Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1[F:11])([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)ccc1F
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 3-tert-butyl-4-fluorotoluene (5.92 g, 34.4 mmol) in carbon tetrachloride (60 ml), N-bromosuccinimide (6.1 g, 34.4 mmol) and benzoyl peroxide (containing 25% of water) (1.1 g, 3.44 mmol) were added, followed by stirring for 30 min. while heating under reflux. The mixture was evaporated to remove the solvent; the thus obtained residue was mixed with n-hexane and filtered to remove the insoluble matter. The filtrate was evaporated to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (7.01 g, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitroaniline to yield 2-[(3-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1[N:55]=[C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)[O:53][N:52]=1>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH2:60][CH:56]2[C:54]2[O:53][N:52]=[C:51]([CH3:50])[N:55]=2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1noc(C2CCCN2)n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: Cc1noc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole. MS(m/e): 453.4
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].Br[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: Brc1ncccn1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil), 280 mg (5.76 mmol) in 10 mL of DMF at 0° C. was added 0.52 mL (4.8 mmol) of ethyl glycolate. After 10 minutes, 0.92 g (5.76 mmol) of 2-bromopyrimidine was added. The reaction mixture was stirred 15 min at 0° C. then ice bath was removed. After four hours, reaction mixture was quenched with methanol and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water, then extracted with 20% isopropanol/chloroform. The combined organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by radial chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 0.45 g (52%) of the desired product as a colorless oil. MS (ion spray) 183.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:19].[H][H]>C(O)C.[Pd]>[NH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:19]
Reactant: COc1cc2c(cc1O)C(Cc1c(OC)cccc1[N+](=O)[O-])N(C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1O)C(Cc1c(N)cccc1OC)N(C)CC2
Yield: 96.6 %

Procedure:
A mixture of the 1-(2'-methoxy-6'-nitrobenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (3b) (1 g) and 5% palladium-charcoal (0.2 g) in absolute ethanol (150 ml) was shaken with hydrogen at room temperature and atmospheric pressure overnight (19 hours). The mixture was filtered through celite, and the filtrate was evaporated to dryness to leave a transparent brown oil. This crystallized from methanol-ether to give 1-(2'-amino-6'-methoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (4b) (0.885 g, 93%), mp 158°-160°. Recrystallization from absolute ethanol gave feathery needles, mp 161°-162°; λmaxKBr 2.88 and 2.96 μ (OH and NH2); λmaxEtOH (c) 285.5 nm (5480); nmr τ 3.02-3.87 (5H, aromatic H), 6.24 (6H, s, O--CH3), and 7.66 (3H, s, N--CH3); mass spectrum m/e 327 (M+ - 1), 296, 205, 192, 177, and 148.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=O)[CH2:7][CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[S:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:23]([C:22]3[CH:24]=[CH:25][C:19]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:20][CH:21]=3)[CH:9]=[C:8]([CH3:11])[CH:7]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C=O)CC(=O)c1ccc(Cl)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 64(iii), but using 2-(4-chlorophenacyl)propionaldehyde [prepared as described in step (ii) above] and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale brown powder (yield 35%), melting at 196-198° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23](=[O:37])[CH2:24][CH2:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.OCC(N1CCCC1C(F)(F)F)=O.O[CH2:52][C:53]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:54]>>[N:55]1([C:53](=[O:54])[CH2:52][O:33][C:32](=[O:34])[CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([N:20]3[CH2:21][CH2:22][C:15]4([NH:14]/[C:13](=[N:12]/[C:10]([C:3]5[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=5)=[O:11])/[NH:17][CH2:16]4)[CH2:18][CH2:19]3)=[O:37])=[CH:36][CH:35]=2)[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1
Reactant: O=C(CO)N1CCOCC1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)cc4)CC3)N2)nc1Cl
Agent: O=C(CO)N1CCCC1C(F)(F)F
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)OCC(=O)N5CCOCC5)cc4)CC3)N2)nc1Cl

Procedure:
The title compound was prepared by an analogous method to Example 4.0, replacing 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid with [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Intermediate B), and 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) with 2-hydroxy-1-morpholin-4-yl-ethanone; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (2H, br hump), 7.15 (2H, d), 6.87 (2H, d), 6.72 (2H, br s), 4.93 (2H, s), 4.82 (2H, s), 3.63 (2H, m), 3.56 (4H, m), 3.42 (2H, m), 3.40 (8H, m), 2.74 (2H, t), 2.59 (2H, t), 1.59 (4H, m). LC-MS Rt 3.10 mins; 658.4 [M+H]+, Method 10minLC_v002.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[O:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[O:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccoc1C(=O)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc(Br)oc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 11.1 %

Procedure:
To a stirred solution of N-benzyl-3-methylfuran-2-carboxamide (1.18 g, 5.49 mmol) in acetonitrile (25 mL) was added N-bromosuccinimide (0.98 g, 5.49 mmol). The reaction mixture was stirred for 16 hours, and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was washed with 1 N sodium hydroxide solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-20% ethyl acetate in hexanes to afford N-benzyl-5-bromo-3-methylfuran-2-carboxamide as a colorless solid (0.18 g, 11%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 6.54 (br s, 1H), 6.28 (s, 1H), 4.58 (d, J=5.9 Hz, 2H), 2.40 (s, 3H); MS (ES+) m/z 294.1 (M+1), 296.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:25])=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A mixture of 1-benzenesulfonyl-5-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (16.9 g, 46.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (13.21 g, 46.2 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (1.52 g, 9.3 mmol) in 1,2-dichloroethane (200 mL) was heated under reflux for 90 minutes then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as white solid (13.7 g, 61%). LCMS (Method B): RT=4.35 min, M+H+=443/445/447. 1H NMR (400 MHz, CDCl3): 8.46-8.46 (m, 2H), 8.39 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.64-7.64 (m, 1H), 7.55-7.52 (m, 2H), 5.67 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:27].[Na+]>CC(O)(C)C>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:26])=[O:27])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: [OH-]
Reactant: C=C(c1ccc(CC#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C=C(c1ccc(CC(N)=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 100 °C
Yield: 32.7 %

Procedure:
To a solution of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl-acetonitrile (15 mg, 0.044 mmol) in 1 mL of t-BuOH was added NaOH (1 mL of 2N solution, 2 mmol). The mixture was heated at 100° C. for 24 hours. After acidification and extraction with EtOAc, the organic fraction was dried over Na2SO4, filtered and concentrated in vacuo. Purification by PTLC gave 5.2 mg of the amide product.
Reaction SMILES: [CH3:1][O:2][C:3]1(OC)[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COC1(OC)CC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC1=CC(=O)NC1=O
Yield: 70.5 %

Procedure:
To a solution of 3,3-dimethoxypyrrolidine-2,5-dione (12.3 g, 77 mmol) in toluene (500 mL) was added TsOH·water (1.46 g, 7.7 mmol). A Dean Stark Trap was attached and the reaction mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. The mixture was concentrated and purified by column chromatography (from petroleum ether/EtOAc=2/1 to petroleum ether/EtOAc=1/1) to afford 3-methoxy-1H-pyrrole-2,5-dione (6.9 g, 70% yield) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-6-hydroxynaphthalene (243 mg, TCI) in anhydrous THF (10 ml) was cooled to −78° C., added dropwise with a 1.6 M solution of n-butyllithium in hexane (1.18 ml) over 20 minutes under argon gas atmosphere, and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (1.73 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 2 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (2 ml), and extracted with diethyl ether (40 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-hydroxy-2-naphthaleneboronic acid (378 mg). A solution of this substance in ethanol (1 ml), Compound No. A-1 (230 mg), and 2 M aqueous sodium carbonate (2.4 ml) were added with toluene (3 ml) and (Ph3P)4Pd (115 mg) and stirred at 100° C. for 13 hours. The reaction mixture was added with ethyl acetate (100 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. V-3, 270 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(O)[CH3:8])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][CH:6]=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(C)(O)c1ccccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NCC=C(C)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 2.82 g of 1-acetamido-3-p-biphenylyl-butan-3-ol, 0.1 g of p-toluenesulfonic acid and 70 ml of toluene is boiled for 2 hours under a water separator, 1-Acetamido-3-p-biphenylyl-2-butene is obtained after working up in the customary manner.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[O:8])=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1
Agent: Br
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc(O)cc1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture containing 13 g of 5-(4-methoxybenzoyl)-6-methyl-2(1H)-pyridinone and 100 ml of 48% aqueous hydrogen bromide solution was refluxed for 7 hours and then allowed to stand at room temperature overnight. The reaction mixture was concentrated to dryness on a rotary evaporator. To the residue was added 100 ml of water and the aqueous mixture was neutralized by adding aqueous ammonium hydroxide solution. The solid was collected, washed with water and air dried. The solid was recrystallized from 100 ml of ethanol and dried at 80°-85° C. to yield 11.4 g of 5-(4-hydroxybenzoyl)-6-methyl-2(1H)-pyridinone, m.p. 280°-282° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH:18]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH:18]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
Methanesulfonyl chloride (0.176 g) was added to a solution of methyl 2-(3-hydroxypropyl)-5-nitro-1H-indole-4-carboxylate (Intermediate 21, 0.360 g) in pyridine (1 mL) and DCM (10 mL) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM, washed with aqueous citric acid (5%), aqueous sodium bicarbonate and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in toluene and evaporated to dryness, four times to give methyl 2-(3-methanesulfonyloxypropyl)-5-nitro-1H-indole-4-carboxylate (0.460 g) as an orange gum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:48]=[N:49][O:50][C:51]=1[CH3:52].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:52][C:51]1[O:50][N:49]=[CH:48][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: Cc1oncc1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1oncc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)-5-methylisoxazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (25%) as a white solid: mp 159-161° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-6.91 (m, 4H), 6.50 (s, 1H), 6.11 (s, 1H), 5.94 (d, 1H), 5.85 (ABq, 2H), 4.95 (ABq, 2H), 4.78 (ABq, 2H), 2.37 (s, 3H); MS (ES+) m/z 377.3 (M+1).
Reaction SMILES: O=C1CCC(=O)N1[C:8](=[O:20])[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[NH2:21][C@H:22]([C@@H:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])[C:23]([OH:25])=[O:24].O>C1COCC1>[CH2:29]([O:28][C@@H:26]([CH3:27])[C@@H:22]([NH:21][C:8](=[O:20])[C:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])([CH3:11])[CH3:10])[C:23]([OH:25])=[O:24])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](OCc1ccccc1)[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture comprising of tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylcarbamate (1 g, 3.33 mmol) (prepared according to the procedure described in EP1486498A1 page 20) and (2R,3S)-2-amino-3-(benzyloxy)butanoic acid (0.697 g, 3.33 mmol) in THF (40 ml)/water (10 ml) was treated with TEA (1.392 ml, 9.99 mmol) and stirred at 50° C. for 4 hours. The resulting mixture was concentrated in vacuo and EtOAc (20 ml) was added. The pH was adjusted to pH2 with 1M HCl. The organic portion was separated and the aqueous phase was back extracted with EtOAc (30 ml). The combined organic portions were washed with a saturated solution of brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Na].CO[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[O:11][CH3:12].[C:14](OC)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O.CO>[CH3:12][O:11][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[C:4](=[O:13])[CH3:14]
Reactant: COC(C)=O
Reactant: COC(=O)c1ccncc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnccc1C(C)=O
Yield: 46.3 %

Procedure:
A dry 50 mL three neck flask fitted with a reflux condenser and internal thermometer was charged with dry methanol (20 mL). Sodium (516 mg, 0.022 mol) was added in portions and after all the sodium had dissolved the methanol was removed by distillation. The resulting sodium methoxide was cooled and a mixture of methyl-3-methoxyisonicotinoate (2.50 g, 0.015 mol) and methyl acetate (6.65 g, 0.090 mol) was added dropwise. The mixture was refluxed for four hours, allowed to cool and dissolved in water (9.0 mL) and concentrated hydrochloric acid (6.0 mL). The resulting mixture was heated to reflux for 2.5 hours, cooled, and basified with 5% sodium bicarbonate. The mixture was extracted with chloroform (4×50 mL) and the combined extracts dried over sodium sulfate, concentrated, and chromatographed through a short column of silica gel to afford 3-methoxy-4-acetylpyridine (1.05 g, 46%). mp. 36°-37° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:16]([CH2:15][N:12]1[CH:13]=[CH:14][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])=[N:11]1)=[O:18]
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(Cn1ccc(NC(=O)c2ccc(Cl)s2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
57.4 According to general method B, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-amide. White solid. MS 472.4 ([M+H]+)
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][C:10]2([C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])[CH2:9]1)=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][C:10]2([C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])[CH2:9]1)=[O:7]
Reactant: CC(=O)SCC(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Agent: N
Product: O=C(O)[C@@H]1CC2(CN1C(=O)CS)C(=O)CCC2=O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield (8S)-7-(2-mercapto-1-oxoethyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.