium hydroxide solution and then dried over MgSO4. Concentration under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([NH2:16])[CH:8]=1.[N:20]1(CCCl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:29][C:30](C)=O>>[NH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:29][CH2:30][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([NH2:16])[CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: CC(C)=O
Reactant: Nc1cc(Oc2cccc(O)c2)ccc1[N+](=O)[O-]
Agent: [Na]
Product: Nc1cc(Oc2cccc(OCCC3CCCCN3)c2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 13.4 g of the sodium salt of 4-(3-hydroxyphenoxy)-2-amino-nitrobenzene in 100 ml of acetone was stirred with 7.5 g of piperidino-ethyl-chloride for three hours on on steam bath. Then the solvent was evaporated under reduced pressure, the residue was dissolved in diluted acetic acid and the solution was made alkaline with ammonia. To isolate the free 4-[3-(2-piperidyl-ethoxy)-phenoxy]-2-amino-nitrobenzene the emulsion was worked up over ethyl acetate and after evaporating the solvent 17 g of the compound were obtained in an oily form, which could be used directly for hydrogenation.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[Br:15]Br.O>CC(O)=O.II>[Br:15][C:9]1[C:2]([OH:1])=[C:3]([O:13][CH3:14])[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: BrBr
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: COc1c(O)c(Br)cc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To the mixture of aldehyde 153 (28.0 g, 142 mmol) and I2 (1.5 g) in AcOH (160 mL) was added Br2 (8.0 mL, 157 mmol) at 0° C. The mixture was warmed up to r.t. and stirred at r.t. for 15 hours. The mixture was poured into water (2.0 L) with stirring. The mixture was stirred at r.t. for 30 min. The mixture was extracted with EtOAc (1 LX2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the compound 154 (38 g, 98%).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]([O:29][CH3:30])=[C:22]([O:31][CH3:32])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:36]([C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[NH2:37].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:36]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=2)[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]=1[O:29][CH3:30]
Reactant: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(OC)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 169 mg of [2-(3,4-dimethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 40 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(3,4-dimethoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (89 mg) as a light brown solid.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Na].[CH2:27]([OH:29])[CH3:28]>>[CH2:14]([C:3]1[C:4](=[O:13])[C:5]2[C:10]([C:11](=[O:12])[C:2]=1[O:29][CH2:27][CH3:28])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCO
Reactant: CCCCCCCCCCCCC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: [Na]
Product: CCCCCCCCCCCCC1=C(OCC)C(=O)c2ccccc2C1=O

Procedure:
Eight parts of 3-chloro-2-n-dodecyl-1,4-naphthoquinone were added in one portion to a solution of 0.54 parts of sodium metal dissolved in 100 parts of ethyl alcohol at ambient temperature. The resulting dark suspension was heated at reflux for two hours. Excess ethyl alcohol was removed in vacuo and the dark residue was recrystallized from 2-propanol to yield 7.6 parts of 2-n-dodecyl-3-ethoxy-1,4-naphthoquinone, m.p. 36°-38° C.