Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[CH3:15].[N:16]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:16])=[CH:5][C:4]=1[CH3:15]
Reactant: COC(=O)CNc1ccc(OC)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 7.5 %

Procedure:
N-(4-methoxy-3-methylphenyl)glycine, methyl ester (Intermediate 96, 5 g, 0.0239 mol) was dissolved in a mixture of glacial acetic acid (45 ml) and water (3 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (1.7 g, 0.0251 mol) in water (5 ml) over 30 minutes and the reaction was stirred for one hour. Zinc dust (6 g, 0.093 mol) was added over 11/2 hours at the same low temperature and stirred at room temperature for 1 hour. The reaction was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, then dried (MgSO4) and evaporated to give a yellow oil. This was purified by flash column chromatography on silica (Merck 9385; 100 g) eluting with ether-hexane 1:1 to give the title compound as an orange oil (0.4 g, 7%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([CH3:24])[C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]([F:33])([F:32])[C:27]1[CH:31]=[CH:30][NH:29][N:28]=1>>[CH3:23][O:22][C:6]1[C:5]([CH3:24])=[C:4]2[C:9]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]([N:29]3[CH:30]=[CH:31][C:27]([C:26]([F:33])([F:32])[F:25])=[N:28]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(C)c(OC)ccc23)cc1
Yield: 19 %

Procedure:
Compound 87c was synthesized from compounds 46b and 86a following the procedure as described for compound 86a, as a white solid in 19% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39](=[O:41])[CH3:40])=[CH:18][C:17]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:14])=[O:15])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1)C(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester (1.41 g, 3.10 mmol) in methylene chloride (100 mL) and Et3N (0.44 mL, 3.10 mmol) was added acetyl chloride (0.25 mL, 3.1 mmol). The reaction was stirred for 3 h. The solvent was removed and replaced with EtOAc (150 mL). The organic solution was washed twice with 5% citric acid, saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and the solvent was removed. The resulting crude product was purified using silica gel flash chromatography (20% hexanes in EtOAc). (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained in 63% yield (0.96 g) as an off white foam. MS (APCI) m/z 490.2 (M−1).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:4]=1.CCN(S(F)(F)[F:39])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:39][CH2:2][C:3]1[C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CF)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of 1-methylethyl 4-[({2-(hydroxymethyl)-6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (131 mg, 0.28 mmol) in CH2Cl2 (5 mL) was cooled to −78° C. DAST (0.12 mL, 0.85 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured into aqueous NaHCO3 and extracted with EtOAc (50 mL×2). The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a purplish-red oil. The crude material was purified by flash chromatography on a silica gel column eluted with 20% EtOAc/CH2Cl2 to give 86 mg (66%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.3 Hz), 7.80-7.75 (m, 1H), 7.31 (d, 1H, J=8.8 Hz), 5.58 (d, 2H, J=47.4 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.22 (bs, 2H), 3.92 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:25][CH2:26][CH3:27])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39]C)=[O:38])[CH:34]=[CH:33][CH:32]=1>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>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:25][CH2:26][CH3:27])[C:9]([O:13][CH2:14][C:15]3[CH:16]=[C:17]([C:31]4[N:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][CH:32]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: CCCc1c(OCc2cccc([Sn](C)(C)C)c2)ccc2c1ccn2CC(C)(C)C
Reactant: COC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(OCc2cccc(-c3cccc(C(=O)O)n3)c2)ccc2c1ccn2CC(C)(C)C
Temperature: 110 °C

Procedure:
1-(Bromomethyl)-3-iodobenzene was used to alkylate 1-(2,2-dimethyl-propyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (3.4 g, 7.3 mmol), hexamethyldistannane (5.0 g, 15 mmol), Pd(PPh3)4 (0.80 g, 0.69 mmol), and THF (40 mL) was heated at 60° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography to give 1-(2,2-dimethylpropyl)-4-propyl-5-{[3-(trimethylstannyl)-benzyl]oxy}-1H-indole as a yellow oil. A mixture of the above stannane (0.35 g, 0.70 mmol), methyl 6-bromopyridine-2-carboxylate (0.22 g, 1.0 mmol), Pd(PPh3)4 (0.10 g, 87 μmol), and degassed toluene (10 mL) was heated at 110° C. for 24 h under N2 and then allowed to cool to rt. The reaction mixture was purified by silica gel chromatography (hexanes:ethyl acetate—1:0→2:1) to give a yellow oil. MS (ESI): 471.1 (M+H). A similar procedure as outlined in example 26 was followed for the saponification of the above ester. 1H NMR (DMSO, 500 MHz) 13.18 (br s, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 8.09 (t, 1H), 8.01 (d, 1H), 7.61-7.53 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.40 (d, 1H), 5.19 (s, 2H), 3.91 (s, 2H), 2.84 (t, 2H), 1.68-1.58 (m, 2H), 0.93 (s, 9H), 0.91 (t, 3H). MS (ESI): 457.1 (M+H).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]=3[Cl:29])[CH3:21])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:30][CH2:31][CH2:32]O>>[N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:32][CH2:31][Br:30])[C:23]=3[Cl:29])[CH3:21])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Reactant: OCCBr
Product: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(OCCBr)c1Cl
Yield: 70.5 %

Procedure:
Methyl 5-(1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 11A, 600 mg, 1.4 mmol) and 2-bromoethanol (120 μL, 1.7 mmol) were coupled using a procedure analogous to Example 4, Step A to give 529 mg of the title compound (71%), 1H NMR (400 MHz, d6-DMSO) δ 8.85 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.39-7.31 (m, 5H), 7.10 (dd, J=8.0 and 1.6 Hz, 1H), 5.98 (m, 1H), 4.40-4.37 (m, 2H), 3.81-3.79 (m, 5H), 1.81 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][N:29]([C:13](=[O:15])[CH2:12][N:5]4[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:11]5[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]4)[C:28]=3[CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2cccnc21
Product: O=C(Cn1nc(C(F)(F)F)c2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-70% EtOAc in hexanes) to provide 58 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.65 (dd, J=2.6, 4.7 Hz, 1H), 8.32 (s, 0.8H), 8.24 (d, J=8.2 Hz, 1H), 7.72 (s, 0.2H), 7.44-7.52 (m, 2H), 7.33 (dd, J=4.3, 8.2 Hz, 1H), 7.13-7.23 (m, 2H), 5.76 (s, 0.4H), 5.65 (s, 1.6H), 3.93 (m, 2H), 2.89 (t, J=6.3 Hz, 2H), 2.17 (m, 1.6H), 2.06 (m, 0.4H); MS: (ES) m/z calculated for C21H17F4N6O [M+H]+ 445.1, found 445.1.
Reaction SMILES: [C:1](O[C:5](=[O:7])C)(=[O:3])C.[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14].CC(CC(O)=O)=O.[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C(O)=O>[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7].[CH:1]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:15])([OH:14])[OH:16])[OH:8])=[O:3].[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=P(O)(O)CCCNO
Agent: CC(=O)CC(=O)O
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: O=CO
Solvent: O
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.5 h

Procedure:
Formic acid (2 ml.) was added dropwise to acetic anhydride (2.45 ml.) at ambient temperature with stirring. After the stirring was continued at the same temperature for 30 minutes, 3-(N-hydroxyamino)propylphosphonic acid (3.10 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for an hour and then concentrated under reduced pressure to give an oily residue, which was dissolved in water (25 ml.). To the aqueous solution was added dropwise a solution of diacetic acid salts of N,N'-dibenzylethylenediamine (3.60 g.) in water (15 ml.) under ice-cooling and with stirring. The resultant mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was crystallized with a mixture of methanol (30 ml.) and ethanol (40 ml.). The crystals were separated by filtration, washed with ethanol (20 ml.) and then dried to give crystals (3.34 g.). The same crystals (1.00 g.) were recovered from the filtrte and the washings by concentrating them under reduced pressure to a volume of 40 ml. and allowing the concentrate to stand overnight at 4° C. A part (3 g.) of the combined crystals, as obtained above, was recrystallized from a mixture of water and ethanol (1:6) (40 ml.) to give N,N'-dibenzylethylenediamine bis[3-(N-formyl-N-hydroxyamino)propylphosphonate] (2.60 g.) in the form of needles.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1)(=O)C.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Nc1ccc(OC(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
18.8 g (0.08 moles) 4-acetylaminotetrafluoroethoxybenzene of Step 1 are dissolved, accompanied by ice cooling at 0° C., in 150 ml concentrated sulfuric acid. Nitration is carried out at the same temperature with a mixture of 10.3 ml (0.15 moles) concentrated nitric acid (d=1.4 g/ml) and 10 ml concentrated sulfuric acid. After standing overnight this mixture is poured onto approximately 500 g ice. A viscous oil precipitates. The oily phase is decanted and repeatedly washed with water. The oil is made to solidify by means of cooling and scraping. It is, according to DC, a mixture of acetylaminonitro- and aminonitro-compounds. It is then saponfied by means of dissolving and boiling, with reflux, with methanol and concentrated hydrochloric acid and then neutralized with ammonia. The 4-amino-3-nitrotetrafluoroethoxybenzene precipitates. Yellow crystals with a melting point of 78° C. were obtained. Yield: 13.4 g (67% of the theoretical yield)
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.NO.O>CO>[NH2:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Agent: NO
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)nc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 117b (2.44 g, 5.91 mmol), methanol (80 mL), 50% hydroxylamine in water (390 mg, 11.8 mmol) and the reaction was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated, and the resulting residue was purified by column chromatography to afford an 86% yield (1.27 g) of 117c as a yellow solid: mp 103-104° C.; 1H NMR (500 MHz, CDCl3) δ 7.94 (d, 1H, J=2.0 Hz), 7.49 (dd, 1H, J=8.5, 2.5 Hz), 6.53 (d, 1H, J=8.5 Hz), 4.48 (br s, 2H), 4.30 (t, 2H, J=8.5 Hz), 3.88 (dd, 2H, J=8.5, 4.5 Hz), 3.62 (m, 1H), 1.44 (s, 9H); MS (ESI+) m/z 249.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:29])=[C:5]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: COCN(c1cccc(-c2csc(N)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCN(c1cccc(-c2nc(N)sc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
1.26 g (2.94 mmol) of N-[3-(2-amino-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)-benzenesulfonamide were dissolved in 30 ml of dry DCM and 523 mg (2.94 mmol) of N-bromosuccinimide were added. The resulting solution was stirred at r.t. for 30 min. The mixture was diluted with the same solvent and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diisopropyl ether and filtered to afford 1.4 g (93%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[C:20]1([NH:26][C:27](=[S:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:7]12([C:17]([NH:29][NH:28][C:27]([NH:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:30])=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: NNC(=S)Nc1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
Pyridine (0.808 mL, 10 mmol) was added dropwise at room temperature to a stirred solution of 1-adamantanecarbonyl choride (A) (1 g, 5 mmol) and 4-phenyl-3-thiosemicarbazide (B) (0.845 g, 5.05 mmol) in CH2Cl2 (10 mL). After stirring for 4 h, the solvent was removed in vacuo, and the residue washed with water and dried to give 1-(1-adamantylcarbonyl)-4-phenyl thiosemicarbazide (C).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of crude (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g) in dichloromethane (10 mL) was added diisopropylethyl amine (0.337 g, 2.61 mmol) followed by a solution of ethyl chloroformate (0.119 g, 1.09 mmol) in dichloromethane (1 mL) dropwise over 30 minutes at 0° C. and the mixture stirred at this temperature for 2 h. The mixture was then quenched by ice and diluted with dichloromethane and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by preparative LC/MS (high pH) to provide the title compound as an off white solid (60 mg, 18%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (s, 3H), 1.07-1.21 (m, 1H), 1.23 (t, J=7.03 Hz, 3H), 1.29-1.43 (m, 3H), 1.45-1.92 (m, 13H), 2.02-2.24 (m, 2H), 2.81-3.01 (m, 2H), 3.23-3.40 (m, 2H), 3.41-3.69 (m, 5H), 4.10 (q, J=7.29 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([C:12]([Cl:17])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
89.3 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid (Example H3) are slowly heated to reflux temperature together with 60 ml of thionyl chloride and the mixture is then subsequently stirred at this temperature for 4 hours. Thereafter, it is cooled to 25° C. and concentrated to dryness in vacuo. Toluene is added twice more and the mixture is concentrated again to dryness. 94.0 g of the desired product are obtained as a yellow residue.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 42.86 g of 4-chloro-1-naphthol, 27.6 g of p-fluoroacetophenone, 33.12 g of potassium carbonate and 200 ml of dimethylacetamide was heated at 150° C., under argon for 18 hours, then poured into ice water, stirred and extracted with ethyl acetate. The extract was washed with 0.5N sodium hydroxide, 0.5N hydrochloric acid, water and brine, dried and evaporated to a residue. This residue was boiled in hexane, then cooled and the intermediate collected to yield the product as white crystals, mp 95°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]([C:11]#[C:12][C:13]([O:15][CH3:16])=[O:14])=[O:10]>CO>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][C:11](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([O:8][CH3:7])=[O:10])=[CH:3]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccsc1
Solvent: CO
Product: COC(=O)C=C(Nc1ccsc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminothiophene is redissolved in methanol (500 mL) cooled in an ice bath and dimethylacetylenedicarboxylate (80 g; 0.50 mol) is added dropwise. The mixture is stirred at room temperature for 15 hours and 30 minutes, the methanol removed under reduced pressure and 1,2-dichloroethane is added. This solvent is also evaporated off to give dimethyl 3-thienylaminobutenedioate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22][CH2:23]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:21][S:22][CH3:23])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CSCCCl
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthioethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness to afford 1-amino-2-nitro-4-methylthioethylthiobenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11]Cl.Cl>ClC1C=CC=CC=1>[Cl:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C(O)c1ccc(CCl)cc1
Temperature: 0 °C

Procedure:
272 parts of 4-methyl-benzoic acid are dissolved in 750 parts of chlorobenzene at 100° C. and are chlorinated at this temperature by the introduction of elementary chlorine under UV light; the chlorination process is ended when 71 parts of hydrochloric acid have been formed. The reaction mixture is then cooled to about 0° C., with stirring, and the precipitate which has separated out is filtered off, freed from chlorobenzene by being washed several times with low-boiling petroleum ether and dried. 307 parts of 4-(chloromethyl)-benzoic acid with a melting point of 196° to 200° C. are obtained.