Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 100 °C
Yield: 35.8 %

Procedure:
3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of 2-chloro-5-nitroaniline (1.72 g) in pyridine (10 ml) at 20° C. The reaction mixture was heated to 100° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was poured into water (100 ml). The resulting precipitate was collected, washed with water and dried. The solid was triturated under methylene chloride (20 ml) to give N-(2-chloro-5-nitrophenyl)-3,4-dimethoxybenzamide (1.2 g), m.p. 231-232° C.; NMR Spectrum: (DMSOd6) 3.82 (s, 6H), 7.08 (d, 1H), 7.62 (m, 1H), 7.82 (d, 1H), 8.08 (m, 1H), 8.54 (d, 1H), 10.07 (m, 1H);
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][S:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCSCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2.5 g, 10.24 mmol) and dihydro-2H-thiopyran-4(3H)-one (1.42 g, 12.29 mmol) in dichloroethane (50 mL), acetic acid (3.6 ml, 61.47 mmol) was added and reaction stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (6.5 g, 30.73 mmol) was added and stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. Column chromatography purification of crude gave methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 71.0%).
Reaction SMILES: [OH:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:7]1[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3][C:2]1=[O:1])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(=O)cc(O)o1
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75340.3 %

Procedure:
A suspension of 2-hydroxy-6-methyl-4H-pyran-4-one (23.92 g, 0.189 mmol) and dimethylformamide dimethyl acetal (45.2 mL, 0.34 mmol) in toluene (100 mL) was stirred at room temperature for 4 hours and concentrated to provide 25.8 g (75%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 182 (M+H)+; 1H NMR (CDCl3) δ 8.22 (s, 1H), 5.67 (s, 1H), 3.47 (s, 3H), 3.39 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=1[OH:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:33])([F:34])[F:35])[C:26]=3[Cl:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Product: CC(NC(=O)c1coc(Oc2cccc(C(F)(F)F)c2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 74.1 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-chloro-3-trifluoromethyl-phenol (53 mg, 0.26 mmol) to give the title compound (52 mg, 74%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[S:14][C@@H:15]2[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27](=[O:39])[N:16]2[CH:17]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:18]=1>ClCCl>[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:15]2[S:14]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CC(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A solution of 3-chloroperbenzoic acid (0.40 g.) in dichloromethane (10 ml.) was dropwise added to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.92 g.) in dichloromethane (10 ml.) and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed in turn with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide (0.56 g.), mp 173° to 175° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[N:32]=[CH:31][N:30](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:29]=5)[CH:26]=4)[N:21](C4CCCCO4)[N:20]=3)[CH:14]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:29]1[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:15]2[CH:14]=[C:13]([C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:32][CH:31]=[N:30]1
Reactant: O=C(N[C@@H]1CCc2ccccc21)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CCc2ccccc21)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Yield: 9.1 %

Procedure:
To a stirred solution of N-((1R)indanyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.292 g, 0.391 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 60° C. for 18 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0150 g, 9% yield). 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.55 (s, 1H), 8.23 (d, 1H), 8.13 (d, 1H), 7.96 (dd, 1H), 7.70 (m, 2H), 7.36 (m, 1H), 7.28 (m, 1H), 7.23 (m, 2H), 5.67 (t, 1H), 3.08 (m, 1H), 2.92 (m, 1H), 2.60 (m, 2H), 2.08 (m, 1H). ES-MS (m/z) 421 [M+1]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CCOC(C)=O>CN(C=O)C>[NH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccccc1Nc1ccccc1
Yield: 92.6 %

Procedure:
To a stirring solution of N-phenyl-o-phenylene diamine (20 g, 180.55 n M) in 200 ml of DMF at RT was added K2CO3 (16.5 g, 120 mM) followed by tert-butyl bromoacetate (21.17 g 108.55 mM). The resulting mixture was stirred at RT until TLC (Hex:AcOEt 3:1) showed completion of reaction. The mixture was filtered to remove the K2CO3 and then diluted with 800 mL of EtOAc and 200 mL of Et2O. This solution was washed successively with H2O (2×400 mL), brine (1×400 mL), 1 N HCl (2×400 mL), and H2O (1×400 mL), and the organics dried (MgSO4) and concentrated to give a greenish-black oil. The resultant oil was purified by silica gel flash column chromatography using hexane/EtOAc 4/1 and the combined filtrates evaporated in vacuo to give 30 g of product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:8]3/[C:9](=[O:14])[NH:10][C:11]4[C:7]/3=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:13][CH:12]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: CNC(=O)c1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized from N-methyl-2-oxoindoline-5-carboxamide (11 mg, 0.0578 mmol) and 1H-indazole-6-carbaldehyde (10 mg, 0.0636 mmol) according to the method described for Example A1 to obtain 3.0 mg, 17%. 1H NMR (400 MHz, d6-DMSO) δ 13.33 (s, 1H), 10.88 (s, 1H), 8.24-8.22 (m, 1H), 8.18 (s, 2H), 7.93-7.88 (m, 2H), 7.84 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 2.68 (d, J=4.0 Hz, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H14N4O2+H]+ 319.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]Cl.CC(C)=O.[I-:19].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][I:19]
Reactant: [I-]
Reactant: COc1ccc(CCl)c(OC)c1OC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc(CI)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
46.64 g (215.2 mmol) of 2,3,4-trimethoxybenzyl chloride in 466 ml of abs. acetone are treated with 156.7 g (4.86 equivalents) of sodium iodide, and this mixture is stirred at RT for 2.75 h while excluding light. The reaction mixture is treated with approximately 3 l of (cold) ether, and the organic phase is washed once with 10% sodium thiophosphate solution and twice with saline (both kinds of solutions being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and evaporated on a RE, at approximately 30° C. The residue, which is the desired title compound, is dried again under HV and subjected to further processing as a crude product. 1H-NMR (200 MHz, CDCl3): 7.03 and 6.59 (each d; each 1H); 4.47 (s, 2H); 4.05, 3.85 and 3.84 (each s, each 3H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:18])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([O:18][CH3:33])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(O)CCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(OC)CCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Racemic ethyl 1-(biphenyl-4-ylmethyl)-5-hydroxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Example 17, 174 mg, 0.431 mmol) was dissolved in degassed N,N-dimethylformamide (2 mL), cooled to 0° C. under an atmosphere of nitrogen and treated with sodium hydride (19 mg, 0.47 mmol, 60% dispersion in mineral oil, 1.1 equiv) and then methyl iodide (0.096 mL, 1.55 mmol, 3.6 equiv). After stirring for 15 min, the mixture was warmed to ambient temperature and stirred for an additional 1 hr. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to provide racemic ethyl 1-(biphenyl-4-ylmethyl)-5-methoxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C@@H:17]([OH:21])[C:18](O)=[O:19]>C1(C)C(C)=CC=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[C@H:17]([OH:21])[C@H:16]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[S:15][C:3]=2[CH:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc([C@H](Sc2cc(Cc3ccccc3)ccc2N)[C@@H](O)C(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3cc(Cc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of 6.71 g of (2S, 3S)-3-(2-amino-5- benzylphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionic acid [prepared as described in step (b) above] dissolved in 400 ml of xylene was heated under reflux for 8 hours whilst stirring. At the end of this time, the mixture was cooled to room temperature and the crystals which precipitated were collected by filtration and washed with xylene and hexane to give 5.8 g of the title compound, melting at 200-202° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (0.1 M) was added acetic anhydride (1.1 equiv.). The resulting mixture was stirred at RT for 45 min. After concentration, the residue was partitioned between EtOAc and water. The organic phase was washed with water and then with brine. After drying over sodium sulfate the solution was concentrated in vaccuo to give crude (R)-tert-butyl 2-(acetamidomethyl)morpholine-4-carboxylate which was used in the next step without further purification. LCMS (m/z) (M+H)=159.1 (-Boc), Rt=0.53 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:27])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH2:30])=[O:28])=[CH:7][CH:6]=2)[CH:9]=[CH:10]3)[CH2:21][CH2:20]1
Reactant: N#C[O-]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(N)=O)cc3)ccn2c1=O
Reaction time: 3 h
Yield: 87.7 %

Procedure:
54 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in a mixture of 3 ml of acetic acid and 2 ml of water. 2 ml of an aqueous solution of 19 mg of sodium cyanate was added to the obtained solution at 35° C. and they were stirred at that temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 53 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureidophenyl)-4H-quinolizine-3-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][NH2:52]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:52]\[CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: CN
Solvent: CO
Product: C/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.143 mmol) in methanol (2 mL) was added methylamine (40% in water, 0.1 mL) at room temperature, and the mixture was stirred under nitrogen for 1 h. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with chloroform. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-9-(methylimino)-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (30 mg, 29%) as a blue solid: 1H NMR (500 MHz, CDCl3) δ 11.94 (s, 1H), 7.88 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 5.91 (s, 1H), 5.26 (s, 1H), 5.00 (dd, J=10.0, 6.0 Hz, 1H), 4.75-4.72 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.61 (s, 3H), 3.57 (dd, J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.36 (m, 1H), 3.34 (d, J=4.5 Hz, 3H), 3.29 (d, J=19.5 Hz, 1H), 3.15 (t, J=9.5 Hz, 1H), 2.52 (d, J=4.5 Hz, 1H), 2.36 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 711 (M+H); HPLC 93.4% (AUC), tR 10.83 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([NH:20][C:18]3[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[N:16]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)cc1

Procedure:
N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-5-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and ]-4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale orange foam (0.040 g, 30%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.25 (d, J=7.9 Hz, 2H), 8.14 (d, J=7.4 Hz, 2H), 7.59-7.56 (m, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.29-7.25 (m, 2H), 7.08-7.03 (m, 1H), 6.94 (s, 1H), 3.61 (s, 2H), 3.16 (s, 3H), 3.08-3.03 (m, 4H), 3.01-2.96 (m, 4H). MS=512 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:23][CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCS(=O)(=O)Nc1ccc(CN)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(CNC(=O)COc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a N,N-dimethylformamide (DMF) (5 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)phenyl]ethanesulfonamide hydrochloride (451 mg, 1.80 mmol, Journal of Medicinal Chemistry 2003, 46(14), 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (46 mg, 0.38 mmol) and triethylamine (506 mg, 5.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 341 mg (56% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
Combine 1-bromo-4-fluoro-2-methylbenzene (30.0 g, 159 mmol) in concentrated sulfuric acid (100 mL), cool to about −5° C., and treat dropwise with nitric acid (11.00 mL, 174 mmol) over 20 minutes. Allow reaction mixture to warm to RT and stir for 30 min. Pour onto crushed ice with stirring and partition with tert-butyl methyl ether (MTBE) (200 mL). Separate the aqueous layer and extract with MTBE (2×50 mL). Combine organic layers, dry and concentrate under reduced pressure to provide 1-bromo-4-fluoro-2-methyl-5-nitrobenzene as an orange-colored viscous oil (39.0 g).