Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].N1C(C)=CC=CC=1C.O.C(=O)(O)O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:28]3[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: O=C(O)O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Temperature: 156.5 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol) described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7 mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated and stirred at 155-158° C. for 2 hours. After returning the reaction system to room temperature, it was dissolved in tetrahydrofuran, saturated bicarbonate water was added and stirred therewith for 10 minutes, the mixture was concentrated under reduced pressure, the precipitated solid was filtered out and subjected to silica gel column chromatography (Fuji Silicia NH Type, eluent-hexane:ethyl acetate=50:50→ethyl acetate alone), the fraction containing the target substance was concentrated and the obtained solid was washed with diethyl ether. It was then dried under reduced pressure to obtain the title compound (1.84 g, 4.63 mmol, 52.6%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[C:34]([CH:40]=[O:41])=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=2)[CH2:30][O:31][CH3:32])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[C:34]([CH:40]([OH:41])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=2)[CH2:30][O:31][CH3:32])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:42]([F:43])([F:45])[F:44]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-iodo-2-nitro-benzene (769 mg, 3.08 mmol) in anhydrous THF (3 mL) was added 2 M phenylmagnesiumchloride in THF (1.62 mL, 3.24 mmol) at −40° C. under an atmosphere of nitrogen. It was stirred at the same temperature for 15 minutes and then 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (1.04 g, 2.36 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 3 h. It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide crude 4-chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was used in the following step without any purification. Mass spectrum m/z: 566.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([S:18]([C:21]#[N:22])(=[O:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([N:8]1[C:21]([S:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:22][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CS(=O)(=O)Cc1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: O=S(=O)(Cc1ccccc1)c1nnnn1Cc1ccccc1

Procedure:
Heating a mixture of benzyl azide (Fr. Moulin, loc. cit.) and benzylsulfonyl cyanide as in Example 2 gives the title compound, m.p. 94°-96° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[C:21]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:26])[O:19][N:18]=1.[F:27][C:28]([F:40])([F:39])[CH:29]([CH3:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[CH3:16][C:17]1[C:21]([S:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH:29]([CH3:38])[C:28]([F:27])([F:39])[F:40])=[CH:32][CH:33]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:24])=[O:23])=[C:20]([CH3:26])[O:19][N:18]=1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(C)C(F)(F)F)cc3)C2=O)CC1

Procedure:
Light brown solid. MS (ESI): 502.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 3,5-dimethyl-isoxazole-4-sulfonyl chloride, 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=O)[CH2:3][SH:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:23]([NH:31][C:32](=[O:39])[C@H:33]([C@H:35]([CH2:37][CH3:38])[CH3:36])[NH2:34])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:23]([NH:31][C:32](=[O:39])[C@H:33]([C@H:35]([CH2:37][CH3:38])[CH3:36])[NH:34][C:5](=[O:7])[C@H:2]([CH2:3][SH:4])[NH2:1])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)NCCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CS)C(=O)NCCc1ccccc1
Reaction time: 16 h
Yield: 168.9 %

Procedure:
N-(t-Butoxycarbonyl)-S-triphenylmethyl)-L-cysteine (0.26 g, 0.55 mmol) was dissolved in DMF (3 mL) with EDC (0.11 g, 0.55 mmol), HOBT (0.074 g, 0.55 mmol) and L-isoleucine-phenethylamide hydrochloride (0.135 g, 0.5 mmol) at .ambient temperature. The pH of the solution was adjusted to 6.5 with triethylamine (0.15 mL, 1.05 mmol). After stirring for 16 h the solvent was evaporated and the residue was partitioned between EtOAc (20 mL) and H20 (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extract was washed with 10% citric acid solution, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave 0.285 g (87%) of the title compound after chromatography (SiO2, EtOAc: hexane, 1:2).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=O)(C)(C)C.N[C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@H:24]1O.Cl.C[N:35](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[NH2:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([O:13][C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@H:24]1[NH2:35])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: N[C@H](CC1CCCCC1)C(O)C(=O)O[C@H]1c2ccccc2C[C@H]1N
Reaction time: 1 h

Procedure:
A solution of Example 3C (0.10 g, 0.33 mmol), (1S,2R)-1-amino-2-hydroxyindane (0.086 g, 0.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.080 g, 0.41 mmol), 1-hydroxybenzotriazole (0.061 g, 0.45 mmol), and N-methylmorpholine (0.05 mL, 0.46 mmol) in 3:1 dichloromethane/DMF (4 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 4M HCl in dioxane (3 mL), stirred for 1 hour, concentrated, then purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 333 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.81 (br s, 2H), 7.40–7.17 (m, 4H), 6.65 (d, 1H), 5.52 (m, 1H), 4.18 (d, 1H), 3.14 (m, 1H), 2.55–2.45 (m, 2H), 1.80–1.67 (m, 5H), 1.57–1.51 (m, 1H), 1.46–1.17 (m, 5H), 1.00–0.90 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:23]1[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:6]([C:23]2[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)=[CH:5][CH:4]=[N:3]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cnc(C(=O)O)nc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.35 g, 6.5 mmol) in dioxane/H2O (5:1, 59 mL) was added K2CO3 (2.8 g, 20.3 mmol), tetrakistriphenylphosphine Pd(0) (340 mg, 0.3 mmol), and 5-bromo-2-pyrimidinecarboxylic acid (1.2 g, 5.9 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum to give the title compound (0.9 g, 36%) as a tan solid: LC-MS (ES) m/z=437 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1

Procedure:
The title compound was prepared from boronic acid (247) (300 mg, 0.79 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethanone (240 mg, 0.95 mmol) in accordance with Method B.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:2]1[C:1]2([CH2:6][CH2:12][C:10](=[O:11])[CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=CC1CCCC1
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCC2)CC1
Temperature: 45 °C

Procedure:
To a solution of cyclopentanecarbaldehyde (Aldrich) (0.82 g, 8.36 mmol) in dry toluene (10 mL), methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added followed by a catalytic amount of concentrated H2SO4 (0.045 mL, 0.836 mmol). The mixture was heated at 45° C. for 1.5 hours, then refluxed for 1 hour using a Dean-Stark trap. The reaction mixture was cooled to room temperature and further methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added. The reaction mixture was heated at reflux for 1 hour, allowed to cool to room temperature and treated with an aqueous 1M NaHCO3 (30 mL) solution. The aqueous was extracted with toluene and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-20% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>CCOC(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a Kontes glass tube was added 2-fluoro-nitrobenzene (3.34 g, 23.7 mmol), 1-methyl-piperazine (3.90 mL, 35.6 mmol), and anhydrous THF (10 mL). The tube was sealed and the reaction mixture was allowed to stir at 60° C. for 1 day. The reaction solution was diluted with EtOAc (150 mL), washed with aq NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5.07 g (97% yield) of the title product. MS (ES) 222.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:29]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C1(c2ccccc2)CCCCC1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 1-phenylcyclohexanecarboxylic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (d, J=8.2, 1H), 7.59 (s, 1H), 7.41 (d, J=7.4, 2H), 7.36 (td, J=2.7, 7.6, 4H), 7.26 (dd, J=6.0, 8.7, 2H), 4.45-4.33 (m, 1H), 3.58 (d, J=13.2, 1H), 3.40 (d, J=13.2, 1H), 2.81 (d, J=7.3, 1H), 2.68-2.59 (m, J=10.2, 2H), 2.41-2.31 (m, J=6.2, 14.8, 3H), 2.28 (d, J=8.8, 1H), 2.20-2.13 (m, 1H), 1.99 (dt, J=7.4, 14.8, 1H), 1.88-1.75 (m, J=9.0, 4H), 1.74-1.53 (m, J=8.8, 36.2, 4H), 1.50-1.40 (m, 1H), 1.36-1.20 (m, 2H); MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]([NH:26][NH2:27])=[O:25])[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](Cl)=[O:54])=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:22]([C:24]([NH:26][NH:27][C:53](=[O:54])[CH2:52][C:49]3[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=3)=[O:25])[N:23]=[C:12]21)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.78 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 9 (400 mg, 0.794 mmol) in CH2Cl2 (15 mL) at 0° C. was added triethylamine (0.221 mL, 1.589 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (0.098 mL, 0.715 mmol) and the resulting mixture stirred for 1 h. The mixture was allowed to warm to room temp and stirred for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (70 mg, 0.109 mmol, 13.78% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.00 (1H, br. s.), 8.35 (1H, br. s.), 7.48-7.53 (2H, m), 7.27-7.38 (10H, m), 7.00-7.07 (2H, m), 6.55 (1H, br. s.), 5.39 (2H, s), 5.05 (2H, s), 4.10 (2H, d, J=3.36 Hz), 3.60 (2H, s), 2.56-2.70 (2H, m), 2.47 (1H, br. s.), 1.88-2.04 (4H, m), 1.59-1.71 (2H, m). LCMS (M+H)=640.35.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CC(C)=O>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:30][CH2:31][OH:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1c(OCCO)c2cccnc2n(-c2ccccc2)c1=O
Yield: 58.5 %

Procedure:
Reflux a stirred solution of 16.2 gm of 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)one and 11.4 gm of anhydrous potassium carbonate powder in 600 ml of dry acetone for 30 minutes. 95% 2-bromoethanol (10.3 gm) is added dropwise to the solution. The reaction is refluxed for 26 hours, cooled and the solvent removed by stripping. The resulting solid is dissolved in 500 ml chloroform and the chloroform solution is washed with 300 ml water, twice with 100 ml of 0.5N sodium hydroxide solution and finally with 100 ml of water. The chloroform solution is dried over magnesium sulfate, filtered and the solvent is removed to give the crude product. The crude product is triturated with warm isopropyl ether to give 10.9 gm of the 3-(n-butyl)-4-(2-hydroxyethoxy)-1-phenyl-1,8-naphthyridin-2(1H)one; which after recrystallization from acetone melts at 138°-140° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:26][S:27]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)(=[O:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitrate salt (515 mg/2 mmol) was suspended in methylene chloride (5 mL) and cooled to 0° C. Triethylamine (620 μL/4.4 mmol) was added followed by methanesulfonyl chloride (dropwise, 160 μL/2.1 mmol). After fifteen minutes the reaction was poured into 25 mL of 1 N hydrochloric acid and extracted with methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 3-Methanesulfonyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a light brown solid (520 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 8.05 (m, 2H), 7.3 (d, J=9.1 Hz, 1H), 3.45 (m 4H), 3.15 (m, 4H), 2.8 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:32])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:2].[C:33]([Cl:36])(=[O:35])[CH3:34]>C(O)(=O)C>[ClH:36].[C:33]([NH:31][S:28]([C:23]1[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:8]3[C:9]4[C:4](=[C:3]([CH2:1][CH3:2])[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=4)[CH:5]=[CH:6][C:7]3=[O:32])=[CH:17][CH:18]=2)=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:30])(=[O:35])[CH3:34]
Reactant: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c(CC)n1
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)=O)cc2)c(CC)n1
Product: Cl

Procedure:
A mixture of 4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-sulphonamide (250 mg), acetyl chloride (2 ml) and acetic acid (1 ml) was heated at reflux for 4 hours. The mixture was then concentrated by evaporation and the residue was purified by repeated precipitation from ethanol solution by the addition of ether to give N-acetyl-4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-sulphonamide hydrochloride as an amorphous solid (153 mg); NMR (d6 -DMSO): 1.27(t, 3H), 1.31(t, 2H), 1.69(s, 3H), 2.99(q, 2H), 3.36(q, 2H), 5.63(s, 2H), 6.98(d, 1H), 7.2-7.4(complex m, 5H), 7.5-7.8(m, 3H), 8.06(dd, 1H), 8.40(d, 1H), 11.53(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 490 (M+H)+ ; microanalysis, found: C, 59.9; H, 5.4; N, 7.7%; C27H27N3O4S.HCl.H2O requires: C, 59.6; H, 5.5; N, 7.7%.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH:7]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH2:23][CH2:24][CH3:25])[NH:9][C:10]2=[N:11][NH:12][CH:13]=[C:14]12
Reactant: Nc1cc[nH]n1
Reactant: Cc1occc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccoc2C)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methylfuran-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9]1([CH3:14])OCC[O:10]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>CC(C)=O.O>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C[C@H](O)CC1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C[C@H](O)CC(C)=O
Temperature: 60 °C
Yield: 84.9 %

Procedure:
To a solution of Methyl(3R)-3-hydroxy-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (3) (5 g, 24.5 mmol) (as prepared in Experiment 15) in a mixture of acetone/water (2:1, 30 mL), pyridiniumtosylate (1.84 g, 7.34 mmol) was added and the reaction mixture was refluxed (60° C.) for 1-2 hours. After removing the solvent under vacuum, a 10% NaHCO3 solution was added and extracted with dichloromethane (3×30 mL). The combined organic phases was evaporated under reduced pressure to give methyl(3R)-3-hydroxy-5-oxohexanoate (6) as an oil (3.33 g, 85%).
Reaction SMILES: CC1C=CC(C2C=CC=CN=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:20]=1[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:29])[C@H:24]1[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])=[O:22].C([Sn](CCCC)(CCCC)[C:52]1[N:57]=[CH:56][CH:55]=[CH:54][N:53]=1)CCC>>[F:46][C:43]1[CH:44]=[CH:45][C:19]([C:52]2[N:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[C:20]([CH:42]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:29])[C@H:24]1[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])=[O:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2Br)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: COC(=O)c1cc(C)ccc1-c1ccccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-1-(2-bromo-5-fluorobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 445 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15](O)[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:15]2[CH:14]=[CH:13][C:12]([C:21](=[O:23])[CH3:22])=[C:11]([OH:10])[C:16]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 44.2 %

Procedure:
Combine (6-bromo-pyridin-2-yl)-methanol (1.00 g, 5.32 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.033 g, 5.32 mmol) and tri-n-butylphosphine (1.46 mL, 5.85 mmol, Aldrich Chemical Co.) in tetrahydrofuran (5.3 mL), add 1,1′-(azodicarbonyl)dipiperidine (1.48 g, 5.85 mmol, Aldrich Chemical Co.). After 12 hours at ambient temperature, add diethyl ether (white precipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography to obtain the title compound as a white solid (854 mg, 2.35 mmol): MS (m/z): 286 (M−Br+1).