Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=2)[NH2:10])[O:13][CH2:12][CH2:11][O:3]1
Reactant: CC(=O)c1cccc(N)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2cccc(N)c2)OCCO1

Procedure:
A mixture of 4 g (0.029 mol) of 3-aminoacetophenone and 2.47 ml (0.044 mol; 1.5 equivalents) of ethylene glycol and a small amount of 4-toluenesulphonic acid in 60 ml of anhydrous benzene are heated to reflux with azeotropic removal of water for 4 hours. The solution is left to cool, washed successively with 20% aqueous sodium carbonate and water and then dried (MgSO4). The solvent is evaporated off under reduced pressure to leave a yellow oil, which is purified by chromatography on a column of silica gel using a diethyl ether/petroleum ether (1:1) mixture as eluent, and then crystallized in hexane to yield 3-(2-methyl-1,3-dioxolan-2-yl)aniline, m.p. 75-77° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:18]=[O:19])C.[NH4+].[Cl-]>CCOCC>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH:18]=[O:19])=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C=O)cn1
Temperature: -64 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-2-methoxy-pyridine (8.50 g, 45.2 mmol) in 100 mL dry ether under argon at −64° C. was added 1.6 M n-BuLi in hexanes. The resulting mixture was stirred at −64° C. for 40 minutes and allowed to warm to −35° C. To the resulting suspension was added 7.0 mL of dry DMF over 10 minutes. After 15 minutes, the mixture was allowed to warm to 0° C. and 75 mL of 5% NH4Cl was added. The resulting mixture was separated and the aqueous layer extracted with EtOAc (3×75 mL). The organics were combined, dried (MgSO4), filtered and evaporated under vacuum to give 2-methoxy-pyridine-5-carboxaldehyde as a tannish solid (recrystallized from hexane), 3.76 g (60.6%); m.p. 48.5-50° C.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.Cl[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33]>>[F:30][C:7]1[CH:6]=[C:5]([CH:4]=[N:3][NH:2][C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=2[CH:27]=1)=[O:10]
Reactant: CCCOC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: Cl
Product: CCCOC(=O)NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)c(F)c1

Procedure:
The title compound was prepared as described in Example 85 from 436 mg (1.0 mmol) of the amidine from Example 69 and 135 mg (1.1 mmol) propyl chloroformate. Yield: 0.29 g (60%) of a white crystalline solid, m.p. 157-159° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCl
Reaction time: 1 h

Procedure:
DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1 g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1C=CC=C[CH:13]=1.CN>C(Cl)Cl>[CH3:13][NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 4-bromophenylsulfonyl chloride (25.5 g, 100 mmol), CH2Cl2 (400 mL) and pyridine (1.6 g, 110 mol) was cooled to 0° C. and methylamine gas was added over 45 minutes. The mixture was warmed to room temperature, the solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 2N HCl (2×100 mL), water (1×200 mL), saturated NaHCO3 (1×200 mL) and then brine (1×200 mL). The solvent was dried over MgSO4 and the solvent was removed in vacuo to afford 23 g of N-methyl-4-bromophenylsulfonamide.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH2:16]([O:18][P:19]([CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>C(O)C>[CH2:22]([O:21][P:19]([CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O:18][CH2:16][CH3:17])=[O:20])[CH3:23]
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 0.43 g (18.8 mmol) Na in 50 mL of dry ethanol was added 4.09 g (18.8 mmol) of solid diethyl acetamidomalonate portionwise. This mixture was stirred at reflux under nitrogen for 2 h, then cooled to room temperature. Then, 6.05 g (18.8 mmol) of 2-(diethylphosphonomethyl)benzyl bromide in 40 mL of ethanol was added dropwise and the mixture stirred for 24 h. The salt which precipitated was removed by filtration and the solvent concentrated at reduced pressure to yield a viscous oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure to yield 6.67 g (79%) of the product as a clear oil. IR(neat): 1745.9, 1676.5, 1501.6, 1375.6, 1247.1, 1649.1, 969.4 cm-1. 1H NMR (CDCl3) δ 1.0-1.4 (m, 12H); 2.0 (s, 3H); 2.9 (s, 1H); 3.3 (s, 1H); 3.8-4.4 (m, 10H); 5.8-7.4 (m, 5H). Anal. Calcd. for C21H32NPO8 0.5H2O: C, 54.06; H, 6.92; N, 3.00. Found: C, 53.73; H, 7.11; N, 3.27.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:8]2)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:1][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[CH2:8]2
Reactant: CCCN(CCC)C1Cc2cc(OC)c(C(=O)OC)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cc(CO)c(OC)cc2C1

Procedure:
A solution of 5-carbomethoxy-6-methoxy-2-(di-n-propylamino)indan (Example 57) in THF at 0° C. under nitrogen is treated with excess lithium aluminum hydride. After work-up and purification, the title compound is obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:33]=[CH:32][C:31](OC)=[CH:30][CH:29]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:15][CH:14]=1)[CH3:8].CN1C(CCOS(C2C=CC(C)=CC=2)(=O)=O)CN(CC2C=CC([C:67]([F:70])([F:69])[F:68])=CC=2)C1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:67]([F:70])([F:69])[F:68])=[CH:32][CH:33]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1

Procedure:
Cesium carbonate (8.72 g, 26.76 mmol) is added to a solution of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (2.0 g, 8.92 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (4.34 g, 9.51 mmol) in DMF (50 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography (25% acetone in hexanes) to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.32 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz), 6.65 (d, 2H, J=8.2 Hz), 4.40, 4.32 (ABq, 2H, J=14.7 Hz), 4.14-4.07 (m, 2H), 3.91 (t, 2H, J=5.7 Hz), 3.61-3.55 (m, 1H), 3.33 (t, 1H, J=8.2 Hz), 2.96-2.79 (m, 6H), 2.22-2.15 (m, 1H), 1.87-1.80 (m, 1H), 1.40 (s, 3H), 1.21 (t, 3H, J=7.4 Hz). Rf=0.38 in 50% acetone in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:29])(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[CH:41](O)=O.C=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([NH:21][S:22]([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:41])=[O:29])(=[O:24])=[O:23])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCC3CCCCN3)c2)c1
Reactant: O=CO
Agent: C=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C(=O)NCC3CCCCN3C)c2)c1

Procedure:
A measured amount of 3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide (299 mg, 0.51 mmol, 1 eq) was dissolved in 2.3 mL of DMA. Formic acid (388 ul, 10.28 mmol, 20 eq) was added to solution with stirring followed by the addition of formaldehyde (508 ul of 37% aq. solution). The reaction was then stirred at room temperature overnight. Analysis of an aliquot of the reaction mixture by LCMS indicated the complete consumption of starting material. The reaction was diluted with methanol (2 mL). Preparative reverse-phase HPLC was used to isolate the desired product directly from the crude reaction mixture. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 □M, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. 1H NMR (400 MHz, d6-DMSO): 9.44 (s, 1H), 8.94 (s, 1H), 8.79 (t, 1H), 8.57 (s, 1H), 8.27 (d, 1H), 7.90 (d, 1H) 7.54 (t, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.18 (m, 2H), 6.60 (dd, 1H), 3.82 (s, 3H), 3.59 (m, 2H), 3.00 (s, 1H), 2.90 (s, 3H), 1.62 (m, 7H); MS (EI) for C29H31ClN6O4S: 595 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.C(OC(=O)C)(=[O:19])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:19])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cc[n+]([O-])cc1
Reactant: CC(=O)OC(C)=O
Product: COc1cc(Cl)ccc1-c1cc[nH]c(=O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide (673 mg, 2.86 mmol) and acetic anhydride (10 mL) were heated at reflux for 3 h. The mixture was concentrated under reduced pressure, and a 1:1 solution of H2O/MeOH (20 mL) was added. The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and concentrated under reduced pressure. The resulting residue was dissolved in hot 2-propanol (3 mL), triturated with Et2O, sonicated for 30 min then placed in the freezer. The solid was filtered off providing the title compound (550 mg, 91%) as a tan solid: 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.35-7.33 (m, 2H), 7.01 (s, 1H), 7.08 (d, J=6.6 Hz, 1H), 6.36 (s, 1H), 6.28 (s, 1H), 3.82 (s, 3H); ESI MS m/z 235 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:15][NH:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 50 mL round bottom flask, 2-fluoro-4-nitrobenzoic acid (3.0 g, 0.0162 mol) and DMF (10 mL) was added. To the same flask, TEA (4.6 mL, 0.0324 mol), dimethylamine hydrochloride (2.65 g, 0.0324 mol), HOBt (3.28 g, 0.0243 mol) and EDCI.HCl(4.62 g, 0.0243 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [2.8 g, 81%]. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.62 (dd, J′=8.1 Hz, J″=6.6 Hz, 1H), 3.16 (s, 3H), 2.93 (s, 3H); LC-MS (ESI): Calculated mass: 212.1; Observed mass: 213.1 (RT: 0.37 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[OH:14]
Reactant: COC(=O)c1cc(Cl)c(O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(O)c(Cl)cc1CO
Yield: 34 %

Procedure:
A solution of methyl 5-chloro-4-hydroxy-2-methoxybenzoate (intermediate 53; 204 mg; 0.94 mmol) in 4.6 ml of anhydrous THF was stirred with external ice/water bath cooling. A solution of 1M LiAlH4 in THF was dropped in (1.9 ml; 1.9 mmol). After 5 minutes the external bath was removed and the stirring prosecuted for 3 additional hours. With external cooling 0.072 ml of water were added followed by 0.072 ml of 4N NaOH solution and 0.144 additional ml of water. After filtration the cake was thoroughly washed with THF and the filtrates were concentrated giving the title compound in 34% yield.
Reaction SMILES: [O:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:10][C:11]1[NH:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:3]1([CH2:2][N:15]2[C:11]([CH3:10])=[CH:12][CH:13]=[C:14]2[C:16]#[N:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCCC2(CC1)CO2
Reactant: Cc1ccc(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)n1CC1(O)CCCCCC1

Procedure:
1-Oxaspiro[2,6]nonane (2.5 g), 5-methyl-1H-pyrrole-2-carbonitrile (2.1 g) and Cs2CO3 (6.45 g) in N,N-dimethylformamide (15 mL) was heated at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by reverse phase chromatography, and was eluted with 30%-70% acetonitrile in 0.1% TFA water solution to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[N:13]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[F:1])[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(C(F)(F)F)cc2F)cc(C(F)(F)F)[nH]1
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (9.84 g, 0.03 mol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a light yellow solid (9.99 g, 96%). MS (ISN) 341.2 [(M−H)−]; mp 47° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.96 (s, —CO2H); 7.48 (d-like, 1 arom. H); 7.40 (m, 2 arom. H); 7.18 (m, 1 arom. H); 5.86 (m, —CH═CH2); 5.15, 5.08 (2 d-like, CH═CH2); 4.03 (t, J=6.6, OCH2—CH2—CH2═CH2); 2.47 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.07 (—C═O); 158.44; 134.79; 132.18; 129.70; 121.55; 119.31; 117.04; 114.54; 66.84; 32.90.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34](O)=[O:35].N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1)C(F)(F)F
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a stirred solution of 46 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 3 mL CH2Cl2 at RT, was added 10 μl (0.1 mmol, 1 eq) trifluoroacetic acid and 80 μl pyridine (1 mmol, 10 eq). Stirring was continued overnight, and the reaction mixture was evaporated to dryness. Column chromatography on silica gel (heptane/EtOAc 6:4) yielded 6 mg (12%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifluoro-acetamide as a light yellow powder, MS: 557 (MH+).
Reaction SMILES: [Cl:1][Si:2]([Cl:9])([Cl:8])[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].N1C=CC=CC=1.[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:1][Si:2]([Cl:9])([Cl:8])[N:3]([Cl:16])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: ClCl
Reactant: C[Si](C)(C)N[Si](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)N(Cl)[Si](Cl)(Cl)Cl
Reaction time: 4 h
Yield: 75 %

Procedure:
In accordance with L. P. Filonenko and A. M. Pinchuk in J. Gen. Chem. USSR 49, 302 (1979), 13.8 g (0.063 mol) compound A1 and 5.1 ml (0.063 mol) pyridine are initially introduced into a reaction vessel in 180 ml carbon tetrachloride. 5 g (0.141 mol) chlorine are condensed at -40° C. and transferred to the reaction vessel. After stirring for 4 hours, the precipitate is filtered off and washed and the solvent is distilled off from the combined filtrates. Subsequent fractionation leads to 16.4 g of the yellowish liquid A2 in a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12
Reactant: COc1ccc(Cl)c(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)ccc2Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of Example 96 (0.030 g, 0.055 mmoles) in dichloromethane (3 ml), BBr3 (1M in dichloromethane, 0.27 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as pale green solid (0.018 g, 62% yield). MP: 192-195° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.95(s,1H),8.15(s,1H), 8.05(dd, J=7.9,1.2Hz, 1H), 7.86(m, 1H), 7.65-7.49(m,4H), 7.39(d, J=8.7Hz, 1H), 7.35(br s,1H), 7.11(t, J=7.5Hz, 1H), 6.97(dd, J=7.6,3.2Hz, 1H), 6.86(d, J=2.8Hz, 1H), 6.07(q, J=6.9 Hz, 1H),1.88(d, J=7.0Hz, 3H). Mass: 527.90(M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20](Cl)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[OH-].[NH4+:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:25])(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2Cl)c(Cl)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
2 m. moles of 3,5-Dichloro-4-(2-Chloro-4-Nitrophenoxy)Benzene-1-Sulfonyl Chloride (932 mg) in 5 ml of dichloromethane was cooled to −78° C. and 2 ml of ammonium hydroxide solution added to it. The reaction was stirred for 4 hours. The solvent was evaporated to give 755 mg (94% yield) of pure 3,5-dichloro-4-(2-chloro-4-nitro phenoxy) benzenesulfonamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:14]=[N:15][N:16]([CH3:18])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O1CCOCC1>[CH3:18][N:16]1[CH:17]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:14]=[N:15]1
Reactant: Cn1cc(Br)nn1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(CO)cc2)nn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of [4-(hydroxymethyl)phenyl]boronic acid (7.10 g), 4-bromo-1-methyl-1H-1,2-3-triazole (5.00 g), sodium carbonate (6.59 g) and tetrakis(triphenylphosphine)palladium(0) (3.59 g) in a mixed solvent of water (30.0 mL)-1,4-dioxane (100 mL) was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, the organic layer was concentrated under reduced pressure, and the residue was extracted with dichloromethane (×3). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.40 g).