Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:42]([C:36]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=3)([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[OH:43])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1ccc(C(=O)c2cccnc2)cc1OC
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2cccnc2)c2ccc3nc(OC)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.05 mL, 0.125 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (32.9 mg, 0.135 mmol, Intermediate 10) in dry THF (2 mL) in a dry ice-acetone bath. After 5 minutes, a solution of (3,4-dimethoxyphenyl)(pyridin-3-yl)methanone (32.9 mg, 0.135 mmol, Intermediate 88: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-100% EtOAc-Hexanes) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (d, J=1.8 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (dt, J=8.0, 2.0 Hz, 2H), 7.57-7.52 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.29-7.25 (m, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.66 (dd, J=8.4, 2.2 Hz, 1H), 6.44-6.42 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.76 (s, 3H); MS m/e 593.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[N+:5]([O-:25])[C:6]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([CH2:16][CH2:17][O:18]C4CCCCO4)[CH2:13]3)=[CH:9][C:7]=2[N:8]=1)[CH3:2]>CS(O)(=O)=O.CO>[CH2:1]([C:3]1[N:4]=[N+:5]([O-:25])[C:6]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([CH2:16][CH2:17][OH:18])[CH2:13]3)=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CCOC1CCCCO1)C3
Agent: CS(=O)(=O)O
Solvent: CO
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CCO)C3
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Methanesulfonic acid (3 drops) was added to a stirred solution of tetrahydropyranyl ether 160 (1.10 g, 3.2 mmol) in MeOH (30 mL) and the mixture was stirred at 20° C. for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with 5% MeOH/DCM, to give 1-oxide 161 (783 mg, 94%) as a yellow solid: mp 96-99° C.; 1H NMR δ 8.23 (s, 1H, H-9), 7.72 (s, 1H, H-5), 3.80 (t, J=6.5 Hz, 2H, CH2O), 3.25-3.33 (m, 2H, H-6, H-8), 3.02 (q, J=7.6 Hz, 2H, CH2), 2.68-2.86 (m, 3H, H-6, H-7, H-8), 1.84 (q, J=6.5 Hz, 2H, CH2), 1.43 (t, J=7.6 Hz, 3H, CH3), 1.40-1.45 (m, 1H, OH); 13C NMR δ 167.1, 153.8, 147.9, 147.6, 132.3, 122.7, 114.3, 61.5, 39.4, 39.1, 37.9, 37.5, 30.6, 12.3; HRMS (FAB+) calcd for C14H18N3O2 (MH+) m/z 260.1399, found 260.1397.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[F:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:18]1
Reactant: FC1CCNC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(F)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
1-(2-Bromoethoxy)-2-methoxy-4-nitrobenzene (0.2346 g, 0.8499 mmol) and 3-fluoropyrrolidine (0.3187 g, 2.5496 mmol) were combined in DMF (5 mL). Triethylamine (0.43 g, 4.2495 mmol) was added. The reaction was heated to 80° C. and stirred for 18 h. The reaction was cooled to RT and diluted with EtOAc (50 mL). The organics were washed with water (3×100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatatron (98:2 CH2Cl2:MeOH). The product was subjected to hydrogenation using 10% Pd/C under 1 atm of H2. The reaction was stirred for 18 h and was then filtered through celite and the celite washed with EtOAc (2×10 mL). The organics were concentrated to give 0.0442 g (0.1740 mmol, 20%) of the product. 1H NMR (CDCl3) δ 6.75 (d, 1H, J=8.4 Hz), 6.28 (s, 1H), 6.19 (d, 1H, J=8.3 Hz), 5.26-5.13 (m, 1H), 4.10 (t, 2H, J=5.7 Hz), 3.80 (s, 3H), 3.10-2.78 (m, 6H), 2.27-2.05 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[C:4]([F:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[C:22]([CH3:28])([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[CH:3][C:4]=2[F:12])[C:22]([CH3:28])([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: Fc1cc(F)c2ccoc2c1Br
Product: CC1(C)CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Yield: 52.1 %

Procedure:
Beginning with 1.17 gm (5.01 mMol) 4,6-difluoro-7-bromobenzofuran and 1.14 gm (5.26 mMol) 1-benzyl-3,3-dimethyl-4-oxopiperidine, 0.97 gm (52%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [Cl:1]C1C=CC2C3=C(C4CCCCC4)C4C=CC(C(OC(C)(C)C)=O)=CC=4N3CC(C(OC)=O)=CC=2C=1.Cl[C:38]1[CH:39]=[CH:40][C:41]([CH:47]=[O:48])=[C:42]([B:44]([OH:46])[OH:45])[CH:43]=1>>[Cl:1][C:39]1[CH:38]=[CH:43][C:42]([B:44]([OH:46])[OH:45])=[C:41]([CH:47]=[O:48])[CH:40]=1
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Product: O=Cc1cc(Cl)ccc1B(O)O
Yield: 70 %

Procedure:
The title compound 24a was synthesized following the 2-step procedure reported for the synthesis of 10-tert-butyl 6-methyl 3-chloro-13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 21a, using 5-chloro-2-formylphenylboronic acid in the first step, instead of 4-chloro-2-formylphenylboronic acid 34a, and was obtained with an overall yield of 70% as a yellowish solid; m/z 507 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[OH-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40]>O1CCCC1.[Pd](Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-:41])=[O:40])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Temperature: 26 °C
Reaction time: 0.33 h

Procedure:
A 4 m3 reactor was initially charged with 1773 kg of a 13% by weight solution of 4-chlorophenylboronic acid in tetrahydrofuran at 18-22° C. Within 20 minutes, 538 kg of 25% by weight aqueous sodium hydroxide solution and 140 kg of water were metered in with stirring at 22-30° C. After full addition, the reaction solution was stirred at 22-25° C. for 30 minutes. 2.28 kg of triphenylphosphine, 372 g of palladium(II) chloride and 252 kg of molten 1-chloro-2-nitrobenzene were added to the reaction solution. The reaction solution was heated to 66° C. for 18 h. After full reaction of the 4-chlorophenylboronic acid, the reaction solution was cooled to 45° C. and extracted with 794 kg of 10% by weight aqueous hydrochloric acid. After phase separation, a solution of 4-chloro-2′-nitrobiphenyl in tetrahydrofuran was obtained (conversion 99%).
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C1(C=CC(O)=CC=1)O.Br[CH2:31][C:32](=[CH2:38])[C:33](OCC)=[O:34]>O1CCCC1.[Zn]>[CH2:31]=[C:32]1[C:33](=[O:34])[O:1][C:2]([CH2:3][O:4][C:5]2[CH:15]=[CH:14][C:8]3[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=3[CH:6]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:38]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: O=C(COc1ccc2ccc(=O)oc2c1)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(COc2ccc3ccc(=O)oc3c2)(c2ccccc2)OC1=O
Temperature: 0 °C
Yield: 77.8 %

Procedure:
To a solution of 4a (0.84 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 18 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound; Yield: 77.8%; mp: 105°-106° C.; IR(KBr) νmax : 1758, 1719, 1616; UV(CHCl3) λmax (log ε): 321 (4.22), 243 (3.62); 1H-NMR (CDCl3): δ3.24 (dt, 1H, 4'-H), 3.66(dt, 1H, 4'-H), 4.17, 4.24 (two d, 2H, OCH2), 5.71 (t, 1H, vinylic H), 6.24 (d, 1H, 3-H), 6.31 (t, 1H, vinylic H), 6.72 (d, 1H, 8-H), 6.78 (dd, 1H, 6-H), 7.35 (d, 1H, 5-H), 7.40-7.52 (m, 5H, aromatic H), 7.62 (d, 1H, 4-H). Anal Calcd for C21H16O5:C, 72.41; H, 4.63. Found: C, 72.30; H, 4.67.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:16]=[CH:15][N:14]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1cccc(F)c1Oc1ccnc(Cl)c1
Yield: 94.4 %

Procedure:
Using the method of Example 3, Step A, 2,6-difluorophenol (821 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2,6-difluorophenoxy)pyridine (1.44 g, 94% yield) as an oil. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.26 (m, 1H), 7.04-7.10 (m, 2H), 6.80-6.86 (m, 2H).
Reaction SMILES: [CH:1]1([CH:6]2[CH:10]([CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:9]([OH:21])[CH2:8][CH:7]2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])OCC[O:2]1.Cl>CC(C)=O>[OH:21][CH:9]1[CH2:8][CH:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH:6]([CH:1]=[O:2])[CH:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCC=CCC1C(O)CC(OCc2ccccc2Br)C1C1OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)CCCC=CCC1C(O)CC(OCc2ccccc2Br)C1C=O

Procedure:
In a round-bottomed flask with a magnetic stir bar is placed an amount of the ketal, 1f . To this flask is added a sufficient amount of a mixture of 2 parts acetone to 1 part 1N HCl to bring the ketal completely into solution. This material is stirred by TLC until the starting material is consumed, typically overnight. The crude mixture containing the product 1g is extracted with ether and the ether extract is re-esterified in situ with, preferably, TMS-diazomethane. The organic extracts are concentrated under reduced pressure at 0° C. and used immediately without further purification.
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].[Na+].[Na+].C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O.[Ca+2]>>[C:8]([OH:10])(=[O:9])[C@@H:6]([C@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Ca+2]
Agent: [Na+]
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
The experiment of Example 1 was repeated by following the same procedure, except the strain of Acetobacter curtus No. 21 (FERM-P No. 2881) was used in place of the strain of Acetobacter curtus No. 4. From the culture broth, clean microbic cells were obtained by following the procedure of Example 3. The clean cells were suspended in about 30 ml of acetone and then subjected to centrifugation. This cleaning of the cells with acetone was repeated to give a total of three cycles. The clean cell was dried at a temperature of not more than 30° C under reduced pressure to afford acetone-dried microbic cells. The treatment of Example 5 was repeated by following the same procedure, except 0.1 g of the acetone-dried cells were used and 1.0 g of sodium calcium cis-epoxysuccinate was used as the substrate. The substrate in the mixture was wholly used up to produce sodium L(+)-tartrate and calcium L(+)-tartrate. The amount of sodium L(+)-tartrate was 0.49 g and that of calcium L(+)-tartrate was 0.48 g and the combined yield was 97 percent. The L(+)-tartaric acid obtained by following the procedure of Example 3 was found to have an optical purity of 100 percent.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[P:7](=[O:11])([OH:10])([OH:9])[OH:8].[O-2].[O-2].[Ti+4:14]>>[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Ti+4:14].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Ti+4:14].[Ti+4:14]
Reactant: O=P(O)(O)O
Agent: [Ti+4]
Agent: C[N+](C)(C)C
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 180 °C

Procedure:
0.05 mol of tetramethylammonium hydroxide (N(CH3)4OH) in aqueous solution was mixed with 0.15 mol of orthophosphoric acid (H3PO4). Then 0.05 mol of titanium dioxide in the anatase form (i.e., native TiO2) was added to the reaction mixture. After thorough mixing, the mixture was sealed inside a pressure reactor at 6~7 atm and heated in an oven at 180° C. for three days. After cooling, rinsing, filtration, and drying, a tetramethylammonium form of layered titanium phosphate (NMe4TP) was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Yield: 68.3 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) was added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution was stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane (5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–20% ethyl acetate/hexanes) to give (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl }-3-fluoro-4-methyl-benzamide (120 mg, 68%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N+:13]([O-])=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C2C(C3C=CC=CC=3)=CC3C(=NC=CC=3)[N+]=2[O-])C=CC=CC=1.C[Mg]Cl>C1COCC1>[CH3:24][C:12]1[N:13]=[C:14]2[C:9]([CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15]2)=[CH:10][CH:11]=1
Reactant: [O-][n+]1c(-c2ccccc2)c(-c2ccccc2)cc2cccnc21
Reactant: [O-][n+]1cccc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A cooled (0° C.) mixture of 6,7-diphenyl-1,8-naphthyridine 1-oxide and 2,3-diphenyl-1,8-naphthyridine 1-oxide (Intermediates C) (1 g, 3.35 mmol) in dry THF (10 ml) under an atmosphere of N2 was treated dropwise with methylmagnesium chloride (1.676 ml, 5.03 mmol). The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc and water. The aqueous portion was extracted with EtOAc (2×100 ml) and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in acetic anhydride (5 ml) and heated at 120° C. for 10 mins using microwave radiation. The resulting mixture was partitioned between DCM (150 ml) and water. The organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was loaded onto a Isolute™ SCX-2 cartridge and eluted with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford a brown oil which was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title product;
Reaction SMILES: Cl.CN.[Br:4][C:5]1[S:9][C:8]([CH:10]=O)=[CH:7][CH:6]=1.[C:12]([BH3-])#[N:13].[Na+].CCCCCCC.ClCCl>C(O)C.CO.C(OCC)(=O)C>[Br:4][C:5]1[S:9][C:8]([CH2:10][NH:13][CH3:12])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CNCc1ccc(Br)s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
14 g (209 mmol) of methylamine hydrochloride are added to a solution of 5 g (42 mmol) of 5-bromothiophene-2-carboxaldehyde in 80 ml of ethanol and 40 ml of methanol. The reaction medium is cooled to 0° C. and 5.8 g (83.8 mmol) of sodium cyanoborohydride are added. The reaction medium is stirred at 0° C. for 5 hours, hydrolysed and diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is taken up in a 70/30 heptane/dichloromethane mixture and then filtered. 6.7 g of crude residue are obtained.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([S:18]([N:13]2[CH2:14][C:15](=[O:17])[CH2:16][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:28])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][CH2:12]2)(=[O:19])=[O:20])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(O)C2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(=O)C2)cc1
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
Tertrapropylammonium perruthenate (0.75 gm, 0.05 equiv) was added to a stirred suspension of 1,4-bis-(toluene-4-sulfonyl)-[1,4]diazepan-6-ol (13 gm, 30.7 mmoles, Saari et al., J. Org. Chem., 1971, 36, 1711), N-methylmorpholine N-oxide (5.38 gm, 1.5 equiv) and crushed 4 A molecular sieves (20 gm) in dry DCM (100 mL). After 1.5 hr, this was poured onto a short column of silica gel and eluted with a mixture of 10% EtOAc in DCM to give 1,4-bis-(toluene-4-sulfonyl)-[1,4]diazepan-6-one (8.9 gm, 60%) as a white solid: 1H NMR (CDCl3) δ 2.44 (s, 6H), 3.71 (s, 4H), 3.91 (s, 4H), 7.32 (d, 4H, J=8.1 Hz), 7.65 (d, 4H, J=8.1 Hz). A solution of this ketone (8.9 gm, 21.1 mmole) in dry DCM was cooled in an acetone/dry ice bath and DAST (8.4 mL, 3 equiv) was added over 5 min. The reaction was allowed to warm to RT and, after 20 hr, it was cooled in an ice bath and water was added dropwise to decompose the excess reagent. The pH of the aqueous phase was adjusted to 10 with aq. NaOH solution and additional DCM (300 mL) was added. The organic phase was separated, dried (Na2SO4) and the solvent removed. The residue was crystallized from acetone/water to give 6,6-difluoro-1,4-bis-(toluene-4-sulfonyl)-[1,4]diazepane (6.47 gm, 69%) as fluffy white crystals: 1H NMR (CDCl3) δ 2.44 (s, 6H), 3.41 (s, 4H), 3.68 (t, 4H, J=12.3 Hz), 7.33 (d, 4H, J=8.0 Hz), 7.64 (d, 4H, J=8.0 Hz). A solution of the difluoride (3.41 gm, 7.75 mmole) and phenol (2.9 gm, 4 equiv) in a 30% solution of HBr in HOAc (50 mL) was heated at 60° C. for 6 hr. The reaction was concentrated and the residue was suspended in ethanol to deposit the bis-HBr salt of 6,6-difluoro-[1,4]diazepane as a tan solid (1.82 gm, 79%). This salt (600 mg, 2.04 mmole) was suspended in MeOH (10 mL) and aq. NaOH (0.41 mL, 10 N, 2 equiv) was added with stirring. The resulting solution was eluted through a Varian Mega Bond Elut SCX cartridge followed by 10 mL of MeOH. 6,6-Difluoro-[1,4]diazepane was eluted off the SCX cartridge with 50 mL of 2 N solution of NH3 in MeOH. Removal of the solvents left it as an oil (211 mg, 76%): 1H NMR (CDCl3) δ 2.93 (s, 4H), 3.21 (t, 4H, J=13.9 Hz).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.I[C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]#[C:7][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(C#CCCCCO)cc1
Reaction time: 2.5 h

Procedure:
To 40 ml of triethylamine were added 3.68 g of methyl p-iododihydrocinnamate, 1.49 g of 5-hexyl-1-ol, 40 ml of cuprous iodide and 77 mg of bis(triphenylphosphine)-palladium chloride, and the mixture was stirred under nitrogen flow for 2.5 hours. After adding 50 ml of ethyl acetate, the mixture was filtered to remove the resulting precipitate, washed three-times with 30 ml of water, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 4.0 g of methyl p-(6-hydroxy-1-hexynyl)dihydrocinnamate as an oil. 4.0 g of this oil was stirred with 1.2 g of 5% palladium on carbon in 50 ml of methanol under a hydrogen atmosphere to obtain 2.41 g of methyl p-(6-hydroxyhexyl)dihydrocinnamate. To this compound was added 1.0 g of phosphorus tribromide with ice-cooling, and the mixture was heated at 80° C. for 2 hours, poured into 50 ml of ice-water. The mixture was extracted twice with 50 ml of ethyl acetate, dried over magnesium sulfate and evaporated under a reduced pressure to obtain a residue, which was then applied to a silica gel column and eluted with chloroform/hexane (1:1) to obtain 2.1 g of the title compound as a colorless oil.