Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]1.Br.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=1
Reactant: COc1ccc(C)cc1C1CC(C)(C)CC(C)(C)C1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(O)c(C2CC(C)(C)CC(C)(C)C2)c1
Yield: 47.6 %

Procedure:
To a solution of 1-methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)benzene (1.0 g, 3.84 mmol) produced in Example (104b) in acetic acid (5 mL) was added 48% hydrobromic acid (10 mL, 59.3 mmol), followed by reflux for 12 hours. Saturated aqueous solution of sodium hydrogencarbonate was added to the cooled reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 450 mg of the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1
Yield: 96.1 %

Procedure:
3-nitrophthalic anhydride (0.79 g, 0.0041 mol) and m-aminobenzoic acid (0.56 g, 0.0041 mol) were refluxed as above overnight. Concentration of the solution under vacuum by rotary evaporator and crystallisation of the product from EtOH/H2O yielded 1.23 g (76%) of 126 as a vibrant yellow powder: mp=354-355° C.; Rf0.77 (A): Rf0.84 (C): Rf0.54 (D): IR (cm−1): 2740-3100 (OH), 3088 (C═CH), 2665 (C—H), 1776 (C═O), 1725 (bs, C═O), 1614 (C═C), 1542 (N═O), 1460 (C═C), 1420 (C═C), 1382 (C—O), 1356 (N═O), 1120 (C—O), 717 (C═CH); MS m/z (rel intensity) 311 (100), 267 (65), 191 (60).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].C(N(CC)CC)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>C1C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[CH3:14][C:7]1([CH3:13])[C:6]2[C:11](=[C:2]([O:1][CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC(=O)c2c(OCOCC[Si](C)(C)C)cc(C#C[Si](C)(C)C)cc21
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 1.67 g, 5.8 mmol) in anhydrous benzene was treated with triethyl amine (1.41 g, 11.6 mmol) and catalytic amount of 4-(dimethylamino)pyridine followed by 2-(trimethylsilyl)ethoxymethyl chloride (1.93 g, 11.6 mmol) and the resulting reaction mixture was refluxed for 3 days. It was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-6% ethyl acetate in hexane as the eluent to afford the title product as a yellow oil (1.58 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C(C)C)=[C:15]([I:23])[CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:24].ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:23])[CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:24]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(Br)c(Cl)c3)n2)cc1I
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: Oc1ccc(-c2noc(-c3ccc(Br)c(Cl)c3)n2)cc1I
Yield: 86 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 86% yield, as creamy solid. 1H-NMR (CDCl3) 8.47 (d, 1H, J=1.98 Hz); 8.28 (d, 1H, J=1.95 Hz); 8.03 (dd, 1H, J=8.49, 1.98 Hz); 7.92 (dd, 1H, J=8.37, 1.98 Hz); 7.84 (d, 1H, J=8.37 Hz); 7.08 (d, 1H, J=8.52 Hz); 5.65 (b, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.P(=O)(O)(O)O.C(OCC)(=O)C>CS(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(OCc2ccc3ccccc3n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol (1.74 g, 5.6 mmol), prepared in step 1, and dicyclohexylcarbodiimide (3.71 g, 18 mmol) in DMSO (25 ml) was added 1M solution of phosphoric acid in DMSO (2.7 ml), and the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was then added and the precipitated dicyclohexylurea was filtered off. The filtrate was washed with water, and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride-ethyl acetate 15:1) to afford 1.25 g of 2-nitro-5-(2-quinolylmethoxy)benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(C)ccc3n2)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(C)ccc3n2)cc1
Yield: 74 %

Procedure:
A mixture of 3.2 g of 4-chloro-6-methyl-2-(4-methylphenyl)quinoline, 3.06 g (24 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 160° for 4 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 3.18 g of crude product. Recrystallization from n-butanol gave off-white prisms, mp 242°-244° dec.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:26]=[C:25]([CH2:27][CH3:28])[N:24]([CH3:29])[N:23]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:26]=[C:25]([CH2:27][CH3:28])[N:24]([CH3:29])[N:23]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Temperature: 78 °C
Yield: 85 %

Procedure:
5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.240 g, 0.6179 mmol) and ethyl formate (0.148 mL, 1.84 mmol) were dissolved in anhydrous ethanol (6 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.2 mL, 3.21 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.2187 g, 0.525 mmol, 85%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:54][S:55]([C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1)(=[O:57])=[O:56].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>COCCOC.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([C:4]2[N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([S:55]([CH3:54])(=[O:57])=[O:56])[CH:59]=3)[N:3]=2)[NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cccc(S(C)(=O)=O)c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a degassed mixture of Intermediate 66.3 (48 mg, 0.063 mmol), 3-(methylsulfonyl)phenylboronic acid (16 mg, 0.0755 mmol), tri-ortho-tolylphosphine (3.8 mg, 0.0.13 mmol) and NaHCO3 (21.7 mg, 0.258 mmol) in 2 mL DME/H2O (3:1), was added Pd(OAc)2 (1.4 mg, 0.0063 mmol). The mixture was stirred at 80° C. for 1.5 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), and concentrated. The crude mixture was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 8 mg of Intermediate 66.4 as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12]2[N:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)=[CH:19][C:11]1=2>>[Cl:6][C:7]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C:12]2[N:16]=[CH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[C:24]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:25]=3)=[CH:19][C:11]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Reactant: C1CCNC1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCCC5)c4)cc32)c1Cl
Temperature: 87 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
Pyrrolidine (1 mL) was added to 1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (32 mg). The reaction mixture was stirred at 87° C. for 72 hours and then concentrated. The residue was purified by normal phase column chromatography eluting with 5% methanol in CH2Cl2 to give the title compound as a yellow solid (35% yield). LCMS: m/z=442.21 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.03 (4H, m), 3.33 (2H, m), 3.53 (6H, m), 4.53 (2H, d, J=1.3 Hz), 5.06 (1H, bs), 6.43 (1H, d, J=0.8 Hz), 6.68 (1H, dd, J=5.4, 1.4 Hz), 7.02 (1H, m), 7.12 (2H, m), 7.79 (1H, d, J=1.8 Hz), 8.15 (1H, d, J=5.6 Hz).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:12])=[CH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>CO.O=[Pt]=O>[Br:1][C:2]1[C:11]2[CH:10]([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CC1=CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Agent: O=[Pt]=O
Solvent: CO
Product: CC1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21

Procedure:
A mixture of Example 132A (90 mg) in methanol (18 mL) was hydrogenated in the presence of PtO2 (18 mg) for 16 hours. The reaction mixture was filtered and concentrated to provide the desired product in quantitative yield. MS (ESI) m/e 397 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.71 (m, 2H), 7.39 (m, 2H), 7.03 (d, 1H), 6.92 (d, 1H), 3.05 (m, 1H), 2.69 (m, 2H), 1.7 (m, 4H), 1.07 (d, 3H).
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:23][C:19]1[N:18]([CH3:17])[CH:22]=[CH:21][CH:20]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: Cn1cccc1C=O
Agent: [Cl-]
Product: Cn1cccc1CNCCOc1ccc2ccccc2c1F
Yield: 65 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 1-methyl-1H-pyrrole-2-carbaldehyde in 65% yield as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[S:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=2[N:28]=[CH:27]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:35]([C:33]1[CH:32]=[CH:31][C:30]3[S:26][CH:27]=[N:28][C:29]=3[CH:34]=1)=[O:36])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(O)c1ccc2scnc2c1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc3scnc3c2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(Benzothiazole-5-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and benzothiazole-5-carboxylic acid. MS calcd. for C26H19ClN3O4S [(M+H)+] 504.1, obsd. 503.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[C:32]([F:34])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([OH:31])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:35])[CH:5]=1)[CH3:2].[OH-].[K+].Cl[C:39]([F:49])([F:48])C(C1C=CC=CC=1)=O>C(#N)C>[F:48][CH:39]([F:49])[O:31][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:23][C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][C:7]3[C:6]([F:35])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:33][C:32]=3[F:34])[N:10]=2)=[N:19][CH:20]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC(F)F)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: -75 °C
Reaction time: 4 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-1, 0.211 mmol, 1. eq.) were suspended in 843 μl of 30% aq. potassium hydroxide solution (5.72 mmol, 27 eq.) and 843 μl of acetonitrile. The suspension was cooled with a freezing mixture to −75° C. 93 μl of 2-chloro-2,2-difluoro-1-phenylethanone (0.632 mmol, 3 eq.) were added dropwise. The freezing mixture was removed. The reaction mixture was stirred at 80° C. bath temperature for 4 hours. Then the mixture was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. Preparative HPLC purification provided 4 mg (0.01 mmol, 3.2%) of the analytically pure target compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C@@H:9]1[C:25](=[O:26])[N:11]2[C:12]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]12>C(O)=O>[CH:1]([NH:8][C@@H:9]1[C:25](=[O:26])[N:11]2[C:12]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:24])[Cl:23])=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]12)=[O:3]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 0.58 h
Yield: 87 %

Procedure:
Acetic anhydride (8 ml) was added to a solution of 2,2,2-trichloroethyl 7β-amino-3-methylceph-3-em-4-carboxylate (6.91 g, 20 mmole) in 98-100% formic acid (40 ml.), and the orange solution was allowed to stand at room temperature for 35 minutes and then successively evaporated at 30°/15 mm and 30°/1 mm. The orange residue was dissolved in ether (200 ml) and the solution was washed successively with 2N-hydrochloric acid, water and 5% aqueous sodium hydrogen carbonate solution (50 ml of each) and water (100 ml), dried and evaporated to give the title ester as a pale yellow foam (6.50 g, 87%), [α]D + 96° (CHCl3), λmax. 262-263 nm (E1cm1% 152), νmax. (CHBr3) 3400 (NH), 1786 (azetidin-2-one), 1740 (CO2R), and 1700 and 1510 cm-1 (CONH), τ (CDCl3) 1.74 (CHO), 7.79 (C3 -CH3) (Found: Cl, 27.5, 27.2; S, 8.2. C11H11Cl3N2O4S (373.7) requires Cl, 28.5; S, 8.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:22].[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:22])[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]3[C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[CH:3][C:2]=2[F:1])[CH2:28]1)[CH3:24]
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(-c2nccs2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nccs4)c3c2F)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To 1.0 g (3.06 mmol) of the 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.46 g of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.39 g of 3-[(ethylamino)methyl]pyrrolidine. The reaction was warmed to 60° C. for one hour and was then taken to room temperature and stirred overnight. The solids were filtered and washed with ether to give 0.32 g of 7-[3[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-3-quinolinecarboxylic acid, mp 200°-207° (dec).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([CH3:26])=[CH:21][CH:20]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[CH:21][C:22]=1[CH3:26]
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Reactant: Cc1ccc(N)cc1O
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Yield: 84.2 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.087 g of 5-amino-o-cresol, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.168 g of 4-(3-hydroxy-4-methyl-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 240-242° C.; mass spectrum (EI, m/e): M 335.1260.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:6](C2C=CC(OC)=CC=2)[C:5]1=[O:23])=[N+:2]=[N-:3]>C(#N)C.O>[N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH:6][C:5]1=[O:23])=[N+:2]=[N-:3]
Reactant: COC(=O)COC[C@@H]1[C@H](N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Solvent: O
Solvent: CC#N
Product: COC(=O)COC[C@H]1NC(=O)[C@H]1N=[N+]=[N-]
Yield: 79.7 %

Procedure:
A solution of (±)-(cis)-[(3-azido-1-(4-methoxyphenyl)-2-oxo-4-azetidinyl)methoxy]acetic acid, methyl ester (2.054 g, 6.44 mmole) in acetonitrile (40 ml) was cooled to -5° C. A solution of ceric ammonium nitrate (10.62 g, 19.32 mmole) in water (30 ml) was added rapidly over ca. forty-five seconds. The reaction was warmed to +10° C. over fifteen minutes, diluted with water (100 ml), and extracted with ethyl acetate (two 80 ml portions). Sodium chloride was added to the aqueous layer which was again extracted with ethyl acetate (ca. 150 ml). The organic extracts were washed with saturated potassium bicarbonate, saturated sodium sulfite solution, brine, and dried (sodium sulfate). Filtration followed by solvent removal yielded 1.56 g of crude product which was chromatographed on silica gel (55 g, 230-400 mesh). Elution with 70% ethyl acetate-hexane yielded 1.1 g of the title compound as a heavy oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH:12]([CH3:14])[CH3:13].CN(C)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl.O>[CH:12]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]=1[NH:1][C:25](=[O:26])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1N
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)Oc1ccccc1
Yield: 76.9 %

Procedure:
To a solution of 4-amino-3,5-diisopropylphenol (1.02 g, 5.27 mmol) in dichloromethane (10 ml) was added N,N-dimethylaniline (770 mg, 6.34 mmol), then a solution of phenyl chloroformate (910 mg, 5.81 mmol) in dichloromethane (2 ml) was dropped thereinto with ice-cooling and stirring, and the mixture was stirred for 30 minutes. The reaction solution was diluted with water and extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 34 g, developing solvent; hexane:acetone=5:1) to provide 1.27 g (77%) of phenyl N-(2,6-diisopropyl-4-hydroxyphenyl)carbamate as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1.Cl.[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C>[CH3:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[CH:11][C:2]1[N:3]2[N:14]=[N:15][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2nc(Cl)cnc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2c1ncc1nnnn12
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution was made of 0.5 g. of 2-chloro-5-methylquinoxaline, 10 ml. of 0.1N HCl and 0.6 g. of sodium azide in 35 ml. of denatured ethanol. The reaction mixture was stirred for 6 hours at reflux temperature. When the mixture was allowed to cool, the product, 6-methyltetrazolo[1,5-a]quinoxaline, crystallized in 91 percent yield and was separated by filtration. The product had a melting point of 160°-62°C., and was identified by nuclear magnetic resonance analysis and elemental microanalysis, the results of which were as follows.