Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrobenzoic acid (47.51 g, 0.257 mol) and thionyl chloride (100 mL, 1.370 mol) is refluxed for several hours and concentrated in vacuo to give the title product which is used in Example 2 without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]([OH:15])[C:13]3[S:16][CH2:17][CH2:18][S:19][C:12]=3[C:11]2=[O:20])=[N:8][CH:9]=1.Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]1)=[O:23]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:11]([O:20][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]3)=[O:23])[C:12]3[S:19][CH2:18][CH2:17][S:16][C:13]=3[C:14]2=[O:15])=[N:8][CH:9]=1
Reactant: CCN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 28.8 %

Procedure:
A suspension of sodium hydride (1.11 g.) in anhydrous tetrahydrofuran (120 cc.) is treated for 20 minutes at about 10°-15°C. with 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (11.6 g.), and a solution of 1-chlorocarbonyl-4-ethylpiperazine (20.4 g.) in anhydrous tetrahydrofuran (160 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (400 cc.). The ether solution is washed twice with ice-cold normal sodium hydroxide solution (total 300 cc.) and three times with distilled water (total 300 cc.), treated with decolourising charcoal (0.2 g.), dried over anhydrous sodium sulphate, filtered and evaporated. The residue (13.8 g.; m.p. 140°C.) is dissolved in boiling ethanol (25 cc.). After cooling for three hours at 2°C, the crystals which have appeared are filtered off, washed twice with ice-cold ethanol (total 20 cc.) and dried under reduced pressure (20 mm.Hg). 6-(5-Chloropyrid-2-yl)-5-(4-ethylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (4.9g.), melting at 163°C, is thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18]C)(=[O:8])=[O:7])[CH3:3].B(Br)(Br)Br.CO.C(OC(C)C)(C)C>C(Cl)Cl>[CH3:3][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])(=[O:7])=[O:8])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N=CN(C)C
Agent: BrB(Br)Br
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1O
Reaction time: 5 h

Procedure:
A solution of 2.82 g (9.8 mmol) of N-dimethylaminomethylene-2-methoxy-4-nitro-benzenesulfonamide in 70 ml of DCM is mixed slowly at room temperature with 13 ml of a 1 molar solution of boron tribromide in DCM. After 5 hours, 3 ml of the 1 molar solution of boron tribromide in DCM is added again, and it is stirred for another 16 hours. The batch is mixed with MeOH and diisopropyl ether. The precipitate that is formed is suctioned off, washed with EtOH and diisopropyl ether and dried. 1.94 g (7.1 mmol, corresponding to 72% of theory) of the product is obtained.
Reaction SMILES: [C:1]([NH:6][CH2:7][CH:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]>C(Cl)Cl>[C:1]([NH:6][CH2:7][C@@H:8]([C@H:14]([OH:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)NCC(C(C)=O)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)NC[C@H](C(=O)OCC)[C@@H](C)O
Yield: 69.9 %

Procedure:
In a 100 ml-volume stainless steel autoclave whose atmosphere had been displaced with nitrogen was added a solution of 2.31 g (10 mmole) of ethyl 2-(N-carboethoxyamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of Ru2Cl4 ((+)-BINAP)2NEt3 in 18 ml of methylene chloride, and a reaction was conducted at 45° C. under a hydrogen pressure of 75 kg/cm2 for 20 hours. The reaction mixture was taken out and concentrated under reduced pressure of 20 mmHg. The concentrate was purified by silica gel chromatography using a 8/2 (by volume) mixture of hexane and isopropanol as an eluent to obtain 1.63 g (yield: 70%) of ethyl (2S, 3R)-2-(N-carboethoxyamino)methyl-3-hydroxybutanoate having an optical purity of 90 %ee as determined in the same manner as in Example 2, except for using a 1000:100:1 (by volume) mixture of hexane, tetrahydrofuran and methanol as an eluent.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:17]([O-])=O.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1.C(Cl)Cl>[NH2:17][C:3]1[C:2]([Cl:1])=[C:9]([N:10]2[CH2:15][CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:12][C:11]2=[O:16])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1
Reactant: N#Cc1cc(N2CCNCC2=O)c(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This amine was dissolved in THF (2.000 mL) and DCM (2.000 mL), then TEA (0.030 mL, 0.214 mmol) was added followed by BOC2O (0.033 mL, 0.143 mmol). After stirring at room temperature for 2 h, LC-MS indicated completion, it was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate (20 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc2cccc(Cl)c2s1

Procedure:
16.6 g of the 7-chloro-2-benzo[b]thiophenecarboxylic acid prepared in A above was added to thionyl chloride (48 ml) and toluene (10 ml) and refluxed for 4 hours. Excess thionyl chloride was then removed and the resultant residue was treated with toluene (20 ml). The toluene was then removed under reduced pressure to produce 17.8 g of 7-chloro-2-benzo[b]thiophenecarboxylic acid chloride as a reddish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:6][CH2:5]2.[CH2:15]([O:17][C:18](=[O:22])[CH:19](Cl)[CH3:20])[CH3:16].C(O)(C(F)(F)F)=O.Cl>CN(C=O)C.[Mn].[Ni](Br)Br.N1C=CC=CC=1C1C=CC=CN=1>[CH3:14][S:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:19]([CH3:20])[C:18]([O:17][CH2:15][CH3:16])=[O:22])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)N1CCc2cc(Br)ccc21
Reactant: CCOC(=O)C(C)Cl
Agent: Br[Ni]Br
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc2c(c1)CCN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14 %

Procedure:
5-bromo-1-(methylsulphonyl)indoline (13.4 mmol, 3.7 g) and ethyl-2-chloropropionate (17.4 mmol, 2.38 g) were dissolved in DMF (7 ml) in a protective gas atmosphere at room temperature. Subsequently, manganese (26.8 mmol, 1.47 g), (2,2′-bipyridine) nickel(II)-dibromide (0.938 mmol, 0.351 g) and TFA (0.348 mmol, 27 μl) were added and stirring was carried out at 50° C. for 1.5 h. After cooling the reaction mixture to room temperature, hydrolysis was carried out at room temperature with 1 N HCl (25 ml) and the mixture was extracted with diethyl ether (3×25 ml). The combined organic phases were washed with water (25 ml) and aq. sat. NaCl solution (25 ml) and dried over magnesium sulphate. After removing the solvent in a vacuum and purifying the residue by column chromatography (SiO2, diethyl ether/hexane=3:1), 0.558 g (14% yield) of ethyl 2-(1-(methylsulphonyl)indolin-5-yl)propanoate were obtained.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2B(O)O)[CH:31]=[CH:30][CH:29]=1>>[CH3:26][O:25][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:37]=3[N:28]=[CH:29][CH:30]=[CH:31]4)=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Reactant: OB(O)c1cccc2cccnc12
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccc4cccnc34)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270, Step A) and 8-quinoline boronic acid by following the procedure described for Example 270 (Steps B and C). 1H-NMR (MeOD, 300.15 MHz): δ 8.82 (d, 1H, J=2.6), 8.39 (d, 1H, J=8.1), 7.92 (d, 1H, J=7.9), 7.74–7.63 (m, 2H), 7.58–7.51 (m, 3H), 7.18 (d, 2H, J=8.5), 7.08 (d, 2H, J=8.7), 6.88 (d, 2H, J=8.7), 4.28 (t, 2H, J=6.0), 4.20 (t, 2H, J=6.3), 3.90–3.80 (m, 1H), 3.30 (s, 3H), 3.04–2.84 (m, 2H), 2.29 (qn, 2H, J=6.3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]([CH3:45])[CH:36]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.C(OCC)(=O)C.Cl>O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]([CH3:45])[CH:36]=3)[C:17]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][OH:31])=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(C(C(=O)NS(=O)(=O)c2ccc(CCO)cc2)c2ccc3c(c2)OCO3)c2ccc(Cl)cc21

Procedure:
Lithium aluminium hydride (6 mg, 0.16 mmol) was added to a stirred solution of ethyl 2-(4-[2-(1,3-benzodioxol-5-yl)-2-(6-chloro-1-methyl-1H-3-indolyl)acetyl]sulfamoylphenyl)acetate (the product of Example 89, 80 mg, 0.14 mmol) in tetrahydrofuran (6 ml) at 0° C. under a nitrogen atmosphere. After 40 mins ethyl acetate (1 ml) was slowly added and the reaction mixture was poured into hydrochloric acid (50 ml). The product was extracted into ethyl acetate (2×50 ml), dried (MgSO4) and concentrated. Recrystallisation (methanol/ether) gave the product as a white crystalline solid (50 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][N:16]1[CH:20]=[C:19](I)[CH:18]=[N:17]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu](I)I>[CH3:15][N:16]1[CH:20]=[C:19]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cn1cc(I)cn1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.164 g, 0.819 mmol) in 3 mL of isopropanol under an atmosphere of nitrogen was added 1-methyl-4-iodo-1H-pyrazole (0.204 g, 0.983 mmol), ethylene glycol (0.051 g, 0.82 mmol), copper iodide (0.031 g, 0.16 mmol), and potassium phosphate (0.695 g, 3.28 mmol). The reaction was heated to 100° C. for 8 h, cooled to rt, and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-100% ethyl acetate in hexanes to provide tert-butyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate that gave a mass ion (ES+) of 281.1 for [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23].C=O.[C:27]([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:27])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
To a stirred solution of N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide (4a, 1.0 g) and formaldehyde (1 mL) in methanol (20 mL) and acetic acid (1 mL) was slowly added sodium cyanoborohydride (0.30 g). After 15 minutes, the reaction mixture was cooled to 5° C. for 16 hours to precipitate the product, which was collected by filtration and washed with water (100 mL) to furnish 0.63 g (60% yield) of the title compound as a pale yellow solid. LC-MS-TOF (m/z) 351 (MH+); tR=2.58, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.97 (s, 3H), 2.02 (s, 6H), 2.97 (s, 3H), 4.63 (s, 2H), 7.41 (d, 2H), 7.68 (d, 2H), 8.88 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]4[NH:39][N:38]=[N:37][N:26]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 0.098 g (0.23 mmol) 7-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-heptanenitrile, 0.41 g (3.5 mmol) trimethylsilylazide and 86 mg (0.25 mmol) di-n-butyltin oxide in 5 ml toluene overnight at 80° C. After concentrating by evaporation, take up the residue in water, acidify with dilute hydrochloric acid and extract with methylene chloride. Wash the organic phase with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile). 61 mg (55% of theor.) of the title compound is obtained as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].Cl.[NH2:34][OH:35].C(=O)(O)[O-].[Na+].C(Cl)Cl>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:34][OH:35])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccccc4)CC3)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NO)c4ccccc4)CC3)cc21
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of the 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-phenacyl-1-piperazinyl)-quinoline-3-carboxylic acid (0.44 g, 1 mmole) [H. Kondo et. al., J. Med. Chem., 29, 2020 (1986)] in absolute methanol (20 ml) was added a solution of hydroxylamine hydrochloride (0.14 g, 2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) in water (2 ml). The mixture was heated at reflux for 36 hr and allowed to cool to room temperature. CH2Cl2 (50 ml) was added, and the layers were separated. The organic phase was washed successively with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a solid which was purified by flash column chromatography (silica gel, with CH2Cl2/methanol (10:1) as the eluant) and crystillization from CH2Cl2/methanol (5:1) to give 1-ethyl-6-fluoro-4-oxo-7-[4-(2-hydroxyimino-2-phenylethyl)-1-piperazinyl]-1,4-dihydroquinoline-3-carboxylic acid as an off-white amorphous solid (0.31 g, 68%). Mp: 203° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.2), 2.64 and 3.25 (two m, 8H), 3.43 and 3.73 (two s, 2 H), 4.56 (q, 2H, J=7.2), 7.15 (d, 1H, J=7.2), 7.36-7.79 (m, 5H), 7.88 (d, 1H, J=13.2), 8.92 (s, 1H), 10.99 and 11.48 (two s, 1H), 15.07 (br s, 1H). Anal. Calcd. for C24H25FN4O4•1.5 H2O: C, 60.10; H, 5.89; N, 11.68. Found: C, 60.19; H, 5.81; N, 11.64.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[C:9]1([CH3:19])[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1>>[C:1]([O:5][CH2:6][CH2:7][O:8][CH2:3][CH2:2][CH:1]1[O:4][CH2:14][C:9]([CH3:10])([CH3:19])[CH2:6][O:5]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCCOCCC1OCC(C)(C)CO1

Procedure:
A mixture of hydroxyethyl acrylate (11.6 g), an equivalent amount of 2-ethylenyl-5,5-dimethyl-1,3-dioxane (EDD) (14.2 g), and a catalytic amount of p-toluenesulfonic acid (100 mg) was heated at 65° C. overnight. Gas chromatography showed that reaction occurred. The unreacted starting materials were removed at 40° C. under 0.05 mm Hg.
Reaction SMILES: [N:1]1([CH:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]([O:10]C)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19]>O1CCOCC1>[ClH:19].[N:1]1([CH:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(c1ccc(C)cc1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(C(=O)O)N2CCCCC2)cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a solution of methyl 2-(piperidin-1-yl)-2-p-tolylacetate (273 mg, 1.10 mmol) in dioxane (2 ml), was added 37% HCl (3.35 ml, 110 mmol). The reaction was heated under microwave irradiation at 100° C. for 4 hours. The solvents were evaporated and the residue was triturated with Et2O to collect 2-(piperidin-1-yl)-2-p-tolylacetic acid hydrochloride (242 mg, 81% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C:44]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C:44]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccc(Cl)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-chlorophenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 49 (3.4 mg, 0.012 mmol) to give a white solid (5.1 mg, 51% yield). Anal. Calcd. for C43H51ClN4O6S m/z 786.4. found: 787.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.29 (d, J=8.25 Hz, 1H), 7.25-7.18 (m, 5H), 7.18-7.10 (m, 7H), 7.03 (d, J=7.70 Hz, 1H), 6.89 (d, J=6.60 Hz, 1H), 6.79 (d, J=6.60 Hz, 1H), 5.32 (t, J=4.40 Hz, 1H), 5.17-5.12 (m, 1H), 5.03-4.93 (m, 1H), 4.75 (dd, J=9.90, 7.15 Hz, 1H), 3.93 (dd, J=15.40, 11.55 Hz, 1H), 3.68 (s, 3H), 3.58 (dd, J=15.12, 4.67 Hz, 1H), 3.21-3.09 (m, 1H), 2.90-2.76 (m, 3H), 2.76-2.67 (m, 2H), 2.44-2.27 (m, 3H), 2.02-1.97 (m, 2H), 1.97-1.90 (m, 1H), 1.90-1.77 (m, 3H), 1.76-1.46 (m, 11H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9](O)=[O:10]>>[CH3:5][O:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9]([Cl:3])=[O:10]
Reactant: COc1nc(C(F)(F)F)cc(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1nc(C(F)(F)F)cc(C)c1C(=O)Cl
Temperature: 60 °C

Procedure:
Thionyl chloride (2 mL) was added to 2-methoxy-4-methyl-6-(trifluoromethyl)-nicotinic acid (68 mg, 0.29 mmol) and then the mixture was heated at 60° C. for 1 hour. The mixture was evaporated to dryness.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCn1c(CO)nc2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-methanol (501 mg, 3.38 mmol) and allyl bromide (0.29 mL, 3.38 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (0.71 mL, 4.06 mmol). The reaction mixture was stirred at 60° C. overnight. Then the mixture was cooled to room temperature and quenched with saturated NaHCO3 (25 mL). Then it was extracted with CH2Cl2 (3×25 mL). The combined organic layer was washed with brine (2×25 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (180 mg, 28%). 1H NMR (CDCl3) δ 4.85 (br s, 5H), 4.98 (d, 1H, J=17.1 Hz), 5.17 (d, 1H, J=10.5 Hz), 5.88-6.01 (m, 1H), 7.20-7.26 (m, 3H), 7.66 (t, 1H, J=3.9 Hz).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1([C:18]2[CH:19]=[CH:20][C:21](=[O:31])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C1C=CN=CC=1)C.ClCCl>[O:31]=[C:21]1[N:22]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[C:18]([C:12]2([NH:11][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:19]=[CH:20]1
Reactant: NC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1
Yield: 99.7 %

Procedure:
Phenylacetyl chloride (1.6 g) was added to a well stirred suspension of 5-(1-aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone (2.9 g), poly-4-vinylpyridine (2.1 g) and a catalytic amount of 4-(N,N-dimethylamino)pyridine in 70 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate concentrated to give 4.1 g of oil. Column chromatography (silica gel, elution with ethyl acetate) afforded 2.1 g of foam. Recrystallization from ethyl acetate/hexanes gave 1.7 g of analytically pure product as needles, m.p. 152°-153° C.