Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:13](=O)[CH2:14][CH3:15].C([BH3-])#N.[Na+]>CO>[CH3:12][N:8]1[C:7]2[C:2]([NH:1][CH2:13][CH2:14][CH3:15])=[CH:3][CH:4]=[CH:5][C:6]=2[NH:10][C:9]1=[O:11]
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1cccc2[nH]c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
To 0.87 g (5.3 mmol) of 7-amino-1-methyl-1,3-dihydro-2H-benzoimidazol-2-one in 50 mL of methanol was added 1.94 mL (26.7 mmol) of propionaldehyde and 1.0 g (16 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 5 h and concentrated in vacuo. The crude solid was partitioned between water and ethyl acetate, the biphasic mixture was filtered to remove particulates and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with a 50% ethyl acetate/hexanes mixture to give 0.69 g (63%) of the title compound as a cream colored powder.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([O-])([OH:18])=[O:17]>>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Cl)cc1)C1CCCCC1
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
To 50 ml fuming nitric acid are added batchwise at -25° C. 6.4 g (28.8 mmol) of 4-(cyclohexylcarbonyl)-chlorobenzene. The solution is stirred for 10 minutes at -25° C. and then poured onto ice water. The precipitated product is suction filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([Si:9](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].Cl>CCCCCCC>[CH2:1]([Si:9]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Si](Cl)(Cl)Cl
Reactant: COCCOCCO
Agent: Cl
Solvent: CCCCCCC
Product: CCCCCCCC[Si](OCCOCCOC)(OCCOCCOC)OCCOCCOC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a dry flask fitted with an agitator, thermometer, additional funnel and reflux condenser was charged 222.8 g (0.90 mole) of octyltrichlorosilane and 225 g of heptane. The mixture was blanketed with nitrogen, heated to 80° C. and 333.7 g (2.78 mole) of 2-(2-methoxyethoxy)ethanol was added slowly over a 2 hour period. Hydrogen chloride was evolved from the mixture. After the addition was complete heating of the reaction was continued for 24 hours at 80° C. Then the solvent and all volatile components of the mixture were removed under vacuum, producing 451 g of the clear, colorless liquid product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.C[Si](CC(N)=O)(C)C.[CH3:19][C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28](N)[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=[O:21]>C(OCC)(=O)C.O.C(Cl)Cl>[CH3:19][C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[CH2:28][C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=[O:21]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Temperature: 40 °C
Yield: 195.6 %

Procedure:
Phosphorus oxychloride (0.89 g.) and dry dimethylformamide (0.44 g.) were mixed under ice-cooling and then warmed for 30 minutes at 40° C. Dry methylene chloride (20 ml.) was added thereto and then distilled off. To the residue were added dry ethyl acetate (10 ml.) and then 2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl]acetic acid (syn isomer) (1.8 g.) with stirring and ice-cooling. The mixture was stirred for 40 minutes at the same temperature to give clear solution. On the other hand, trimethylsilylacetamide (6.36 g.) was added to a suspension of 7-aminocephalosporanic acid (1.65 g.) in dry ethyl acetate (25 ml.) with stirring at ambient temperature, after which the mixture was stirred for 1 hour to give a clear solution. To this solution was at a time added the above-obtained ethyl acetate solution with stirring at -20° to -25° C., and the resulting mixture was stirred for 2 hours at the same temperature. Water (30 ml.) was added to the reaction mixture at the same temperature, and then the mixture was stirred for 5 minutes at ambient temperature. The ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined and water (50 ml.) was added thereto. The mixture was adjusted to pH 7.5 with sodium bicarbonate, and the aqueous layer was separated. Ethyl acetate (40 ml.) was added to the aqueous layer, and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid with stirring and ice-cooling. The ethyl acetate layer was separated, and the aqueous layer was further extracted twice with ethyl acetate (30 ml.). The ethyl acetate layers were combined, washed with an aqueous solution of sodium chloride and treated with activated charcoal. The solvent was distilled off to give 7-[2-methoxyimino-2-{2-2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanic acid (syn isomer) (3.05 g.), mp 205° C. (dec.).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Clc1nc2ccccc2o1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C24H21N3O2S, 415.52; m/z found 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.83-6.68 (m, 11H), 4.20-2.47 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([CH3:7])[CH2:5][OH:6].[CH3:9][C:10](=[CH2:12])[CH3:11]>>[C:10]([O:6][CH2:5][CH:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8])([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: COC(=O)C(C)CO
Product: COC(=O)C(C)COC(C)(C)C
Yield: 43.5 %

Procedure:
Treatment of rac. methyl-3-hydroxy-2-methylpropionate with isobutylene using the procedure described in Example 1 gave rac.-methyl 3-tert. butoxy-2-methylpropionate in 43.5% yield as a colorless liquid, b.p. 75°-85° C. (bath temperature) (11 mm Hg.).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][N:6]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[C:28]([CH:34]([CH2:36][CH3:37])[CH3:35])[CH:27]=2)=[C:20]([Cl:38])[CH:19]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)=[O:8])C.B(Br)(Br)Br>C(Cl)Cl>[CH:34]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[OH:32])[O:25][C:21]1[C:20]([Cl:38])=[CH:19][C:18]([N:6]([CH2:5][C:4]([OH:39])=[O:3])[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:8])=[CH:23][C:22]=1[Cl:24])([CH2:36][CH3:37])[CH3:35]
Reactant: CCOC(=O)CN(C(=O)Oc1ccc(OC)cc1)c1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(C)c1cc(Oc2c(Cl)cc(N(CC(=O)O)C(=O)Oc3ccc(O)cc3)cc2Cl)ccc1O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of [[4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenyl]-(4-methoxy-phenoxycarbonyl)-amino]-acetic acid ethyl ester (6.4 g, 0.01 mol) in CH2Cl2 (128 mL) was cooled to −60° C. under nitrogen atmosphere. To that 1M BBr3 (boron tribromide) solution (44.44 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25° C. over 5 h. then diluted with more CH2Cl2 (30 mL) and quenched with H2O. After stirring at 20-25° C. for 30 min, organic phase was separated, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (chloroform:methanol) gradient elution from 95:5 to 90:10 to give pure [[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-(4-hydroxy-phenoxycarbonyl)-amino]-acetic acid (3.3 g, 58% yield)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[CH2:15]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:20]([CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:37]=[N:36][N:35]=2)=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(CCl)Nc1c(F)cc(F)cc1F
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCN(CC(=O)Nc1c(F)cc(F)cc1F)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
N-(Chloroacetyl)-2,4,6-trifluoroaniline (313.0 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (780.0 mg), potassium iodide (230 mg) and triethylamine (2.1 g) were suspended in dimethylformamide (12 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (100 mL) was added, and the mixture was washed four times with brine (200 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-pentyl-N-[[[(2,4,6-trifluorophenyl)amino]carbonyl]methyl]-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (434.8 mg). Yield: 42%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[N:15][C:14]=2[C:23]2[N:27](COCC[Si](C)(C)C)[N:26]=[CH:25][CH:24]=2)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl>CCO>[NH:27]1[C:23]([C:14]2[N:15]=[CH:16][C:17]3[C:22]([C:13]=2[CH2:12][O:11][C:8]2[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:24][CH:25]=[N:26]1
Reactant: COc1cc(C=O)c(OCc2c(-c3ccnn3COCC[Si](C)(C)C)ncc3ccccc23)cn1
Agent: Cl
Solvent: CCO
Product: COc1cc(C=O)c(OCc2c(-c3ccn[nH]3)ncc3ccccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 0.02 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (0.1 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated. The crude was purified on silica gel using MeOH and DCM as eluent to give 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 83%) as a white solid. NMR (400 MHz; CDCl3) δ=10.17 (s, 1H), 9.25 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.73 (t, 1H), 7.60-7.68 (m, 2H), 7.03 (s, 1H), 6.70 (d, 1H), 5.85 (s, 2H), 3.85 (s, 3H). LRMS (M+H+) m/z 361.1.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)[CH2:5][CH3:6].Cl>C1COCC1.O>[CH2:4]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)[CH2:5][CH3:6]
Reactant: CCCc1nc(C(=O)OCC)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.2 g) was added to a solution of ethyl 2-propylthiazole-4-carboxylate (example 56, step b) (0.24 g) in a mixture of THF (4 mL) and water (1 mL). The resulting suspension was stirred overnight at RT. The reaction was acidified with aqueous HCl solution (2M, 3 mL) and evaporated. The residue was partitioned between brine (5 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 0.17 g.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[CH2:28][C@H:27]4[C@:29]5([CH2:33][N:32]([CH2:34][C:35]([F:38])([F:37])[F:36])[S:31](=[O:40])(=[O:39])[NH:30]5)[C@H:24]([CH2:25][CH2:26]4)[CH2:23][C:22]=3[CH:41]=2)O1>>[CH:7]([N:5]1[CH:6]=[C:2]([C:18]2[CH:19]=[CH:20][C:21]3[CH2:28][C@H:27]4[C@:29]5([CH2:33][N:32]([CH2:34][C:35]([F:38])([F:37])[F:36])[S:31](=[O:39])(=[O:40])[NH:30]5)[C@H:24]([CH2:25][CH2:26]4)[CH2:23][C:22]=3[CH:41]=2)[N:3]=[CH:4]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1cnc(Br)c1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: CC(C)n1cnc(-c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)c1

Procedure:
Prepared from 4-bromo-1-isopropyl-1H-imidazole (Step 1) and homochiral boronate from Example 24 Step 1 by the procedure described for Example 76 Step 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH3:16].[CH:18]1(C(Cl)=O)C[CH2:19]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15]([CH:16]1[CH2:19][CH2:18]1)=[O:17]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2[nH]cc(CONC(C)=O)c2c1
Product: COc1ccc2[nH]cc(CONC(=O)C3CC3)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 13, but replacing the acetic acid chloride with cyclopropanecarboxylic acid chloride, the title compound is obtained.
Reaction SMILES: N1C=CN=C1.[I:6]I.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([N:22]([CH:26]([CH:35]2[CH2:37][CH2:36]2)[C:27]2[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[S:19][C:20]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([N:22]([CH:26]([CH:35]2[CH2:37][CH2:36]2)[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][I:6])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[S:19][C:20]=1[CH3:21]
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CI)cc1)C1CC1

Procedure:
0.35 g of imidazole, 1.32 g of iodine and then 1.6 g of the product of Example 4 are added, at room temperature, to 1.36 g of triphenylphosphine in 50 ml of methylene chloride.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10]>CO.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][OH:10]
Reactant: COc1c(C=O)cc(Br)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(CO)cc(Br)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Sodium borohydride (4 g) was added in portions to a stirring solution of crude 5-bromo-2-methoxy-3-nitrobenzaldehyde (20.5 g) in methanol (350 mL) and tetrahydrofuran (150 mL) at 0° C. After 1 h, the methanol was removed in vacuo. The residue was treated with cold water (150 mL) and extracted with diethyl ether (2×150 mL). The combined organic layer was evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in petroleum ether (10–40%) gave the title compound (17 g) as a solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[CH:18]=[O:19]>CN(C)C=O>[CH3:16][N:15]1[C:11]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([CH:18]=[O:19])[C:13]([CH3:17])=[N:14]1
Reactant: OC1CCCCC1
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(OC2CCCCC2)c1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.3 %

Procedure:
Under a nitrogen gas atmosphere, 3.48 g (0.0347 mole) of cyclohexanol was added at 0° C. to 50 ml of an N,N-dimethylformamide solution containing 1.45 g (0.03625 mole) of suspended sodium hydride. The resulting mixture was stirred at 0° C. for 1 hour. Thereafter, a solution of 5 g (0.0315 mole) of 5-chloro-1,3-dimethyl-4-formylpyrazole in 20 ml of N,N-dimethylformamide was added dropwise at 20° C. over 1 hour. The reaction mixture was stirred at 20° C. for 5 hours. The reaction mixture was then poured into 300 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to obtain 0.3 g of 1,3-dimethyl-5-cyclohexyloxy-4-formylpyrazole.
Reaction SMILES: O.[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33].Cl.C([OH:38])C>O>[OH2:15].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33].[OH2:38].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33]
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h

Procedure:
1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (0.629), from the previous alternative, and aqueous hydrochloric acid (2 molar) were combined in refluxing ethanol (13 mL) and water (1.3 mL). The mixture was cooled, granulating overnight, chilled in ice and the resulting slurry was filtered. The product solids were dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Mot wt (calc) 438.41, MS: 439.35 (MH+), 437.20 (M−). 1H NMR (DMSO-d6): δ 3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H), 10.21 (s, 1H).; HPLC retention time 9.29 minutes.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21](O)[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)[CH3:14].B(F)(F)F.CCOCC>O1CCOCC1>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)[CH3:14]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCC(O)c1ccc(CC)cc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCC(c1ccc(CC)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a flame-dried flask containing a mixture of 325 mg of 4-hydroxycoumarin and 500 mg of 1-(4-ethylphenyl)-butan-1-ol of Preparation 21 in 10 mL of dioxane under an argon atmosphere is added 1.25 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is flash column chromatographed with 40% ethyl acetate in hexane to yield 360 mg of the title product as a white solid.
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][CH2:6][C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])C.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH:8]1[C:4](=[O:18])[CH2:5][CH2:6][C:7]1=[O:17]
Reactant: CCOC(=O)CCC(=O)Cc1ccc(Cl)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)C1c1ccc(Cl)cc1Cl

Procedure:
For example, the 2-aryl-1,3-cyclopentanediones may be prepared by the base-promoted cyclization of the appropriate δ-aryl levulinic acid ester. This is illustrated by reacting ethyl-5-(2',4'-dichlorophenyl)-4-ketopentanoate with sodium ethoxide in the presence of a toluene solvent to form 2-(2',4'-dichlorophenyl)-1,3-cyclopentanedione. The δ-aryl levulinic acid esters used as reactants in the above synthesis can be prepared using conventional esterification techniques of the appropriate δ-aryl levulinic acids.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[K].[O:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[I-].[Na+]>>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:17]2[C:18](=[O:20])[CH2:19][O:15][C:16]2=[O:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1OCCCCCl
Reactant: O=C1COC(=O)N1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Product: Nc1ncccc1OCCCCN1C(=O)COC1=O

Procedure:
Using 15.05 g (75 mmol) of 2-amino-3-(4-chlorobutyloxy)pyridine, 10.44 g (75 mmol) of oxazolidine-2,4-dione potassium salt and 11.24 g (75 mmol) of sodium iodide, the same procedure as in Reference Example 11 was followed, to yield 12.34 g (62.0%, yellow powder) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Solvent: CO
Product: Nc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 17 h

Procedure:
3 g (12.1 mmol) of 1-(3-fluorobenzyloxy)-4-nitro-benzene is dissolved in 125 ml of methanol. 150 mg of Pt 5% on charcoal is added and hydrogenation done under normal pressure for about 17 h. The catalyst is filtered and the solution evaporated to yield 2.51 g (95%) of crude brownish material. MS: m/e=218.4 (M+H)+.