Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([F:35])[F:34])=[CH:29][CH:28]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([O:11]C)=[O:10])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C@@H:8]([C:13]1[C:14]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([F:35])[F:34])=[CH:29][CH:28]=2)=[C:15]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:16]2=[N:17][C:18]=1[CH3:19])[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)F)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2sc3c(c2c(-c2ccc(C(F)F)cc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 25 °C
Reaction time: 64 h
Yield: 61.9 %

Procedure:
2 M Aqueous sodium hydroxide solution (1.93 mL, 3.86 mmol) was added to a solution of (S)-methyl 2-(tert-butoxy)-2-(4-(4-(difluoromethyl)phenyl)-2-methyl-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (183 mg, 0.39 mmol) in 1:1 tetrohydrofuran/industrial methylated spirit (4 mL) at room temperature. The resulting mixture stirred at room temperature for 64 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous solution was adjusted to pH 4 by the addition of 2 M aqueous hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the crude product as a pale orange solid. This was purified by flash column chromatography on silica eluting with methanol in dichloromethane (3-5%) to give the title compound (111 mg, 63%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ=1.01 (s, 9H), 1.90-1.35 (m, 6H), 2.70 (s, 3H), 2.85-2.78 (m, 2H), 5.07 (brs, 1H), 6.75 (t, 1H), 7.34-7.41 (brm, 1H), 7.61 (d, 2H), 7.80-7.70 (brm, 1H). LCMS (run time=5 minutes, basic): Rt=3.04 minutes; m/z 460.22 [M+H+].
Reaction SMILES: [H-].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]>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>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(/C=C/c1ccncc1)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Solvent: O
Product: O=C(CCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 113.6 %

Procedure:
Trinbutyltin hydride (0.36 mL, 1.34 mmol) was added slowly by syringe pump to a room temperature mixture of Example 14A (0.2 g, 0.78 mmol) and Pd(PPh3)4 (27 mg, 0.023 mmol), stirred overnight, diluted with water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was putrified by flash column chromatography on silica gel with 80% ethyl acetate/hexanes to provide 227 mg (100%) of the desired product. MS(ESI(−)) m/e 255 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:4])=[O:3].[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CO>[CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[S:34])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
To a suspension of 237 (20 mg, 0.059 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (26 mg, 0.146 mmol). The reaction mixture was stirred for 2 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/MeOH (19:1), to afford a solid material that was dissolved in a minimum MeOH and precipitated with hexane to afford title compound 238 (9.6 mg, 31%) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 12.48 (s, 1H), 11.81 (s, 1H), 8.69(d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.03(d, J=12.13 Hz, 1H), 7.55 (s, 2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 3H), 6.86(d, J=5.5 Hz, 1H), 3.83 (s, 2H), 3.54 (s, 3H). MS (m/z): 516.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(I)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(I)ccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-iodopicolinate 5AN (2.83 g, 10.78 mmol) in MeOH (30 ml) was added NaBH4 (1.59 g, 43.12 mmol) portion wise at 0° C. Reaction mixture was allowed to warm up to r.t. After stirring for 3 days at r.t, it was quenched with, 14 ml of 1N NaOH. Reaction mixture was diluted with DCM (200 ml). The organic layer was washed with water (2×30 ml), dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with 3/1 EtOAc/Hexane to give the desired product (4-iodo-pyridin-2-yl)-methanol 6AN (2.27 g, 90%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.C([O:12][C:13](=O)/[CH:14]=[CH:15]\[O-])C.[Na+]>CCO.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]3[N:9]=[CH:15][CH:14]=[C:13]([OH:12])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C\[O-]
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccnc2cc(C3CC3)nn12
Temperature: 80 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (415 mg, 3.37 mmol) and sodium (Z)-3-ethoxy-3-oxoprop-1-en-1-olate (0.791 g, 5.73 mmol) in EtOH (3 mL) and toluene (1 mL) was heated to 80° C. in a resealable tube. After 16 hrs the solvent was removed in vacuo. The resulting residue was dissolved in a minimal amount of warm water and triturated with 1 N HCl with cooling (0° C.) until the pH ˜1. The resulting solid was filtered and washed with water to afford 2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ol as an off-white solid that was advanced without further purification. M+H+ found=176.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[CH:14][O:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH3:24])[CH3:20].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:10]2[C@@H:14]([O:15][CH2:16][CH3:17])[C@H:23]([CH3:24])[C:22]([O:25][CH2:26][CH3:27])([O:21][CH2:19][CH3:20])[O:13][C:11]=2[CH3:12])=[O:18])=[CH:6][CH:7]=1
Reactant: CC=C(OCC)OCC
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCO[C@@H]1C(C(=O)Nc2ccc(Cl)cc2)=C(C)OC(OCC)(OCC)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (1.3 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium (0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (2 g) was added dropwise. The mixture was stirred at room temperature for two hours and evaporated to dryness. The residual gum was purified by medium pressure liquid chromatography on K60 silica using ethyl acetate/petroleum ether b.p. 60°-80° C., 15/85 v/v as eluting solvent to give two stereoisomers. The first isomer after trituration with n-hexane gave trans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.2 g), m.p. 104°-106° C. The second isomer, again after trituration with n-hexane, gave cis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (1.3 g), m.p. 125°-127° C.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCI
Reactant: O=c1ccoc(CO)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1c(CO)occc1=O
Yield: 54 %

Procedure:
To a solution of 2.75 g (0.042 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 5.93 g (0.042 mole) of 2-hydroxymethyl-3-hydroxy-4-pyrone, and the resulting mixture heated to 50°. A 12.4 g (0.046 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atomsphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 6.34 g (54%) of oily product, 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone: NMR (CDCl3): δ1.22 (3H, t, J = 7Hz), 2.30 (2H, t, J = 5.5 Hz), 4.63 (2H, s), 6.35 (1H, d, J = 6 Hz), 7.73 (1H, d, J = 6 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:22])[C@@:10]([NH2:21])(C(OC(C)(C)C)=O)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@H:10]([CH2:11][O:12][CH3:13])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: COC[C@@](N)(C(=O)NCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)—N-benzyl-2-Boc-amino-3-methoxypropanamide (9.8 g, 31.8 mmol) was dissolved in 15 mL of DCM and then 15 mL of TFA was added to the solution. The mixture was stirred at room temperature for two hours. The solvent and TFA was removed by evaporation and a white solid was obtained (12.4, 100%). Upon analysis, it was determined that on average each molecule contained 1.6 TFA. 1H NMR (500 MHz, DMSO) δ 3.30 (s, 3H), 3.69 (m, 2H), 4.05 (m, 1H), 4.35 (m, 2H), 7.25 (m, 3H), 7.35 (m, 2H), 8.23 (br., 2H), 8.95 (m, 1H). LC-MS (m/z) calcd. 208.1. Found 209.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][N:30]=[C:31]=[S:32]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:31]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[S:32])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: COCCN=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: COCCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 60 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 170 μl (5 molar equivalents) of 2-methoxyethyl isothiocyanate was added and the reaction mixture was maintained at 60° C. for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 125 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=93%) which was characterized as follows:
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[NH:17]C(=O)C(C)(C)C)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)CC.[OH-].[Na+]>[NH2:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[CH:9]([CH3:10])[NH:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(NCc1ccccc1)c1cnccc1NC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(NCc1ccccc1)c1cnccc1N
Yield: 89.8 %

Procedure:
A solution of N-[3-[1-(phenylmethylamino)ethyl]-4-pyridinyl]-2,2-dimethylpropanamide (12.2 g) in 200 ml n-propanol and 25 ml 10% aqueous sodium hydroxide was stirred at reflux for sixteen hours and thereafter cooled, stirred with water and extracted with ethyl acetate/ether. The organic extract was washed with water and saturated sodium chloride solution and thereafter dried (anhydrous magnesium sulfate), filtered and concentrated to 8.7 g oil. This oil was eluted with 20% methanol in dichloromethane through silica via flash column chromatography to yield 8 g oil. This oil was eluted with 10% methanol in dichloromethane through silica via HPLC to yield 7 g oil. Following unseccessful attempts to purify this oil as salts, the reconverted free base was again eluted with 20% methanol in dichloromethane through silica via HPLC to yield 5.5 g oil. A 3.5 g portion was converted to the dimaleate salt in methanol/ether to yield 4.5 g solid, d 78°-80°. This salt was reconverted to the free base to afford a solid which was recrystallized from 50% ether/hexane to yield 1.9 g crystals, m.p. 107°-109°.
Reaction SMILES: O=[C:2]([CH:11]1[C:16](=O)[CH2:15][CH2:14][O:13][CH2:12]1)[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]([NH2:35])=[NH:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]2[N:35]=[C:2]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[C:11]3[CH2:12][O:13][CH2:14][CH2:15][C:16]=3[N:34]=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C1CCOCC1C(=O)CCN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(CCN4CCCC4=O)n2)COCC3)ccc1-n1cnc(C)c1

Procedure:
1-(3-oxo-3-(4-oxotetrahydro-2H-pyran-3-yl)propyl)pyrrolidin-2-one (202 mg, 0.84 mmol), 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (1 equiv.) and potassium carbonate (2 equiv.) were heated to 50° C. over night in EtOH (5 mL). The crude product was extracted into DCM and solvent was evaporated. The crude product was purified by flash chromatogaphy (0-100% EtOAc in heptanes) followed by prepHPLC to afford the titled compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:23])=[CH:5][C:6]([O:20][CH2:21][CH3:22])=[C:7]([CH:19]=1)[C:8]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:23][C:4]1[C:3]([C:1]#[N:2])=[CH:19][C:7]([C:8]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:9])=[C:6]([O:20][CH2:21][CH3:22])[CH:5]=1
Reactant: CCOc1cc(C)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Yield: 30 %

Procedure:
After dissolving tert-butyl N-(5-cyano-2-ethoxy-4-methylbenzoyl)-N-methylcarbamate (79.6 g) in carbon tetrachloride, azobisisobutyronitrile (4.1 g) was added and the mixture was heated to reflux. N-bromosuccinimide (50.3 g) was gradually added to the reaction mixture in small portions at a time. After heating to reflux for 2 hours, the mixture was filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (29.81 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[NH2:5].[Cl:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:19][C:6]1[C:7]([CH3:18])=[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:2]([Cl:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: Cc1c(Cl)c(N)cc(Cl)c1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.9 %

Procedure:
Into a magnetically stirred solution of 3-chloro-4-(2,4-dichlorophenoxy)-5-methylaniline (9.0 grams, 29.7 mmol) in benzene (60 milliliters) was added solid N-chlorosuccinimide (4.4 grams, 32.7 mmol). The mixture was stirred at room temperature for 1.5 hours, transferred to a separatory funnel and washed with saturated Na2SO3 solution (3x), water (2x) and brine (1x). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product (10.08 grams) as a dark brown oil. Flash column chromatography on 500 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 2,5-dichloro-4-(2,4-dichlorophenoxy)-3-methylaniline (2.85 grams, 7.4 mmol, 25%) having a melting point of 96° C.-97° C. and 2,3-dichloro-4-(2,4-dichlorophenoxy)-5-methylaniline (2.16 grams, 6.4 mmol, 22%) having a melting point of 95° C. Recrystallization from methanol afforded analytical samples. Elemental analysis of the samples indicated the following:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:19]#[N:20])=[CH:14][CH:13]=1
Reactant: ICC1CCCC1
Reactant: N#CCc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC(CC1CCCC1)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
KHMDS (30.9 mL of a 1 mmol mL−1 solution in THF, 30.9 mmol) was added to a stirred solution of (6-chloropyridin-3-yl)acetonitrile (4.40 g, 28.9 mmol) in anhydrous THF-HMPA (3:1, 72 mL) at −78° C. After 30 min, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added. The solution was stirred at −78° C. for 4.5 h, before being allowed to warm to 20° C. over 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (20 mL), then H2O (100 mL) was added. The mixture was extracted with EtOAc (3×50 mL), then the extracts were dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (n-C6H14-EtOAc) furnished 2-(6-chloropyridin-3-yl)-3-cyclopentylpropionitrile: m/z (ES+)=235.1 [M+H]+. Step 2: This compound (2.30 g, 9.8 mmol) was heated with 50% aqueous H2SO4 (10 mL) at 130° C. for 2 h with stirring. The mixture was allowed to cool down to 20° C. over 16 h, before being neutralised with saturated aqueous Na2CO3 and extracted with CHCl3. The organic extracts were dried (Na2SO4), before being filtered and concentrated to give the title compound: m/z (ES+)=254.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)(O)[O-].[Na+]>O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Oc1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 10 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), m-chlorophenol (26 g), sodium bicarbonate (34 g), and water (200 ml) was stirred at 85° C for 10 hours. After cooling, excess m-chlorophenol was removed by extraction with diethyl ether, and 4-(m-chlorophenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated from the aqueous layer by the addition of 4N hydrochloric acid. After recrystallization from aqueous methanol, the melting point was 230°-232° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([S:16][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 38 %

Procedure:
By using 476 mg of 3,5-di-t-butyl-4-hydroxybenzenethiol, 573 mg of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 175 mg of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 371 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.Cl[CH2:20][CH2:21][N:22]=[C:23]=[S:24]>C(N(CC)CC)C>[CH3:1][CH:2]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:23]1[S:24][CH2:20][CH2:21][N:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: S=C=NCCCl
Reactant: CCCCCC(C)NCc1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCC(C)N(Cc1cccnc1)C1=NCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 3.1 g. of N-(1-methylhexyl)-[(3-pyridyl)methyl]amine dissolved in approximately 20 ml. of ethanol-free chloroform was added 1.8 g. of 2-chloroethylisothiocyanate followed by 2.08 ml. of triethylamine. The reaction mixture was stirred at room temperature overnight and then refluxed for approximately 4 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel while eluting with chloroform/acetone to afford approximately 4.0 g. of the desired product. Yield 91%.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])C.O.Cl>C1COCC1.O>[C:13]1([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[N:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.2 %

Procedure:
LiOH (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[N:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC#N
Product: O=C(O)c1ccc(N2CCOCC2)nc1

Procedure:
3.00 g 6-chloronicotinic acid in 24 ml dry acetonitrile were mixed with 16.6 ml morpholine and heated to reflux for 48 hrs. The mixture was evaporated under vacuum and the residue dissolved in water. The crude product was precipitated by addition of 10% aqueous acetic acid, isolated by filtration and washed with water and methanol to give 1.83 g of the title compound.