Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([CH:10]([CH3:12])[CH3:11])[CH:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4].C1COCC1>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)C1=NN(c2ccc(F)cc2)C(C(=O)OCc2ccccc2)C1C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C(C)C
Yield: 65 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester (29.3, 73.5 mmol) in THF:Water (1:1, 500 mL) at 0° C. was slowly added ceric ammonium nitrate (80.5 g, 147 mmol; commercially available from Sigma Aldrich). The reaction was stirred at 0° C. for 1 hr after which time the THF was removed under reduced pressure and DCM (500 mL) was added. The organic layer was separated and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated, and the product was purified by silica gel chromatography (5-15% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester (18.95 g, 65%):: H-NMR (CDCl3) δ 7.29-7.21 (m, 5 H), 7.07 (d, 2 H), 6.94 (t, 2 H), 5.12 (s, 2 H), 3.89 (s, 3 H), 3.88-3.80 (m, 1 H), 1.31 (d, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].Cl.[NH2:19]O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:19][O:16][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol), and the reaction was stirred at 115° C. for 1 hour. After cooling, aqueous workup provided the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([CH3:9])[C:7](=[O:10])[CH2:6][O:5][CH2:4]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[CH3:9][N:8]1[C:7](=[O:10])[CH2:6][O:5][CH2:4][C@H:3]1[CH2:2][O:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CN1C(=O)COC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COCC(=O)N2C)cc1
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
Dissolve (R)-5-hydroxymethyl-4-methyl-morpholin-3-one (767 mg, 5.29 mmol) in pyridine (18 mL). Cool the reaction to 0° C., add 1.3 g (6.9 mmol) of p-toluenesulfonyl chloride (1.3 g, 6.9 mmol), and stir for 90 min. Pour into 1N HCl (50 mL) and extract with EtOAc (2×100 mL). Wash the combined organic layers with brine (50 mL), dry over Na2SO4, and concentrate to give the crude product. Purify via silica gel chromatography using a 0-100% EtOAc/hexanes gradient to yield 684 mg (43%) of the title compound. MS/ES m/z 300.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[C:19]([CH3:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
A mixture of compound 1 (1.56 g), 2-chloro-4-fluoro-3-methylbenzonitrile (1.27 g), lithium carbonate (1.16 g) and DMSO (37.5 ml) was stirred at 100° C. for 1 hr. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), and crystallized from ethyl acetate-hexane to give the title compound (357 mg) as crystals.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:6]([N:13]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][C:22]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCC/C=C/C(=O)OC(C)(C)C
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
n-Butyllithium (2.5M in hexanes, 27.66 ml) was added to a stirred solution of (S)—N-benzyl-1-phenylethanamine (15.59 g) in THF (150 mL) at −78° C. The reaction mixture was stirred for 30 mins then the product from step (i) (8.5 g) in THF (50 mL) was added and the reaction mixture stirred for 2 h at −78° C. The mixture was quenched with sat. NH4Cl solution and warmed to rt. The product was partitioned between EtOAc and water, the organic phase was washed with water, dried, and evaporated. The residue was purified by column chromatography eluting with 5% EtOAc in isohexane to give the subtitle compound 12.7 g.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 65 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (3.2 g, 11.5 mmol) followed by 4-nitrobenzylamine hydrochloride (2.3 g, 12.6 mmol) and triethylamine (4.8 mL, 34.5 mmol) as for general procedure A. The crude product was recrystallised in the minimum amount of boiling ethyl acetate to give 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (2.95 g, 7.47 mmol, 65%); Rf=0.4 (40:60:EtOAc:petrol). 197.1-199.7° C. λmax (CH3OH)/nm 220, Abs 0.765. IR: 3215, 1676, 1517, 1395, 1341 cm−1. 1H NMR: (300 MHz, d6-DMSO) δ 4.35 (d, 1H, J=16.3 Hz, N—CH2), 4.61 (d, 1H, J=16.3 Hz, N—CH2), 7.28 (m, 4H, Ar—H), 7.45 (m, 3H, Ar—H), 7.58 (m, 2H, Ar—H), 7.79 (m, 1H, Ar—H), 8.05 (m, 2H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ 42.1, 90.5, 123.1, 123.3, 128.4, 128.7, 129.1, 129.9, 130.3, 133.2, 133.3, 138.9, 146.4, 146.5, 149.4, 167.1. LC/MS-ES+ m/z 307.2, 368.2, 377.1. Anal. Calcd. for C21H15CN2O4: C, 63.89; H, 3.83; N, 7.10%. Found C, 63.78; H, 3.92; N, 7.12%. HRMS (EI) m/z Calcd. for C21H15ClN2O4: 394.0720. Found 394.0714.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:14]([C:15]#[C:16][Si](C)(C)C)=[C:13]([CH3:21])[N:12]=[C:11]([NH2:22])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:15]([C:14]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=2)=[N:10][C:11]([NH2:22])=[N:12][C:13]=1[CH3:21])#[CH:16]
Reactant: Cc1nc(N)nc(-c2cccc(C(F)(F)F)c2)c1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1c(C)nc(N)nc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.2 g (3.5 mmol) 4-(3-trifluoromethyl-phenyl)-6-methyl-5-trimethylsilanylethynyl-pyrimidin-2-ylamine (A-36) and 120 mg (0.87 mmol) potassium carbonate in 5 mL MeOH. After stirring for 2 h at RT, the reaction mixture is diluted with DCM and the organic phase is extracted with water. The organic phase is dried over NGP2SO4 and the solvent is removed in vacuo. Yield: 523 mg (54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][CH3:13])[CH:7]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5-fluoro-2-nitrophenol (300 mg), ethyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=O)[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].Cl.[NH2:37][OH:38]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:37][OH:38])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: NO
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=NO)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-{l-[2-(4-fluorophenyl)-2-oxo-ethyl]-piperidin-3-ylmethyl}-urea (20 mg, 42 μmol) in pyridine (0.5 mL) was treated with hydroxylamine hydrochloride (6 mg, 82 μmol) and stirred at room temperature for 16 hours. The solution was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 2.5% methanol in dichloromethane, containing 0.25% aqueous ammonia, to provide a white glassy solid (10 mg, 50%). 1H NMR (300 MHz, CDCl3) δ8.14 (s, 1H), 7.59 (s, 1H), 7.54 (m, 2H), 7.48 (s, 1H), 7.28 (s, 1H), 7.00 (t, J=9 Hz, 2H), 6.15 (bt, 1H), 4.16 (s, 3H), 3.78 (ab, J=15 Hz, 2H), 3.19 (m, 2H), 3.06 (m, 1H), 2.95 (m, 1H), 2.60 (q, J=8 Hz, 2H), 2.26 (m, 1H), 2.09 (m, 1H), 1.78 (m, 3H), 1.60 (m, 1H), 1.19 (t, J=8 Hz, 3H), 1.10 (m, 1H). Mass spec (ES+) m/z 495.4 (M+H+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].Cl>ClCCCl.O>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc2ccccc2c1Br
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc2cc(C(C)=O)ccc2c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 43 g of anhydrous AlCl3 and 24.6 g (0.313 mole) of acetyl chloride in 200 ml of 1,2-dichloroethane at 10° C. was cooled to 0° C. and added dropwise under stirring with a solution of 59.25 g (0.250 mole) of 1-bromo-2-methoxy-naphthalene in 150 ml of 1,2-dichloroethane. The resulting solution was stirred for 15 minutes then poured into a cold solution of 300 ml of water and 100 ml of 2 N hydrochloric acid. The organic phase was separated, washed first with 100 ml of 1 N hydrochloric acid and then with 100 ml of water, dried under vacuum and the obtained residue was crystallized from 2-butanol. Yield 68.11 g (98%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=O)[C:7]([CH3:14])([CH3:13])[C:8]2=O)=[C:4]([CH3:16])[CH:3]=1.C1C=CC=CC=1>Cl.C(O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:14])[CH2:8]2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)c(C)c2c1C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1cc(Cl)c(C)c2c1CC(C)(C)C2
Temperature: 25 °C
Yield: 65 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70ml of ethanol was added 27.32 g of the 6-chloro-2,2,4,7-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 15.67 g of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:33][C:34]#[N:35]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:33][C:34]#[N:35])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]methanone (example 13), sodium hydride and bromoacetonitrile, to give the desired product as a light yellow oil (61%).
Reaction SMILES: C1(CCC(O)CCC2C=CC=CC=2)C=CC=CC=1.[O:19]([CH2:26][CH:27]([OH:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:37]([O:40][CH2:41]C)(=O)C>CCCCCC>[O:19]([CH2:26][CH:27]([O:36][CH2:37][O:40][CH3:41])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC(COc1ccccc1)COc1ccccc1
Reactant: CCOC(C)=O
Agent: OC(CCc1ccccc1)CCc1ccccc1
Solvent: CCCCCC
Product: COCOC(COc1ccccc1)COc1ccccc1

Procedure:
Using the procedure of Example 51 but replacing 1,5-diphenyl-3-pentanol with the resultant compound of Example 4 gave, after silica gel chromatography using 10% ethyl acetate in hexane, 80 mg (49%) of the desired compound (Rf 0.42, 20% ethyl acetate in hexane). 1H NMR (CDCl3) δ3.44 (s, 3H), 4.18 (dd, J=10, 6 Hz, 2H), 4.22 (dd, J=15, 6 Hz, 2H), 4.33 (pentet, J=6 Hz, 1H), 4.85 (s, 2H), 6.9-7.0 (m, 6H), 7.25-7.35 (m, 4H). Mass spectrum (M +NH4)+ =306.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:17]([C:7]12[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2)=[O:18]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C12CC3CC(CC(C3)C1)C2
Temperature: 65 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of 2-aminothiazole (6.1 g, 61 mmol) in 250 mL of THF at 0° C. was added a solution of adamantane-1-carbonyl chloride (11 g, 55 mmol) in 25 mL of THF, followed by triethylamine (17 mL, 0.12 mol). The mixture was warmed to 65° C., stirred for 4 hours, and then allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water and brine. The aqueous washings were combined and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 20-40% ethyl acetate/hexanes gradient) afforded 11 g (78%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.68-1.85 (m, 6H), 1.97 (d, J=3.1 Hz, 6H), 2.12 (s, 3H), 6.96 (d, J=3.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 8.92 (s, 1H); MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH2:3][OH:4].C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26].O>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:3][O:4][C:25](=[S:26])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5]1
Reactant: S=C(Cl)Cl
Reactant: CC(C)(CO)CNCc1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COC(=S)N(Cc2ccccc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
2,2-Dimethyl-3-(2-nitrobenzylamino)-1-propanol (1.07 g, 4.50 mmol) was dissolved in chloroform (20 ml) and the reaction solution was cooled to 0° C. Then triethylamine (1.82 g, 18.0 mmol), thiophosgene (0.52 g, 4.50 mmol) was added thereto and stirred at a temperature as is for two hours and at room temperature for one hour. The reaction mixture was added with water, stirred at room temperature for one hour and then extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 5,5-dimethyl-3-(2-nitrobenzyl)-[1,3]-oxazinan-2-thione (1.12 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O.Cl>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 65 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
5.13 g (0.03 mol) of 2-amino-3-chlorobenzoic acid and 24 ml (0.59 mol) of methanol were added to a 100 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and a hydrogen chloride gas was blown in with stirring at 65° C. After 10 hours, the reaction solution was analyzed by HPLC by the absolute calibration method, and as a result, the yield was 75%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(C(C)C)C(C)C)C.[CH:28]([N:31]([CH:39]([CH3:41])[CH3:40])[P:32](Cl)[O:33][CH2:34][CH2:35][C:36]#[N:37])([CH3:30])[CH3:29].C(OCC)(=O)C.CCCCCCC>ClCCl>[CH3:41][CH:39]([N:31]([P:32]([O:33][CH2:34][CH2:35][C:36]#[N:37])[O:1][CH2:2][C:3]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=1)[CH:28]([CH3:29])[CH3:30])[CH3:40]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(COP(OCCC#N)N(C(C)C)C(C)C)cc(C(=O)OCC)c1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Protocol for preparing the diester phosphoramidite diethyl 5-[[[[bis(1-methylethyl)amino](2-cyanoethoxy)phosphino]oxy]methyl]-1,3-benzenedicarboxylate: 1.29 g (5 mmol) of diethyl 5-(hydroxymethyl)isophthalate [252.27] (98%, Aldrich; CAS 181425-91-2) were dissolved in 20 ml of dry dichloromethane at room temperature and mixed with 2.59 g (40 mmol, 4 eq) of N-ethyldiisopropylamine [129.25] and 1.3 g (11 mmol, 1.1 eq) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite [236.68] (Aldrich; CAS 89992-70-1). After 15 min at room temperature, thin layer chromatography (ethyl acetate/n-heptane (1:4) showed completion of the reaction. The mixture was concentrated and mixed with 30 ml of ethyl acetate/n-heptane (2:3). The precipitated hydrochloride was removed by filtration. The filtrate was concentrated and applied directly to a chromatography column. Elution with ethyl acetate/n-heptane (1:4) gave 1.6 g (70%) of diethyl 5-[[[[bis(1-methylethyl)amino](2-cyanoethoxy)phosphino]oxy]methyl]-1,3-benzenedicarboxylate as a colorless oil. C22H33N2O6P; 1H-NMR 8.59 (m, 1H, arom.), 8.21 (m, 2H, arom.), 4.87-4.75 (m, 2H, CH2 cyanoethyl), 4.41 (q, J=6.98 Hz, 4H, CH2 ethyl), 3.95-3.80 (m, 2H, 2×CH i-Pr), 3.74-3.61 (m, 2H, CH2 cyanoethyl), 2.66 (t, J (P,H)=6.45 Hz, 2H, O—CH2-arom), 1.41 (t, J=6H, 2×CH3 ethyl), 1.23-1.20 (m, 12H, CH3, i-Pr): 31P-NMR (CDCl3): δ 149.94; 13C-NMR (CDCl3): δ=165.8 (C═O), 140.2 (C—CH2—O—P), 132.1 (2×C arom.), 131.1 (2×C—H arom), 129.7 (C H arom), 117.6 (CN), 64.7 (P—O—CH2-arom), 61.4 (2×CH2 ethyl), 58.6 (O—CH2—CH2—CN), 43.4 (2×C—H i-Pr), 24.7 (4×CH3 i-Pr), 20.5 (O—CH2—CH2—CN), 14.4 (CH3 ethyl); HRMS 453.2156 ([M+H]+C22H34N2O6P calculated: 453.21545). Chromatographic purification and analytical characterization were carried out according to the protocols described above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([OH:30])=[O:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[OH:12]/[N:11]=[C:10](/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)\[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][C:28]([OH:30])=[O:29])=[CH:34][CH:35]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(CCC(=O)O)cc2)cc1

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-1-[(E)-hydroxyimino]-3-o-tolyl-propyl}-1-methyl-1H-pyridin-2-one (example 162, step 4) was reacted with 4-(2-carboxyethyl)benzeneboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a light yellow solid, MS (ESI+): m/z=493.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CCNCC2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 96.1 %

Procedure:
To 1.57 g (5.00 mmol) of 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid in 20 ml of acetonitrile was added 1.7 g (20.0 mmol) of piperazine. The mixture was refluxed for four hours, cooled, filtered, and washed with acetonitrile to give 1.83 g of the title compound.