Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7]([Cl:9])[Cl:8].II>>[F:3][C:4]([F:14])([F:15])[C:5]1[CH:13]=[C:12]([Cl:1])[CH:11]=[CH:10][C:6]=1[CH:7]([Cl:9])[Cl:8]
Reactant: ClCl
Reactant: FC(F)(F)c1ccccc1C(Cl)Cl
Agent: II
Product: FC(F)(F)c1cc(Cl)ccc1C(Cl)Cl
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A 500-ml four-necked round bottom flask equipped with thermometer, mechanical stirrer, Dimroth condenser and chlorine-introducing tube was charged with 570.0 g (2.5 mol) of o-trifluoromethylbenzalchloride, 11.5 g (2.5 mol %) of ferric chloride and 1.5 g (0.5 mol %) of iodine. Then, the reaction temperature was raised to 60° C. while the mixture was kept stirred. When the reaction temperature reached 60° C., chlorination was started by continuously introducing chlorine at a rate of 0.5 mol/hr. After the lapse of 2 hr, the reaction temperature was raised to 80° C., and then the reaction was continued for another 5 hr. After the 7-hr reaction, conversion was 97.0%. Then, the reaction liquid was put into a 1000-ml separating funnel, and washed two times with 500 ml of water. The mixed liquid was allowed to separate into two layers and the aqueous layer was removed. The organic phase was dried with magnesium sulfate, and then magnesium sulfate was removed by vacuum filtration. As the result, 634.2 g of 2-trifluoromethyl-4-chlorobenzalchloride (purity: 72.1%) was obtained. The yield of this product was 69.4%. The product was analyzed by gas chromatography, and the result is as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:29]([N:4]1[C:5]2[CH:6]=[C:7]3[N:22]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[NH:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:26])([CH3:1])[C:3]1=[O:25])[CH:28]=[CH2:27]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4ccc(OC)cc4)nc3cc21
Temperature: 150 °C

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), allyl bromide (78 mg; 0.65 mmol) and K2CO3 (233 mg; 1.69 mmol) in acetone (3.2 ml) and N,N-dimethylformamide (1.6 ml) is stirred at 50° C. for 48 h. The mixture is filtered and concentrated in vacuo. The residue is suspended in acetic acid (3 ml), iron (150 mg; powder) is added and the resulting mixture is heated in a microwave apparatus at 150° C. for 900 s. After re-cooling the mixture is filtered and concentrated in vacuo. The desired compound is obtained by preparative RP-HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[C:23]1(=[O:38])[N:27]([CH2:28][C:29](=[O:32])[CH2:30][NH2:31])[C:26](=[O:33])[C:25]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:24]12>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:31][CH2:30][C:29]([CH2:28][N:27]3[C:23](=[O:38])[C:24]4=[CH:37][CH:36]=[CH:35][CH:34]=[C:25]4[C:26]3=[O:33])=[O:32])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCO
Product: O=C(CNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 12, 7-nitro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-nitro-5-(o-chlorophenyl)-2-[ (3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:35]=[O:36])=[CH:3][C:4]=1[CH3:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (2.19 g) in tetrahydrofuran (30 ml) was added 1.6 M butyllithium in hexane (4.69 ml) by syringe under nitrogen atmosphere at −78° C. After 30 minutes of stirring at −78° C., N,N-dimethylformamide (1.16 ml) was added to the solution at −78° C. and then the mixture was allowed to warm to 5° C. over 1.5 hours. Saturated ammonium chloride solution (10 ml) was added to the mixture and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzaldehyde (1.90 g) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 5 h
Yield: 72 %

Procedure:
30.0 g (0.157 mole) of p-toluenesulfonyl chloride were added to a solution of 29.5 g (0.143 mole) of 1-t-butoxycarbonyl-3-hydroxymethylpyrrolidine [prepared as described in Step (2) above] dissolved in 500 ml of pyridine. The mixture was then stirred for 5 hours whilst ice-cooling, after which it was stirred at room temperature overnight. The reaction mixture was poured into 1 liter of water and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under by evaporation reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 1:4 by volume mixture of ethyl acetate and toluene, to give 36.6 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)pyrrolidine as a pale brown oil, which gradually crystallized.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:41])[CH2:37][CH2:38][O:39][CH3:40])[C:15]3[CH:42]=[CH:43][CH:44]=[CH:45][C:14]1=3)=[C:7]([O:46][CH3:47])[CH:6]=[CH:5]2.[ClH:48]>CO.CCOCC>[ClH:48].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:41])[CH2:37][CH2:38][O:39][CH3:40])[C:15]3[CH:42]=[CH:43][CH:44]=[CH:45][C:14]1=3)=[C:7]([O:46][CH3:47])[CH:6]=[CH:5]2
Reactant: COCCC(=O)N1c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)CCOC)[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (51.2 mg, 71.9 μmol) in MeOH (71.9 μl) was added 2 M HCl in Et2O (288 μl). The reaction was stirred at rt for 3 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (42.3 mg, 91%) as a white solid. MS m/z 611/613 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[C:11]=1[C:10](=O)[NH:9][CH:8]=[N:7]2)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[C:11]2=[C:3]([CH2:1][CH3:2])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[N:7]=[CH:8][N:9]=1
Reactant: CCc1c(C(=O)OC)cn2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCc1c(C(=O)OC)cn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
A 1 L round bottomed flask was charged with methyl 5-ethyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (25.0 g, 113 mmol), toluene (375 mL) and diisopropylethylamine (11.8 g, 91.6 mmol). Phosphorous oxychloride (20.7 g, 135 mmol) was then added drop-wise at room temperature (exothermic). Once the addition was complete the reaction mixture was heated to 100° C. for 20 hrs. Analysis of an aliquot by HPLC indicated that the starting material had been completely consumed (Rt starting material=10.6 min, Rt product=15.2 min). The reaction was then cooled and slowly poured into a mixture of saturated sodium hydrogen carbonate solution (500 mL), toluene (500 mL) and ice water (350 mL). After stirring for 30 minutes the organic layer was separated and washed with saturated sodium hydrogen carbonate solution (500 mL). Drying over sodium sulfate, filtration and concentration afforded 30.5 g (>100%) of crude methyl 4-chloro-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate. This material was dissolved in acetonitrile (800 mL) and the solution charged to a 2 L round bottomed flask. Sodium hydrogen carbonate (15.1 g, 180 mmol) and 5-amino-1-benzylindazole (27.8 g, 124 mmol) were then added followed by additional acetonitrile (400 mL). The resulting suspension was then stirred at room temperature for 16 h. HPLC analysis after this time indicated that approximately 17% of the starting indazole remained. The mixture was then heated to reflux for 1 hr after which time only 5% of the starting indazole remained. After cooling, the mixture was concentrated and the residue partitioned between methylene chloride (800 mL) and water (300 mL). The lower organic layer was separated and washed further with water (300 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded 51.3 g (100%) of methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate, which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=2)[CH:10]([CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([C:23]([F:26])([F:24])[F:25])=[CH:16][CH:15]=2)[CH:10]([CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1ccc(C(F)(F)F)c2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1CN(Cc2ccccc2)CC=C1c1ccc(C(F)(F)F)c2ccoc12
Yield: 22 %

Procedure:
Beginning with 0.84 gm (2.2 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(4-trifluoromethylbenzofur-7-yl)piperidine and 1.6 gm p-toluenesulfonic acid monohydrate, 0.18 gm of the desired compound were prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1ccccn1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccccn1)OCC2c1ccc(C(C)C)cc1
Yield: 53 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromopyridine, the title compound was obtained in the same manner as in Example 107.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:16])[CH:22]=1
Reactant: Nc1cccnc1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)O)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4cccnc4)cc3c2C1
Yield: 43.4 %

Procedure:
Beginning with 0.17 gm (0.57 mMol) N,N-dimethyl-8-carboxy-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.06 gm (0.63 mMol) 3-aminopyridine, 0.083 gm (44%) of the title compound were recovered as an off-white foam by the procedure described in Example 25.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccccc1N
Reaction time: 8 h

Procedure:
A solution of methyl 2-[(2-nitrophenyl)thio]benzoate (1.17 g, 4.04 mmol) in methanol (50 mL) was purged with nitrogen prior to the addition of 10% Pd/C catalyst (0.12 g). The mixture was again purged with nitrogen and then purged with hydrogen from a balloon. The mixture was stirred under hydrogen overnight. Additional amount of 10% Pd/C catalyst (0.24 g) was added, and the mixture was stirred under hydrogen overnight. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was subjected to silica gel chromatography eluted with 100% DCM to provide methyl 2-[(2-aminophenyl)thio]benzoate as a yellow oil that crystallized over time. MS (ES, M+H+): 260.2
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.Cl.[CH3:26][NH:27][CH3:28].C(N(CC)C(C)C)(C)C.CCOC(C)=O>CN1C(=O)CCC1.O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[N:27]([CH3:28])[CH3:26]
Reactant: CNC
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2nc(N(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 150 °C
Reaction time: 65 h
Yield: 8.8 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), dimethylamine hydrochloride (106 mg), N,N-diisopropylethylamine (201 mg) in NMP (1.0 ml) was heated at 150° C. with stirring for 65 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE and dried in vacuo to give 5-[5-amino-6-(dimethylamino)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (8 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH2:19]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([NH:19][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 61 %

Procedure:
0.42 g (0.00112 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 1.4 ml of 8M methylamine in ethanol were stirred at room temperature in a mixture of 11 ml of ethanol and 11 ml of dioxane for 48 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. The product-containing fractions were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.224 g (61%) of (4-benzenesulphonyl-6-bromopyridin-2-yl)-methylamine as white crystals; m.p.: 145-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Temperature: 130 °C
Yield: 89.5 %

Procedure:
203.6 g (815 mmol) of 4-bromobenzyl bromide and 215 ml (1.2 mol) of triethyl phosphite are mixed and heated at 130° C. for 1 h with gas discharge. The product is then subjected to fractional distillation (2×10−2 mbar, 120° C.), giving 224 g (89%) of the product as a colourless liquid.
Reaction SMILES: [C:1]1([C:7]([CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH:7]([CH:16]2[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24]2)[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Agent: [Pd]
Product: CCN(CC)CCCC(c1ccccc1)C1Cc2ccccc2C1

Procedure:
A solution of 23.5 g. of 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene in 375 cc. of 95 percent (v/v) ethanolbenzene was stirred while 1.5 g. of 5 percent palladium on carbon was added in one portion. The reaction mixture was stirred for 6 hours at 24° C. under a hydrogen gas atmosphere at 60 p.s.i. After filtering off the hydrogenation catalyst, the filtrate was concentrated to dryness under reduced pressure to provide 1-phenyl-1-(2-indanyl)-4-diethylaminobutane.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCn2ccnc2)c1OCCC(C)c1ccc(F)cc1
Yield: 45 %

Procedure:
Example 8a (50 mg, 0.10 mmol) was reacted with imidazole (8.0 eq.) as described under General Procedure G and the crude mixture was dissolved in DCM and HCl gas was bubbled through it for 3 minutes. Then, solvent was removed under vacuum and the residue was suspended in dry ether and triturated to afford the title compound as a off-white solid (22 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 9.57 (bs, 1H), 7.33 (bs, 1H) 7.19-7.14 (m, 3H), 7.02-6.96 (m, 2H), 4.60 (bs, 2H), 4.37 (bs, 2H), 3.89-3.76 (m, 5H), 2.88-2.93 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.94-1.96 (m, 2H), 1.27 (d, J=6.6 Hz, 3H). MS (ES+) m/z 475.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5](I)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>C(#N)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[N:24][CH:23]=2)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(Cl)c(-c2ccccc2F)cc1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: Oc1cc(Cl)c(-c2ccccc2F)cc1-c1ccnnc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
2-Chloro-2′-fluoro-5-iodobiphenyl-4-ol (Preparation 75, 610 mg, 1.76 mmol) was dissolved in acetonitrile (3 mL) and 4-(tributylstannyl)pyridazine (843 mg, 2.28 mmol), caesium fluoride (533 mg, 3.51 mmol), copper iodide (67 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium (0) (204 mg, 0.176 mmol) were added. The reaction was stirred at 80° C. for 18 hours and then the cooled reaction mixture was partitioned between ethyl acetate (100 mL) and water. The organic layer was separated and dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with heptane:ethyl acetate 1:1 to 100% ethyl acetate. Fractions containing product were evaporated and then triturated with dichloromethane to give the title compound (210 mg, 40%) as a yellow solid
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH:6]([O:8][CH2:9][CH3:10])=[CH2:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:6]([O:8][CH:9]([O:5][CH2:1][CH2:2][C:3]#[CH:4])[CH3:10])[CH3:7]
Reactant: C#CCCO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCOC(C)OCC
Reaction time: 2 h
Yield: 85.4 %

Procedure:
3-Butyn-1-ol (46.33 g, 0.661 mole) in methylene chloride (700 mL) was treated with ethyl vinyl ether (0.661 mole, 63.2 mL) and pyridinium p-toluenesulfonate (0.033, 8.31 g) (note: upon addition of pyridinium p-toluenesulfonate an exothermic reaction takes place). After stirring 2 hours, the reaction mixture was concentrated and filtered through a pad of silica gel (ethyl acetate:hexane, 1:1) to provide the title compound as a colorless liquid (80.29 g, 85.5%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](Cl)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])Cl>CO.[Zn].[Cl-].[Zn+2].[Cl-]>[F:1][C:2]([F:18])([F:19])[C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)=[C:4]([F:6])[F:7]
Reactant: CCOc1ccc(C(Cl)(C(F)(F)F)C(F)(F)Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CO
Product: CCOc1ccc(C(=C(F)F)C(F)(F)F)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 1,1,1,3,3-pentafluoro-2, 3-dichloro-2-(4-ethoxyphenyl)propane (29.5 g) in methanol (40 cm3) was added dropwise to a suspension of zinc powder (9.1 g) and zinc chloride (0.45 g) in methanol (80 cm3) whilst the temperature was maintained at 35° C. After the addition was complete the mixture was stirred at the ambient temperature ca. 23° C.) for 2 hours. After dilution with water and filtering off the zinc, the mixture was extracted with chloroform, the extracts washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)prop-2-ene (19.0 g) as a mobile liquid.