Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N1C=CC=[CH:18][CH:17]=1>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:18][CH2:17]2
Reactant: c1ccncc1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(F)ccc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 30 g of 4-fluorophenylacetic acid and 48.9 g of thionyl chloride in 60 ml of 1,2-dichloroethane was added a catalytic quantity of pyridine, and the solution was then refluxed for 5 hours under an atmosphere of nitrogen. Following removal of the 1,2-dichloroethane, the product was added dropwise to an ice cooled suspension of 48.6 g of aluminum chloride in 200 ml of dichloromethane. Following stirring for 30 minutes, ethylene gas was blown into the reaction vessel, and after a further 5 hours of stirring, dilute hydrochloric acid was added, and following separation of the organic layer, the aqueous layer was extracted with toluene. The toluene extract was combined with the organic layer and washed subsequently with water, a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate and the solvent removed by evaporation, and subsequently purified by distillation (75° C., 2 Torr) to obtain 19.4 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])/[C:4](/[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si](C(C)(C)C)(C)C)[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40])=[CH:5]/[C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:42])/[C:4](/[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40])=[CH:5]/[C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.2 %

Procedure:
To a solution of (Z)-2-[[4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (47 mg, 0.0773 mmol) in THF (1 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.085 mmol, 85 μL) and the reaction was stirred for 3 days at ambient temperature. The reaction was diluted with ethyl acetate and was then washed with in turn with water and brine. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to yield 39 mg of (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester as a yellow solid (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH3:14])[CH2:11][C@H:10]1[C:15]([O:17]C)=[O:16].[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH3:14])[CH2:11][C@H:10]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)[C@@H]1CN(C)C[C@H]1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reaction time: 2 h

Procedure:
To a solution of methyl (3S,4R)-4-(2,4-difluorophenyl)-1-methylpyrrolidine-3-carboxylate, from preparation 37 (800 mg, 3.13 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (150 mg, 6.27 mmol) at room temperature. The reaction mixture was stirred for 2 hours and the solvent concentrated in vacuo. The crude residue was dissolved in water (20 mL) and partitioned with ethyl acetate (2×20 mL). The phases were separated and the aqueous phase was acidified using 2M hydrochloric acid solution (3.13 mL). The aqueous phase was evaporated and the residue was azeotroped with toluene (6×20 mL) to afford an oily residue (1000 mg) which was used without further purification in the subsequent step.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:48]([F:51])([F:50])[F:49])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:42])(=[O:41])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][C:21]=3[F:43])[C:15]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:14]2)[CH:12]=1>>[C:37]([O:36][C:34]([NH:33][S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[C:15]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:14][N:13]([C:11]3[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=3[C:48]([F:50])([F:51])[F:49])[C:17]2=[O:18])=[C:21]([F:43])[CH:22]=1)(=[O:42])=[O:41])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 95 %

Procedure:
Propionyl bromide was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) according to the procedure of Example 26 to give a 95% yield of the title compound as a white solid, mp 167°-169° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 726 (M+Li)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1cccc(Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
A mixture of methyl 2-(bromomethyl)-6-chlorobenzoate (4.0 g, 15.6 mmol), diethylamine (5 mL, 48.1 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in acetone (60 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording methyl 2-chloro-6-[(diethylamino)methyl]benzoate (3.97 g, 99% yield), which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[NH:19][N:18]=[C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:21]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: N#Cc1ccc(N)cc1
Product: COc1ccc2c(Nc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5,6-dimethoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 401(MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a solution of 4-fluoro-2-methylbenzoic acid (4.0 g, 26.0 mmol) in THF (30 mL) in a pressure vessel was added cesium carbonate (8.45 mg, 26.0 mmol) and iodomethane (2.0 M in tert-butyl methyl ether, 13.0 mL, 26.0 mmol). The vessel was sealed and the reaction was stirred at 70° C. for 16 h. After cooling to rt, the reaction was quenched with saturated sodium bicarbonate (10 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), and then the organic phase was dried (Na2SO4) and concentrated under reduced pressure to give the crude product. This material was triturated with acetone and hexanes to afford pure product (3.8 g, 87%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 2.60 (s, 3H), 3.86 (s, 3H), 7.05-7.12 (m, 2H), 7.96 (s, 1H); ES-MS m/z 168.2 (MH+); HPLC RT (min) 3.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2noc(C3CNCC(c4ccc(C(F)(F)F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.82 g (1.67 mmol) of the compound from Example 185A was initially charged in 13 ml of dichloromethane, and 1.3 ml (1.90 g, 16.78 mmol) of trifluoroacetic acid were added at RT. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 0.65 g (99% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)[OH:4].O=[C:18]([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:31][O:30][C:28]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH:18]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=2)[OH:4])[CH3:32])=[CH:26][CH:25]=1)=[O:29]
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 82.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (prepared as described in Preparation 14), 2.35 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 4.8 g of sodium cyanoborohydride, 3.14 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:28]=2)=[O:24])[CH:20]=[C:19]([Cl:41])[C:18]=1O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH:28]=2)=[O:24])=[CH:20][C:19]=1[Cl:41])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (3.55 mL, 21.1 mmol) was added to a cooled (−75° C. ) solution of 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 17.6 mmol) and triethylamine (9.8 mL, 70.4 mmol) in dry dichloromethane (70 mL). After stirring for 3 h at ˜−70° C., the reaction was quenched with solid ammonium chloride (6 g). The solvent was evaporated and ethyl acetate was added. The solution was washed with 1 N HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO4), filtered, evaporated and dried under high vacuum to give trifluoromethanesulfonic acid, 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]phenyl]methyl]amino]carbonyl]phenyl ester (9.46 g, 97%) as pale orange oil.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[O:51]=[C:52]1[NH:1][CH:2]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:31][CH:32]=2)[C:3](=[O:4])[N:5]1[C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCCCC4)cc3)C2=O)n1
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.16 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (142 μL, 105 mg, 0.81 mmol) and was transferred via cannula to a solution of diphosgene (14 μL, 23 mg, 0.12 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{2,5-dioxo-4-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as a white solid (26 mg, 27%).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[Na+].[Na+].[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]#[N:4])[CH2:16][CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(CC#N)CC1

Procedure:
Chloroacetonitrile (14.7 ml, 234 mmol) was added slowly to a well stirred suspension of sodium carbonate (32 g, 300 mmol) and acetylpiperazine (30 g, 230 mmol) in toluene (200 ml). The mixture was heated under reflux for 3 hours. The reaction was cooled, filtered and the filtrate evaporated under reduced pressure. The resulting solid was recrystallised from ethyl acetate to afford the title compound as a yellow solid, 18.6 g.
Reaction SMILES: ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:8][CH:9]([CH3:13])[C:10](Br)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:8][CH:9]([CH3:13])[C:10]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(Br)C(=O)Br
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To 200 ml of dichloromethane are added 23.7 g (0.176 M) of aluminium chloride. The mixture is cooled to 10° C. and 10 g (0.089 M) of chlorobenzene are added dropwise. The resulting mixture is stirred for one hour at 15° C. followed by dropwise addition of 9.2 ml (0.089 M) of 2-bromopropionyl bromide. The reaction medium is then stirred for 16 hours at room temperature. The reaction medium is then poured into an ice/water mixture. The organic phase is separated out by settling, washed twice with demineralised water and then dried over sodium sulfate. After evaporating under vacuum, an oil is obtained, which crystallises to give 21 g of 2-bromo-1-(4-chlorophenyl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (112 mg, 0.31 mmol), N,N-diisopropylethylamine (163 μL, 0.94 mmol) and 1-methyl-1H-pyrazol-3-ylamine (30 μL, 0.31 mmol) were combined in methylene chloride (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (110 mg, 81%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C19H23ClN4O4S [M+] 438.11, found 439 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.24-1.61 (m, 6H, 3×CH2), 1.71 (m, 2H, 2×CH of CH2), 1.96 (m, 2H, 2×CH of CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.29 (m, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.71 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 9.15 (s, 1 H, NH).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-3-furancarboxylic acid (0.302;1.58 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.22 ml; 1.58 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.35 g;1.58 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a tan solid after trituration with Et2O (0.3 g;48%), mp=185°-187° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1

Procedure:
A solution of 1,1-dimethylethyl 9-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 63) (9 g, 22.65 mmol), zinc cyanide (3.99 g, 34.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.62 g, 2.265 mmol) in DMF (90 ml) was heated at 80° C. for 24 hrs. The reaction was cooled, diluted with EtOAc (400 ml) and water (400 ml) and filtered to remove insoluble material. The filtrate was separated and the organic layer washed with water, dried over magnesium sulphate and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:9 then 1:3 to give the title compound (5.1 g) as a colourless oil. MS (ES): C15H18N2O3 requires 274; found 174 [M+H−100]+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:12]([N:11]1[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=[C:6]1[CH:2]([NH:1][CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH:3]([CH3:4])[CH3:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc(C(N)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(NCC(=O)CCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To 2-(1-Amino-2-methyl-propyl)-3-benzyl-5,6-dimethyl-3H-pyrimidin-4-one (0.66 g, 2.33 mmol) in DMF (15 mL) was added 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (0.69 g, 2.33 mmol, prepared as described in WO 89/10360) and N,N-diisopropylethylamine (0.301 g, 2.33 mmol). The reaction was stirred for 16 h at room temperature, concentrated under vacuum, dissolved in EtOAc/H2O, washed with water, dried (Na2SO4), and evaporated to give the title compound as a white foam (1.04 g, 89%). MS(ES+) m/e 501 [M+H]+.