Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH2:5]Cl)([CH3:4])[CH3:3].[Mg].[CH3:8][N:9]([CH3:28])[CH2:10][CH2:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1.[Cl-].[NH4+]>CCOCC>[CH3:28][N:9]([CH3:8])[CH2:10][CH2:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])([OH:23])[C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1
Reactant: C[Si](C)(C)CCl
Reactant: CN(C)CCC1Cc2ccccc2C(=O)c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)CCC1Cc2ccccc2C(O)(C[Si](C)(C)C)c2ccccc21

Procedure:
A Grignard reagent is prepared by conventional techniques from 12.2 g. (0.1 mole) trimethylsilylmethyl chloride and 24.3 g. magnesium metal (0.1 atom) and 200 ml. ether. The resulting solution is treated with 27.9 g. (0.1 mole) of 10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 100 ml. ether. Stirring is initiated and the mixture is heated at reflux for 5 hours, then cooled in ice and hydrolyzed with 150 ml. of saturated ammonium chloride. The layers are separated and the ether dried over anhydrous magnesium sulfate and evaporated to give 10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCC>[C:1]1([C@@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:6][CH2:1][CH2:2][CH3:3])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: C[C@H](NC[Si](C)(C)C)c1ccccc1
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@@H](C)c1ccccc1

Procedure:
The title compound was prepared from (S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (85% pure) as a colourless oil (7.1 g, 80%) δC (CD2Cl2)-1.09 (SiMe3), 14.35, 20.16, 24.72, 67.38 (OBu), 19.57 (CMe), 40.30 (NCH2Si), 62.30 (CH), 84.73 (NCH2O), 127.01, 128.15, 128.51, 146.15 (Ph).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14](=O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14]([NH2:22])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 5 h
Yield: 82 %

Procedure:
Ten grams of the (S)-3-(benzyloxycarbonyl)-4-(3-oxobutyl)-5-oxazolidinone from Example 4 is dissolved in 480 ml of distilled tetrahydrofuran, followed by 160 ml of ammonia at 0° C. The reaction mixture is stirred at 0° for 5 hours, then at ambient temperature overnight. After stripping under vacuum to dryness, the reaction mixture yields a white solid which is recrystallized from hot ethyl acetate to give 8.8 g of (S)-2-(benzyloxycarbonylamino)-5-oxo-hexanamide as a white solid (82% yield), mp 142°-144°; [α]D25 =-4.0° (c 0.4, CH3OH).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15].[OH2:16]>>[C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:16])(=[O:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15]
Reactant: O
Reactant: CCCCC(=O)OCC(F)(F)S(=O)[O-]
Agent: [Na+]
Product: CCCCC(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A 100 mL reactor was charged with 6.6 g (28% purity, 7.3 millimoles) of sodium 2-valeryloxy-1,1-difluoroethanesulfinate, 60 mL of water, 0.0047 g (0.014 millimole/0.0019 equivalent) of disodium tungstate dihydrate and 1.9 g (16.4 millimoles/2.25 equivalents) of 30% oxygenate, followed by stirring at room temperature for 1.5 hours. A reaction solution was heated under a reduced pressure to evaporate a volatile component to dryness, thereby obtaining 6.6 g of the target sodium 2-valeryloxy-1,1-difluoroethane sulfonate. In this case, purity was 26% and yield was 88%.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[OH-].[NH4+:27].O>CS(C)=O>[NH2:27][C:9]1[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Nc2nc(SC)nc(Cl)c2C(N)=O)c(OC)c1
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Nc2nc(SC)nc(N)c2C(N)=O)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of the product of Example 10A (1.3 g, 3.4 mmol) in dimethylsulfoxide (50 mL) was added ammonium hydroxide (5.2 mL, 34 mmol). The mixture was heated to 100° C. for 4 hours and was allowed to cool to ambient temperature. Water (50 mL) was added and the precipitate was filtered and washed with ethanol (20 mL) to give the title compound. MS: 364 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCC=O
Product: CCCCNc1ccc(Cl)c(Cl)c1
Yield: 56.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 3,4-dichloroaniline (1.62 g, 10.0 mmol) and butyraldehyde (721 mg, 10.0 mmol) were converted to the title compound (1.24 g, 57%). 1H NMR (CDCl3) δ 7.17 (d, J=8.8 Hz, 1H), 6.65 (d, J=2.9 Hz, 1H), 6.41 (dd, J=2.8, 8.7 Hz, 1H), 3.05 (t, J=7.0 Hz, 2H), 1.65-1.53 (m, 2H), 1.43 (qd, J=7.3, 15.0 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 218.1 (M+H)+.
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][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:19]1(Br)[CH2:21][CH2:20]1>CN(C=O)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][CH:19]2[CH2:21][CH2:20]2)=[CH:4][N:3]=1
Reactant: BrC1CC1
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OC2CC2)c2ccccc12
Temperature: 145 °C
Yield: 3.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 55.7 mmol) in DMF (20 m) was added Cs2CO3 (2.72 g, 8.35 mmol) followed by cyclopropylbromide (6.74 g, 55.7 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.4 g, 32.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.22-8.24 (m, 2H), 8.14 (s, 1H), 8.14-8.12 (m, 1H), 7.74-7.67 (m, 2H), 4.00-3.95 (m, 1H), 0.92-0.90 (m, 4H); MS: MS m/z 220.0 (M++1).
Reaction SMILES: C([O:5][C:6](=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:5])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:23])[F:21])[N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1C(F)(F)F)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][CH2:16][O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1]
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OCCCl)c(I)c1
Yield: 100 %

Procedure:
2-Iodo-4-(trifluoromethoxy)phenol (10 g, 33 mmol), 2-chloroethyl-p-toluenesulfonate (7.9 g, 34 mmol), N,N′-dimethylformamide (50 mL) and potassium carbonate (9.1 g, 66 mmol) were stirred together at 50° C. for 16 hours and then cooled. The suspension was diluted with water (100 mL) and extracted with 60% diethyl ether/hexane (2×100 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a solid (12.1 g, 33 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:3]2[O:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=2[NH:1][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)c(-c2ccncc2)o1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (Method A2; 0.10 g, 0.46 mmol) and 2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH2Cl2 was stirred at room temp. for 2 h, then was treated with 2-(dimethalamino)ethylamine (0.081 g, 0.92 mmol) and stirred for an additional 30 min. The resulting mixture was diluted with EtOAc (50 mL), then was sequentially washed with a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane) to give the desired compound as a white solid (0.12 g, 63%); mp 195-198° C.; TLC (60% EtOAc/40% hexane) Rf 0.47; 1H NMR (DMSO-d6) δ1.30 (s, 9H); 6.63 (s, 1H); 7.30-7.32 (m, 2H), 7.58 (dm, J=6.62 Hz, 2H), 8.16 (dd, J=2.57, 6.99 Hz, 1H), 8.60 (dm, J=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6) δ 28.5 (3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5, 137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 (M+H)+, 15%), 406 ((M+H+2)+, 8%).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[N:34]O)[NH2:33])=[CH:28][CH:27]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:34]=[C:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:33]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 45 mg (50% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])cc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2cc(CCc3ccc(N)cc3)nc2c1
Yield: 92.8 %

Procedure:
A solution of 2-[2-(4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (3.1 g) in a solution of methanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (1.0 g) under atmospheric pressure of hydrogen gas at ambient temperature for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with n-hexane to give a precipitate, which was collected by filtration and dried to give 2-[2-(4-aminophenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (2.59 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1cccnc1
Temperature: 67 °C

Procedure:
A mixture of rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.081 g, 0.33 mmol) (from Example 39b supra), 3-chlorobenzyl bromide (0.080 g, 0.39 mmol) (Aldrich), potassium iodide (0.065 g, 0.39 mmol) and potassium carbonate (0.098 g, 0.72 mmol) in acetone (3 mL) was heated at 67° C. for 2 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-pyridin-3-yl-1,3-dihydro-indol-2-one as an off-white solid. (Yield, 0.05 g, 42%).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>C(O)(C)C>[I:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:31]=1
Reactant: BrCCOc1ccc(I)cc1
Reactant: CCCCCCCCCCCCN
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of dodecylamine (30 g, 162 mmol), diisopropylethylamine (22 ml, 128 mmol), sodium iodide (1.3 g, 8.5 mmol), 1-[2-bromoethoxy]-4-iodobenzene (13.9 g, 42.5 mmol) and isopropanol (250 ml) was stirred and refluxed for 24 h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 50:1 to 20:1) to afford the title compound (15 g, 82%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1B(O)O>>[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1nccs1
Product: O=Cc1ccc(-c2nccs2)cc1
Yield: 82 %

Procedure:
Ex-5A: 4-Thiazol-2-yl-benzaldehyde was prepared from 4-bromobenzaldehyde and thiazole-2-boronic acid in a similar manner as described in Ex-3A, 82% yield. 1H-NMR (CDCl3) δ 10.07 (s, 1H), 8.15 (d, J=8 Hz, 2H), 7.95–7.98 (m, 3H), 7.45 (d, J=3 Hz, 1H). HMRS (EI) calcd. for C10H7NOS: 189.0248; found: 189.0242.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][Br:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(benzyloxy)-phenyl)-ethanone (49.12 g; 217.1 mmol) in CH2Cl2 (750 mL) was added drop wise DIPEA (45.37 mL; 260.5 mmol) and TMSOTf (45.18 mL; 249.6 mmol), both at 0° C. The resulting solution was maintained at 0° C. for 1 h, and then NBS (42.50 g; 238.8 mmol) was added in four portions. The resulting mixture was allowed to warm to RT and stirred 1 hour. Subsequently, the mixture was concentrated in vacuo and the residue was treated with EtOAc and washed twice with water, and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) and crystallization from iPr2O to afford 1-(4-benzyloxy-phenyl)-2-bromo-ethanone.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH3:20][N:8]1[C:2](=[O:1])[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2Nc2ccccc21
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
To a solution of 11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (10 g, 0.048 mol, Synthesis, (1985), 550) in dry dimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (2.1 g, 0.052 mol, 60% dispersion in oil) was added, and the reaction mixture was stirred for 1.5 h. Iodomethane (3.27 ml, 0.052 mol) was slowly added keeping the temperature below 30° C. and the mixture was stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and poured onto ice water (300 ml). The solid was filtered off and washed with plenty of water and dried. This yielded 10.4 g of crude 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo [b,e][1,4]diazepine which was recrystallised from methanol (200 ml), to give 6.7 g (63%) of 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine. M.p. 210°-211° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[N:17]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[N:17]1([CH:22]2[CH2:27][CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCC(N4CCCC4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 16.7 g. of 4-(1-pyrrolidinyl)piperidine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-[4-(1-pyrrolidinyl)piperidino]phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 318°-326° (dec.).
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].Cl.[O:15]1[C:19]([CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18][CH:17]=[N:16]1>CO>[C:7]([NH:22][CH:21]([C:23]([OH:25])=[O:24])[CH2:20][C:19]1[O:15][N:16]=[CH:17][CH:18]=1)(=[O:9])[CH3:8]
Reactant: NC(Cc1ccno1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)NC(Cc1ccno1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
20 ml of pyridine and 20 ml of acetic anhydride were added to a solution of 12.45 g of 3-(5-isoxazolyl)-DL-alanine hydrochloride (prepared as described in Preparation 6) dissolved in 100 ml of methanol, whilst ice-cooling. The mixture was then stirred at room temperature for 8 hours, after which it was allowing to stand overnight. The mixture was then freed from the solvent by evaporation under reduced pressure. The residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 10.39 g (82.3%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:19][C:5]1[CH:4]=[C:3]([Cl:20])[C:2]([Br:1])=[CH:18][C:6]=1[C:7](=[O:8])[N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 82.7 %

Procedure:
To 5-bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide (2.6 g, 7.3 mmol) in dry DMF (30 mL), was added K2CO3 (2.0 g, 7.6 mmol), followed by addition of t-butyl 4-bromobutyrate (2.0 g, 8.8 mmol). The mixture was heated at 60° C. for 12 hrs and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, and dried over MgSO4. After filtration, concentration and purification by silica gel column chromatography eluting with ethyl acetate in hexanes (3/7) gave 4-[4-bromo-5-chloro-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid tert-butyl ester (3.0 g). MS: 496.3 (M+H)+; tR=2.81 min (method 1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C(O[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])C.Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CCNCC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cc[nH]c1C
Reaction time: 0.33 h

Procedure:
To a solution of 1.6 ml of diethylamine in 30 ml of toluene was added 7.5 ml of 2M trimethylaluminum in hexane, and the mixture stirred for 20 minutes. To this mixture was added 1.53 g of 2-methylpyrrole-3-carboxylic acid ethyl ester, and the reaction mixture refluxed overnight. The mixture was cooled, acidified with aqueous 2N hydrochloric acid and extracted twice with ethyl acetate and three times with methylene chloride. Solvent was removed from the combined extracts under reduced pressure, and the residue was flash chromatographed on silica gel, eluting with 75% ethyl acetate/hexane, giving 1.5 g of 2-methylpyrrole-3-carboxylic acid diethylamide, m.p. 120°-121° C., the compound of formula (b).