Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][S:2]([C:5]2[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Solid 2-[4-(chlorosulfonyl)phenoxy]acetamide (Intermediate A91, 65.87 g, 0.264 mol) was added to a solution of 4-methoxy-2-nitroaniline (27.72 g, 0.165 mol) in pyridine (500 mL) at room temperature under argon. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added 0.5 M hydrochloric acid (1000 mL) and stirred for 30 min. The orange solid was collected and recrystallized from acetone to give 42.8 g (68%) of the title compound, nitro sulfonamide as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[O:30][N:29]=1)([CH3:27])[CH3:26]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:31]2[O:30][N:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[CH:32]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)on1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) described in Example 113A in anhydrous THF (1.5 mL), was added 4-chlorophenyl 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from the previous step (104 mg, 0.3 mmol) and 4-(dimethylamino)pyridine (18 mg, 0.15 mmol). The mixture was stirred at rt for 6 h. Concentration in vacuo followed by purification by silica gel chromatography (dichloromethane/ethyl acetate 1:1) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea (79.9 mg, 51%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.40-7.45 (m, 2H), 7.29-7.32 (m, 2H), 6.99-7.02 (m, 2H), 6.18 (s, 1H), 4.00 (s, 6H), 1.24 (s, 6H); LC-MS (ESI) m/z 518 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](O)(=O)[CH2:19][OH:20]>>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][OH:20]
Reactant: O=C(O)CO
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Product: CC(C)(O)Cn1c(CO)nc2cnc3ccccc3c21

Procedure:
Using the general method of Example 24, 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (45 g, 0.19 mol) was reacted with glycolic acid to provide 35.7 g of the desired product as a tan solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:3][CH:4]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dissolve 50.3 g (0.426 mol) 4-aminobenzonitrile in 250 mL CH2Cl2with 36 mL (0.445 mol) pyridine. Chill the solution with an ice/MeOH bath and add 34 mL (0.42 mol) methanesulfonyl chloride dropwise, maintaining the reaction temperature below 0° C. Stir the reaction mixture under N2 for 20 h at ambient temperature. After this time, filter thereaction mixture and extract with 3×250 mL 1 N NaOH. Acidify the aqueous layer with concentrated HCl to pH=7. Filter the precipitate to provide the title compound.
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.Cl.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([CH:23]3[CH2:24][CH2:25][N:20]([C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[F:13])[CH2:21][CH2:22]3)=[O:27])[CH2:29][CH2:30]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
4-Bromophenylsulphonyl chloride (1.02 g) was added to a mixture of 1-[1-(3-fluoro-4-pyridyl)-piperidin-4-ylcarbonyl]piperazine hydrochloride (1.22 g) and triethylamine (3.70 ml) in dichloromethane (45 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave 1-(4-bromophenylsulphonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (1.24 g) as a solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[F:17])[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[F:17][C:16]1[CH:15]=[C:14]2[C:10]([C:11]([CH:22]=[O:23])=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:7][CH3:6]
Reactant: COc1cc2cc[nH]c2cc1F
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(C=O)c[nH]c2cc1F
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
POCl3 (10.9 ml, 71 mmol) is added dropwise to 21 ml of dimethylformamide under N2 at 10-20° C., is stirred 15 minutes, then a 13 ml dimethylformamide solution of 5-methoxy-6-fluoro-indole (J. Med. Chem., 22:63-69, 1979; 10.7 g, 64.7 mmol) is added at a rate to keep the reaction temperature between 10 and 20° C. After the addition is complete, the mixture is stirred for 1 hour. Crushed ice and aqeuous NaOH (12.5 g/50 ml H2O) is added to reaction. The resulting mixture is heated to reflux with a heat gun for 1 minute, cooled to 10° C., and is filtered to give 11.8 g of 6-fluoro-5-methoxy-1H-indole-3-carbaldehyde (95%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].Br[CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[C:8]2[C:12]([O:14][CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31])=[O:13])[CH3:3]
Reactant: Cc1oc(=O)oc1CBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cccc(CO)c3)C[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg) prepared by example 4 was dissolved in DMF (2.0 ml), and thereto 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (143 mg) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then thereto ice water was added. The mixture was extracted with ethyl acetate. The organic layer was washed three times with a cold saturated aqueous sodium chloride solution, followed by a cold saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative thin-layer chromatography (ethyl acetate/acetone) to give (5-methyl-2-oxo-1,3-dioxo1-4-yl)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (62 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[N:35]1([CH:41]([CH3:44])[CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([CH:41]([CH3:44])[CH2:42][NH:43][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[O:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([CH3:1])[C:11]3=[O:12])=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(CN)N1CCCCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCC(C)N3CCCCC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4.00 g of 3-methylflavone-8-carboxylic acid and 1.98 ml of triethylamine in 74 ml of anhydrous tetrahydrofuran was added a solution of 1.50 ml of ethyl chlorocarbonate in 15 ml of anhydrous tetrahydrofuran under ice-cooling and the mixture was stirred for 1 hour. To the mixture, a solution of 2.03 g of 2-piperidinopropylamine in 20 ml of anhydrous tetrahydrofuran was added and the mixture was stirred for 1.5 hours under ice-cooling and further at room temperature for 16 hours. The reaction mixture was treated by the same procedure as in Examples 3(b) to give 4.15 g of colorless crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 106.5°-108.5° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:33](=[O:34])[C:32]4[CH:31]=[CH:30][C:29]([N:26]5[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]5)=[CH:37][CH:36]=4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)c2ccc(C(=O)NC3CC3)cc2)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(C(=O)NC3CC3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 687 was prepared according to the procedure described in Scheme IV from N-cyclopropyl-4-(4-aminobenzoyl)benzamide and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C29H30N3O4: 484.22; found: 484.08.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[O:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CC(=O)N2CCCc3ccccc3C2C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
Cyclohexanoyl chloride (0.34 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.5 g) in chloroform (20 ml, ethanol-free) maintained at 0° C. and triethylamine (0.26 g) added. The mixture was maintained at 0° C. for 30 min then at room temperature for 5 h. The solution was washed with, first, dilute hydrochloric acid and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was recrystallised from chloroform/40°-60° C. petroleum ether to give white crystals of the title compound (0.48 g, 64%) m.p. 187°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25]([C@H:30]2[O:34][C:33](=[O:35])[NH:32][C@H:31]2[CH3:36])[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:32]2[C@@H:31]([CH3:36])[C@@H:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[O:34][C:33]2=[O:35])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(F)cc(F)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(F)cc(F)c3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4S,5R)-5-(3,5-difluoro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][C:21]3=[O:34])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][N:20]([CH2:19][CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[C:21](=[O:34])[CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (0.87 mmol) 7-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 24.1) in 5.0 mL DCM is added at RT 0.5 mL trifluoroacetic acid. The reaction mixture is stirred overnight at RT and is neutralized with aqueous 5% NaHCO3-solution. The layers are separated, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated in tertbutylmethyether, the precipitate is collected and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(N(C)c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(N(C)c2ccccc2)nc1CBr
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-2-(methyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (3.32 g, 12.0 mmol), N-bromosuccinimide (2.35 g, 13.2 mol) and benzoyl peroxide (291 mg, 1.2 mmol) in carbon tetrachloride (45 mL) was refluxed for 17 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil: MS: (+) m/z 354.9, 356.9 (M+1, 79Br/81Br).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:14](Cl)(Cl)Cl>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Product: COC(=O)Cc1ccc(C(C)C)cc1

Procedure:
Prepared from 4-isopropylphenylacetic acid (Lancaster) by the method described in Example 34a). νmax (CHCl3)/cm-1 1735. δH (250 MHz, CDCl3), 1.24 (6H, d, J 6.96), 2.90 (1H, heptet, J 6.93), 3.60 (2H, s), 3.69 (3H, s), 7.16-7.24 (5H, m).
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[N:18]1C=CC=CC=1>ClCCl>[NH2:6][C@H:5]([C:4]([NH2:18])=[O:17])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A solution of the active ester VIII (0.035 g, 0.06 mmol), L-tryptophan methyl ester hydrochloride (0.049 g, 0.19 mmol) and pyridine (0.015 g, 0.19 mmol) in dichloromethane (20 ml) was stirred overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography (ethyl acetate elution) to yield the trytophan amide as a dark red crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1O
Yield: 52 %

Procedure:
4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[O:19])(=[O:12])=[O:11].[Li+].[BH4-].CO>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][OH:19])(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)n2cccc2C=O)c(C)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2cccc2CO)c(C)c1
Reaction time: 1 h
Yield: 87 %

Procedure:
1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrole-2-carbaldehyde (2.77 g, 10 mmol) in THF (100 ml) was treated with LiBH4 (0.44 g, 20 mmol) at rt. The resulting solution was held at rt for 1 h. MeOH, (10 ml) was then added, and the resulting mixture mixture was poured into brine (600 ml), and extracted with EtOAc (3×200 ml). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting oil was then purified on silica gel column to yield [1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol as a light brown oil (2.43 g, 87%). 1H MM (CDCl3) δ 7.17 (dd, 1H, J=3.3, 1.8 Hz), 6.99 (s, 2H), 6.28-6.23 (m, 1H), 6.18 (t, 1H, J=3.3 Hz), 4.42 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])O)=[CH:5][CH:4]=1.[NH3:12].CO.[Cl-].[NH4+]>CCO>[ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[NH:9])=[CH:5][CH:4]=1
Reactant: N
Reactant: Cc1ccc(C(=N)O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of p-methylbenzimidate hydrochloride (8.00 g, 43.09 mmol) in MEOH (100 ml) is added NH3/MeOH solution (2.68M, 24.12 ml, 64.64 mmol). Upon the addition of the NH3, the mixture has a pH around 8.5. To this solution is added ammonium chloride (2.30 g, 43.09 mmol). The reaction mixture is stirred at room temperature for 20 hours, then cooled in refrigerator and the precipitate is removed by filtration. The mother liquor is concentrated to yield the crude product which is taken up in a limited amount of cold EtOH and the white precipitate is filtered. The beige filtrate is concentrated to yield p-methylbenzamidine hydrochloride as an off-white solid (7.15 g, 97%).
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[CH:4]=1.[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]2[O:10][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:4]=1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cccnc1)N1CCCC1
Yield: 35.7 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.55 g, 9.80 mmol) in methanol (10 mL) were added a mixture of 3-pyridine carboxaldehyde (1.03 mL, 10.84 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.50 g, 10.86 mmol). The solution was stirred 3 h at 0° C. and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water. The organic layer was combined with two additional ethyl acetate extracts (2×100 mL), washed with aqueous sodium chloride and dried over MgSO4, filtered and evaporated. Concentration afforded a crude product which was purified by column chromatography on silica (CH2Cl2:MeOH=98:2) to yield to trans-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04110B (0.95 g, 39% yield) as a pale yellow pale solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Crude dimethyl 4-bromo-2-nitrophenylmalonate was heated at 110° C. in 40 mL of 6N hydrochloric acid for 24 hours and then cooled. The precipitate was collected by filtration, washed with water and dried to give 5.3 g (89% yield) of 4-bromo-2-nitro-phenylacetic acid as an off white solid.