Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10].OS(O)(=O)=O.[N+]([O-])(O)=O.[OH-:20].[Na+].[CH3:22]O>O.C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:20][CH3:22])[C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: [OH-]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=[N+]([O-])O
Solvent: O
Product: COc1c(C)c[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
2,3,5-trimethyl-pyridine-N-oxide (1457 g, 10 moles) was dissolved in conc. H2SO4 (1200 ml, 22.08 moles) in a 50 liters reaction vessel. A nitration solution (1750 ml, 32.2 moles conc. H2SO4 and 2065 ml, 29.84 moles 65% HNO3) was added at 90° C. during 1 hour. The solution was stirred at 90° for 1.5 hours and thereafter cooled to 30° C. The pH of the reaction mixture was then adjusted by adding 10M NaOH (11.65 liters, 116.5 moles) during cooling with water so that the temperature was kept below 40° C. The NaOH was added during about 2 hours. Thereafter CH2Cl2 (25 liters) was added and the mixture stirred vigorously for 30 minutes. The phases formed were separated and the CH2Cl2 -phase was transferred to a 100 liters reaction vessel. The water phase was discarded. The methylenechloride was distilled off. To the remainder was added 15 l of toluene which was then distilled off under reduced pressure, followed by another 15 l portion of toluene which was also removed by distillation. 8 liters of methanol was added and the mixture heated to boiling temperature. A solution of NaOH (595 g, 14.9 moles) in CH3OH (16 liters) was added during about 1.5 hours. The reaction mixture obtained was cooled and its pH adjusted to 8 using conc. H2SO4 (250 ml, 4.6 moles). Remaining methanol was distilled off and CH2Cl2 (20 liters) was added to the remainder. The mixture was stirred for about 30 minutes and inorganic salts were filtered off and washed with CH2Cl2. The filtrates obtained were pooled and evaporated, yielding 1287 g of 2,3,5-trimethyl-4-methoxy-pyridine-N-oxide with a purity of 89%. The identity of the reaction product was confirmed with 1H and 13C NMR. 1H-NMR: δ(COCl3) 2.22(s, 3H), 2.27(s, 3H), 2.51(s, 3H), 3.81(s, 3H), 8.18(s, 1H).
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:22][O:21][CH:18]1[CH2:17][CH2:16][C:13]2([CH2:14][CH2:15][CH:10]([CH2:9][OH:8])[CH2:11][CH2:12]2)[CH2:20][CH2:19]1
Reactant: COC1CCC2(CCC(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCC2(CCC(CO)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To a solution of the crude tert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393 mg) obtained in Step 5 in tetrahydrofuran (5 mL) was added a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (3 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:4) to give (9-methoxyspiro[5.5]undec-3-yl)methanol (217 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](Cl)=[O:35])[CH2:29][CH2:28]1.Cl>C(Cl)Cl.O>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)CC1CCOCC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC1CCOCC1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.5 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (30 mg, 0.13 mmol) and DIPEA (42 μl, 0.25 mmol) in DCM (1 ml) was added tetrahydropyran-4-yl acetyl chloride (21 mg, 0.13 mmol) in DCM (1 ml). The reaction mixture stirred at RT for 16 hrs. Upon completion, water and 1M HCl were added and the reaction mixture was washed with DCM (3×5 ml). The combined organic phases were dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC to afford the title compound as colourless oil (1.2 mg, 3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][OH:5])=[C:2]([NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(F)ccc1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1CO
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 2-amino-4-fluorobenzyl alcohol from Step 1 (2.00 g, 14.17 mmol) and methylene chloride (45 mL), was added N,N,-diisopropylethylamine (3.70 g, 28.34 mmol) followed by hydrocinnamoyl chloride (4.78 g, 28.34 mmol) dropwise over 15 min under an argon atmosphere at 23° C. After 16 h, the reaction was diluted with methylene chloride (100 mL), washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was dissolved in methanol (14 mL) and NaOH (1.5 N, 14 mL) was added at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide (3.40 g, 87.8%) as an oil: 1H NMR (CDCl3) δ2.65 (t, J=7 Hz), 3.05 (t, J=7 Hz), 4.48 (s), 6.68-6.74 (m), 7.00-7.34 (m), 7.83-7.91 (m) 8.72 (br s). MS (EI) 273, 255, 212. IR (neat) 3500-3150, 1667 cm−1. Anal. Calc'd. for C16H16NO2F: C, 70.31; H, 5.90; N, 5.13. Found: C, 70.26; H, 6.11; N, 5.03.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:17]=1[C:18](O)=[O:19].S(Cl)([Cl:28])=O>ClC1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:17]=1[C:18]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([Cl:28])=[O:11])=[CH:12][CH:13]=1)(=[O:3])=[O:4])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 120 °C
Yield: 93 %

Procedure:
A mixture of 4-aminosulfonylbenzoic acid (1 mol), 2-methoxy-5-chlorobenzoic acid (1 mol) and thionyl chloride (2.5 mol) in chlorobenzene (700 ml) was heated at 120° C. for 7-9 hours. After the reaction was complete 200 ml of the solvent was removed in vacuo. The mixture was cooled and the precipitate filtered off and washed with heptane to give the title compound, mp. 138-140° C., yield 93% of theory.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:2]2[C:3]([CH2:11][CH3:12])=[N:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=23)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCc1nn2c(c1Br)CCCC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1nn2c(c1C1(O)CCN(C(=O)OC(C)(C)C)CC1)CCCC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridine (4.01 g, 17.6 mmol, from Step 3) in THF (20 mL) was added t-BuLi (1.7 M in pentane, 22.8 mL, 38.7 mmol) dropwise at −78° C. After stirring at −78° C. for 30 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.51 g, 17.6 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 4 h. After the reaction was quenched with aqueous NH4Cl, the mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration was followed by purification by flash chromatography (hexanes: EtOAc=1:1, then 100% EtOAc) to give the title compound as a foamy solid. 1H NMR (500 Mz, CDCl3): δ 1.26 (t, 3H, J=7.4 Hz), 1.49 (s, 9H), 1.75-1.90 (m, 4H), 1.90-2.10 (m, 4H), 2.76 (q, 2H, J=7.6 Hz), 2.89 (t, 2H, J=6.4 Hz), 3.10-3.20 (br, 2H), 3.85-4.05 (br, 2H), 4.09 (t, 2H, J=6.2 Hz). ESI-MS 276 (M-t-Bu-H2O+H); HPLC C: 2.05 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(=O)c2c(Cl)ccnc2n(C)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(N=[N+]=[N-])ccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
1.35 g of Compound 1 was dissolved in 10 ml of DMF and 0.52 g of 90% sodium azide was added thereto. The solution was stirred for 6 hr at room temperature and the solvent was distilled off under reduced pressure. After adding water, the resulting crystals were separated by filtration to give 1.16 g of 5-azido-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 3)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[N+:23]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]2[C:40]3[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=3[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=3)=[N:44]2)[CH2:13][CH2:12]1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3c([N+](=O)[O-])cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) was dissolved in 5.0 mL of CH2Cl2 and treated with 3.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (67 mg) was dissolved in absolute EtOH (1.2 mL) and treated with 141 mg (0.35 mmol, 1.3 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography purification (silica, 10-20% acetone/CH2Cl2) provided 150 mg (85%) of 1-[4-(2,6-dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol. TLC (silica, 10% acetone/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C27H30F3N7O7S, 653.19; m/z found, 654.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.64 and 7.58 (AB pattern, J=8.4 Hz, 4H), 7.20 (t, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H), 3.66 (t, J=5.3 Hz, 2H), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C=O)C.N1C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[C:15]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Temperature: 80 °C

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, 0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The reaction was heated in an open tube to 80° C. for 40 minutes. The reaction was complete by HPLC, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo, 0.09 gm as an oily residue, LC/MS (M+H)+: 271.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[F:11][C:12]([F:35])([F:34])[C:13]([N:15]1[CH2:33][CH2:32][C:18]2([C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[C:21]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=3[O:19]2)[CH2:17][CH2:16]1)=[O:14]>>[F:31][C:27]1[C:21]2[N:22]3[C:26]([CH:9]=[O:10])=[CH:25][CH:24]=[C:23]3[C:18]3([CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]([F:11])([F:34])[F:35])[CH2:33][CH2:32]3)[O:19][C:20]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N1CCC2(CC1)Oc1cccc(F)c1-n1cccc12)C(F)(F)F
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Reaction time: 0.33 h
Yield: 100.7 %

Procedure:
POCl3 (282 μL, 3.0 mmol) was added dropwise at 0° C. under N2 to dry DMF (234 μL, 3.0 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of 2,2,2-trifluoro-1-(9′-fluorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (715 mg, 2.0 mmol) dry DMF (5.4 mL) was added drop-wise and the cooling bath was removed. The reaction was poured over ice, 1M NaOH was added (5 mL), then the pH was adjusted to 7 with 2M HCl. The mixture was extracted with dichloromethane (3×10 mL). The organics were combined, dried with MgSO4, filtered and evaporated to yield a residue that was purified by silica-gel column chromatography eluting with 5-30% EtOAc in hexanes to yield 9-fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (770 mg, quant). ESI-MS m/z calc. 382.1. found 383.3 (M+1)+; Retention time 1.71 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH3:11])([O:6]CC)OCC.C1N=CN(C([N:19]2[CH:23]=NC=C2)=O)C=1>CC(OC(C)=O)=O>[CH2:10]([O:9][C:2](=[O:6])/[C:1](/[C:23]#[N:19])=[C:2](\[O:9][CH2:10][CH3:11])/[CH3:1])[CH3:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(C#N)=C(/C)OCC
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a 2000 mL round-bottom flask was added CH3C(OEt)3 (583.2 g, 3.6 mol, 1.00 eq.) and Compound [CDI] (407.2 g, 3.6 mol, 1.00 eq.) in Ac2O (1000 mL). The mixture was heated to reflux at 130-150° C. for 3 hours. The reaction mixture was concentrated to a small volume and then allowed to cool to room temperature. The mixture was allowed to sit in refrigerate overnight. The precipitated solid was filtered and dried in vacuo to give Compound [CDII] as yellow solid: LCMS (m/e) 184 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:20]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(F)c(Cl)cc2F)ccn1
Temperature: 25 °C
Reaction time: 43 h
Yield: 87.6 %

Procedure:
A solution of 4-chloro-2,5-difluoro-benzoyl chloride (5 g, 23.70 mmol) in dichloromethane (25 mL) was added dropwise to a mixture of 2-methoxypyridin-4-amine (2.94 g, 23.70 mmol), pyridine (5.75 mL, 71.10 mmol) and dichloromethane (100.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature for 43 hours. The mixture was poured into 1N HCl (50 mL). The mixture was filtered using dichloromethane and the solid was isolated. The solid was dried under vacuum to yield 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (6.2 g, 88%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.16-8.05 (m, 1H), 7.97-7.75 (m, 2H), 7.29-7.15 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calc. 298.03. found 299.3 (M+1)+; Retention time: 1.43 minutes (3 minutes run).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(OCC)(=O)C>O1CCCC1.O>[CH3:20][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=[C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])[CH:19]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OC(C(F)(F)F)C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
After 1.33 g of 60% sodium hydride was introduced to 15 ml of tetrahydrofuran and cooled to 5° C., 5.84 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise. The mixture was stirred at 5° C. for 30 minutes, and then 3.0 g of 2-chloro-4-methyl-5-nitropyridine dissolved in 10 ml of tetrahydrofuran was added dropwise, this being stirred at room temperature for 3 hours. After being left at room temperature for 3 days, ethyl acetate and water were added thereto, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus obtained residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=10:1) to give 4.5 g (yield 80%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(O)=[O:2].C(=O)(O)[O-]>C1COCC1>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH:4]([CH2:1][OH:2])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[N:22]
Reactant: COC(=O)c1ccc(CCC(CCCCC#N)C(=O)O)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(CO)CCCCC#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
33 ml (33 mmol) of a 1 M borane-THF complex solution are added dropwise to a solution of 5 g (16.48 mmol) of methyl 4-(3-carboxy-7-cyanoheptyl)benzoate in 62 ml of THF at −15° C., and the solution is stirred at this temperature for 2 hours. Then a further 16 ml (16 mmol) of 1 M borane-THF complex solution are added dropwise at −15° C., and stirring is continued for 45 minutes. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 1 hour. After reaction is complete, 100 ml of saturated bicarbonate solution are added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in ethyl acetate and water, and the aqueous phase is extracted again with ethyl acetate. The combined organic phases are dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1→1:3→100% ethyl acetate). 2.4 g (93% purity, 47% of theory) of a colorless solid are obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]1[C:13](=[O:14])[C@H:12]([OH:15])[C@H:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7]1=[C:8]23.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:15][C@@H:12]1[C@H:11]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7](=[C:8]23)[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:31])[C:13]1=[O:14])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Reaction time: 17 h
Yield: 99 %

Procedure:
A mixture of 3.2 g of (-)-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one hydrochloride and 60 mL of acetic anhydride was stirred under nitrogen at 100° for 17 hours. The excess reagent was removed under reduced pressure and to the residue ice-water was added. The resulting suspension was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine (50 mL) and dried (magnesium sulfate). Removal of the solvent under reduced pressure gave 3.2 g (99%) of (-)-cis-3-(acetyloxy)-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one as an amorphous compound, [α]D25 -190.81° (C 0.48, methanol).
Reaction SMILES: NC1C=C(N2CCN(C)CC2)C=CC=1N.[CH3:16][O:17][C:18]1[C:23]([C:24]2[CH:48]=[CH:47][C:27]3NC(C4NC5C=CC(N6CCN(C)CC6)=CC=5N=4)=N[C:26]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][N:19]=1.[C:49](=O)([O-])[O-:50].[Na+].[Na+].C[O:56]CCOC>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>[OH:56][C:26]1[CH:25]=[C:24]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:48]=[CH:47][C:27]=1[CH:49]=[O:50]
Reactant: COCCOC
Reactant: COc1ncccc1-c1ccc2[nH]c(-c3nc4cc(N5CCN(C)CC5)ccc4[nH]3)nc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1CCN(c2ccc(N)c(N)c2)CC1
Agent: [Na+]
Solvent: O
Product: COc1ncccc1-c1ccc(C=O)c(O)c1
Temperature: 80 °C

Procedure:
Pd(PPh3)4 (9 g, 0.008 mol) was added to a degassed suspension of 4-bromo-2-hydroxybenzaldehyde (5, 34.2 g, 0.17 mol), 2-methoxypyridine-3-boronic acid (6, 28.5 g, 0.186 mol) and sodium carbonate (18.5 g) in 1,2-dimethoxyethane (420 mL) and water (140 mL) and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and filtered through Celite. Celite was washed with chloroform (2×200 mL) and water (200 mL). The organic layer was separated and concentrated in vacuo to a residue which was re-crystallized from EtOAc/hexanes to obtain the desired 2-hydroxy-4-(2-methoxypyridin-3-yl)benzaldehyde (7a) after isolation by filtration (16.25 g). The filtrate from the recrystallization process was evaporated to dryness and the residue purified by flash chromatography (15% EtOAc/hexanes) to obtain the desired 2-hydroxy-4-(2-methoxypyridin-3-yl)benzaldehyde (11.87 g) in an overall yield of 28.12 g (72%). 1H NMR (C6D6) δ 11.06 (s, 1H), 9.95 (s, 1H), 8.18 (dd, J=4.98 Hz, 1.83 Hz, 1H), 7.29-7.71 (m, 2H), 7.60 (dd, J=7.29 Hz, 1.83 Hz, 1H), 7.08-6.96 (m, 2H), 3.99 (s, 3H).