Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=[CH:55][C:6]([CH2:7][N:8]2C[C@H](OCC=C)[CH2:10][C@@H:9]2[C@@H:17]([OH:54])[C@@H:18]([NH:28]C(=O)[C@@H](N2CC[C@](NC(=O)C)(CC(C)C)C2=O)CCC2C=CC=CC=2)[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)=CC=1.[C:57]([NH:60][C@:61]1([C@@H:110]([CH2:112][CH3:113])[CH3:111])[CH2:65][CH2:64][N:63]([C@@H:66]([CH2:101][CH2:102][C:103]2[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=2)[C:67](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:68])[C:62]1=[O:109])(=[O:59])[CH3:58].C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(O)=O)C1=O)(=O)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1CCCCN1C(C1C=CC=CC=1)C1C=CC=CC=1)O>ClCCl>[C:57]([NH:60][C@:61]1([C@@H:110]([CH2:112][CH3:113])[CH3:111])[CH2:65][CH2:64][N:63]([C@@H:66]([CH2:101][CH2:102][C:103]2[CH:104]=[CH:105][CH:106]=[CH:107][CH:108]=2)[C:67]([NH:28][C@@H:18]([CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[C@H:17]([OH:54])[C@H:9]2[CH2:10][CH2:55][CH2:6][CH2:7][NH:8]2)=[O:68])[C:62]1=[O:109])(=[O:59])[CH3:58]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@@](CC(C)C)(NC(C)=O)C2=O)N(Cc2ccc(OC)cc2)C1
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2)C1=O
Reaction time: 0.33 h

Procedure:
Step 8 (A): Preparation of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((R)-1-benzhydrylpiperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 45 mg, 0.126 mmol) in dichloromethane (3 mL) was added Hunig's base (45 mg, 0.38 mmol) to make a clear solution and HATU (62 mg, 0.164 mmol) was then added. After stirring for 20 min, the reaction mixture was added (1S,2S)-2-amino-1-((R)-1-benzhydrylpiperidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Preparation 1,55 mg, 0.126 mmol) and the reaction mixture was stirred at rt for 6 h. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 75 mg of the title compound:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN.Cl>C(O)CO.O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C1Cc2ccccc2N1c1ccccc1
Temperature: 160 °C
Yield: 89.9 %

Procedure:
To a solution of commercially available 1-phenyl-1H-indole-2,3-dione (10.10 g, 45.7 mmol) in ethylene glycol (125 mL) is added powdered potassium hydroxide (7.4 g, 112 mmol), hydrazine hydrate (16.35 mL) and water (4 mL). The reaction is heated to 160° C. for 1.5 hr after which it is cooled to room temperature, made acidic with conc. hydrochloric acid, diluted with water and the resulting solids are collected by filtration. The solid is washed with water, dissolved in dichloromethane, dried and the solvent removed to give the 1-phenyl-1H-indol-2-one (8.6 g, 90% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=[C:10]([C:17]([OH:19])=O)[N:9]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=1)=[O:19])[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2sccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2sccc2c(-c2ccccc2Cl)n1
Yield: 60.8 %

Procedure:
Operations are carried out as for example 7, starting from 2.9 g of 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 2.1 g of N,N-diethyl 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxamide, melting at 119° C., are obtained.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]#[N:11])=[C:4]2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:11][CH2:10][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc2occc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2occc12
Temperature: 50 °C
Yield: 138.7 %

Procedure:
Dissolve benzofuran-4-carbonitrile (0.3 g, 1.96 mmol) in anhydrous THF (5 mL) and add slowly to 1M lithium aluminum hydride in THF (3.91 mL, 3.91 mmol) at ambient temperature. Heat the reaction mixture at 50° C. for 5 h and cool to ambient temperature. Quench the reaction mixture with water until a granular precipitate starts to form and filter through a pad of Celite®. Evaporate the solvent and purify by SCX chromatography to obtain the title compound as a brown oil (0.4 g, 79%). GC-MS m/z: 147 (M+).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13](C(C)(C)C)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 108.4 mmol) was dissolved with stirring in 430 mL glacial acetic acid and the resulting mixture was treated drop wise with fuming nitric acid (90%, 179.26 mL). When the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into a 2.0 L of crushed ice and allowed to stand 30 min. Afterwards, 1.0 L of water was added and the ice water mixture was allowed to melt. The mixture was then filtered, washed with water and dried to provide the title compound (24.57 g, 89%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.O>CN(C=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:20][C:37](=[O:38])[NH:22][N:21]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1ccnc(-c2c[nH]c3ccc(C(=O)NN)cc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4n[nH]c(=O)o4)cc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a solution of 3-(4-isopropylpyrimidin-2-yl)-1H-indole-5-carbohydrazide (400 mg in about 60% pure) in DMF (3 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.47 mL, 2.71 mmol) followed by CDI (242 mg, 1.49 mmol). The mixture was stirred at RT for 5 min then heated in an oil bath at 65° C. for 1 h. It was cooled to RT, treated with 5 mL of H2O and extracted with 3×20 mL of EtOAc. The combine organic solution was washed with 3 mL of brine, dried and concentrated to afford 5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (350 mg). This material was used in next step without further purification. MS (ESI, pos. ion) m/z: 322.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]([NH:23][CH:24]([CH2:26][CH3:27])[CH3:25])[CH3:22]>S(Cl)(Cl)=O>[CH2:21]([N:23]([CH:24]([CH3:25])[CH2:26][CH3:27])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)=[O:20])[CH3:22]
Reactant: CCNC(C)CC
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Solvent: O=S(Cl)Cl
Product: CCC(C)N(CC)C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(2-chlorophenyl)-quinoline-4-carboxylic acid (2.8 g), thionyl chloride (10 ml) and N-ethylbut-2-ylamine (4 g) as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:36]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[Cl:36])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 95 %

Procedure:
A solution of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) (0.40 g, 1.13 mmol) and triethylamine (393 μL, 2.82 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 400 mg (95%) of 4-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (14) as white solids. 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.0 Hz, 3H), 3.62 (s, 3H), 4.30 (q, J=7.0 Hz, 2H), 5.47 (s, 2H), 6.81 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 8.40 (dd, J=1.5, 7.5 Hz, 1H), 8.71 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 373 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCc3c(cnc4[nH]ncc34)C2)cc1
Temperature: 65 °C

Procedure:
To 3,7-bis-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.092 g, 0.22 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 65° C. for 16 hours. On the completion of the reaction, toluene (5 mL) was added. The solvent was removed under reduced pressure to give a dark brown solid. The residue was then partitioned between EtOAc and aqueous NaOH. The organic layer was then separated, washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a residue. The crude product was purified using flash column chromatography (SiO2, 1% methanol in EtOAc) to desired product, 7-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a pale yellow solid (0.047 g, 72%). M.p.=184-186° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.49 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.32-7.26 (m, 2H), 6.94-6.88 (m, 2H), 3.75 (s, 3H), 3.64 (s, 2H), 3.62 (s, 2H), 3.1-3.03 (m, 2H), 2.8-2.72 (m, 2H); LCMS [M+H]: 295.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Cl[CH2:15][CH:16]=O.[OH-].[Na+]>O>[CH3:8][C:7]1[C:2]2[N:3]([CH:15]=[CH:16][N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.27 g of 2-amino-3-picoline was dissolved in 150 mL of water, 14.2 g of sodium hydrogen carbonate and 33.2 g of chloroacetaldehyde (40% aqueous solution) were added thereto, and then stirred at room temperature for 4 hours. The solution was adjusted to pH 10 with a 3N aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were separated by filtration, and then the filtrate was concentrated to obtain 8-methylimidazo[1,2-a]pyridine [3-1] as a brown oily product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH:36]1([CH:39]=[CH2:40])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+].[Cu]I.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]1([C:39]#[C:40][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:38][CH2:37]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: C=CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(C#CC3CC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 40 °C
Yield: 84.9 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr2NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol) and PPh3 (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated to 40° C. for 90 min under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J=8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J=8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=1.9 Hz). Anal. Calcd for C25H19FN4O2: C, 70.41; H, 4.49; N, 13.14. Found: C, 70.33; H, 4.60; N, 13.08.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.N1C=CC=CC=1>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(Br)n1
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Methanesulphonyl chloride (0.74 g) in dichloromethane (5 ml) was added over 2 min to a stirred solution of 2-amino-6-bromopyridine (1.1 g) and pyridine (0.57 g) in dichloromethane (5 ml). After 4 h, the solvent was evaporated in vacuo to give an oil which was purified by FCC eluting with System A (95:5:1) to give the title compound as a white solid (1.2 g), m.p. 90°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH3:16][NH2:17]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g, 39.1 mmol) in THF (100 mL) was cooled to −40° C. before being treated with a solution of methylamine hydrochloride (2.64 g, 39.1 mmol) in 10 ml of water followed by TEA (5.44 mL, 39.1 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 1 hour before being partitioned between 350 mL EtOAc and 30 mL brine. The organic layer was washed twice with brine, dried over MgSO4 and subjected to flash chromatography (330 g silica gel, 0-40% EtOAc/hexane) to afford 4-chloro-N-methyl-3-nitrobenzenesulfonamide (6.38 g, 65%) as a light yellow solid. MS (m/z) 251.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[C:6]=1[N+:16]([O-:18])=[O:17])=[O:4].Cl.CN(C)CCCN=C=NCC.[C:31](O)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:7]1[C:6]([N+:16]([O-:18])=[O:17])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:13]([CH3:14])=[CH:12][C:8]=1[C:9]([O:11][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:10]
Reactant: COC(=O)c1c(C)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 67.4 %

Procedure:
4-(Methoxycarbonyl)-2,5-dimethyl-3-nitrobenzoic acid (9.5 mmol) was suspended in dichloromethane (30 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.82 g, 9.5 mmol) and 4-dimethylaminopyridine (1.16 g, 9.5 mmol) were added. The mixture was stirred at ambient temperature for 0.5 h. tert-Butanol (6 mL, 64 mmol) was added and the mixture was stirred for 15.5 h. tert-Butanol (20 mL, 213 mmol) was added and the mixture was stirred at reflux for 1 h. The dichloromethane was removed and the mixture was stirred at 75° C. for 21 h. Triethylamine (1.3 mL, 9.3 mmol) and diphenylphosphoryl chloride (1.96 mL, 9.5 mmol) were added and the mixture was stirred at 75° C. for 6 h. The mixture was cooled to ambient temperature and then was concentrated. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic portion was washed with 1N sodium hydroxide, brine, dried over sodium sulfate, then filtered and concentrated to afford an orange semi-solid which was purified by column chromatography (silica gel, 5-15% ethyl acetate in hexanes) to afford crude 1-tert-butyl 4-methyl 2,5-dimethyl-3-nitroterephthalate (1.98 g, 6.4 mmol, 68% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.44 (s, 3H), 1.60 (s, 9H); GCMS for C15H19NO6: 309 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[C:14]([C:16]3[C:17]([O:22]C)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=2[O:28][CH3:29])=[O:9])[CH:5]=[CH:6][CH:7]=1.Br.C([O-])(O)=O.[Na+]>CC(O)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]2[C:17](=[O:22])[NH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=1[O:28][CH3:29])=[O:9]
Reactant: COc1ncccc1-c1cc(C(=O)c2cccc(N)c2)c(OC)c(C(C)(C)C)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(C(=O)c2cccc(N)c2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Yield: 66 %

Procedure:
step 3—A solution of 36 (69 mg, 0.177 mmol), 48% HBr (0.075 mL, 0.654 mmol) and AcOH (3 mL) in a sealed tube was heated overnight at 60° C. The reaction mixture was cooled to RT, carefully poured into a cold saturated aqueous NaHCO3 solution and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with EtOAc/hexanes to afford 44 mg (66% yield) of 3-[3-(3-amino-benzoyl)-5-tert-butyl-4-methoxy-phenyl]-1H-pyridin-2-one (38 [I-59]) as a light yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
153 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-phenylpiperazine (0.062 mL, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:16]#[N:17])[CH2:10][C:11](OCC)=[O:12])=[CH:4][CH:3]=1>[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:16][NH:17][C:11](=[O:12])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C#N)Cc1ccc(F)cc1
Agent: [Ni]
Product: O=C1CC(Cc2ccc(F)cc2)CN1

Procedure:
In the same manner as Example 1-(d), 10 g of ethyl 4-(4-fluorophenyl)-3-cyanobutyrate was catalytically reduced with the acid of Raney's nickel to obtain 4-(4-fluorobenzyl)-2-pyrrolidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]2[C:23]([OH:43])=[C:24]([N:32]=[N:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-])=O)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=2)[C:13]=1[OH:44])([O-])=O.[OH-].[Na+]>[Zn].C(O)C>[N:1]1[N:11]([C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]3[C:23]([OH:43])=[C:24]([N:32]4[N:40]=[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]5=[N:33]4)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=3)[C:13]=2[OH:44])[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(-c2cc(C(C)(C)C)cc(N=Nc3ccccc3[N+](=O)[O-])c2O)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Yield: 25.6 %

Procedure:
A mixture of the 3,3′-bis-(2-nitrophenylazo)-5,5′-di-tert-butyl-1,1′-biphenyl-2,2′-diol (3.5 g), zinc powder (6.38 g), 15% aqueous sodium hydroxide (20 ml), and ethanol (40 ml) was boiled under reflux in a nitrogen atmosphere for three hours. The hot mixture was filtered over diatomaceous earth. After cooling in an ice bath and acidification with hydrochloric acid, the precipitated product was collected by suction filtration, washed with water and air dried. Purification of the crude product by dry column chromatography using a mixture of hexane and ethyl acetate (9:1 v/v) as the eluent gave pure 3,3′-bis-(2H-benzotriazol-2-yl)-5,5′-di-tert-butyl-1,1′-biphenyl-2,2′-diol (COMPOUND 2) (0.8 g); m.p. 234° C.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.[CH:44]([C:46]1[CH:47]=[C:48]([Mg]Br)[CH:49]=[CH:50][CH:51]=1)=[CH2:45]>[Ni](Cl)Cl.O>[CH:2]([C:4]1[CH:9]=[C:8]([CH:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH3:45])[CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: CC(Cl)c1ccccc1
Reactant: C=Cc1cccc([Mg]Br)c1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: C=Cc1cccc(C(C)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
Then, 94 g (0.67 mole) of (1-chloroethyl)benzene of the formula (VI) and 5.4 g of the catalyst of nickel chloride (II) with ligands of 1,3-bis(diphenylphosphino)propane were mixed into 500 ml of dried ether. The above Grignard reagent was dropped little by little into this mixture over 2 hours. During the dropping, the temperature in the reactor was maintained at 0° C. After the dropping, stirring was continued for further 24 hours. The reaction mixture was then poured into iced water (1000 g of ice and 500 g of water) and aqueous layer and oily layer were separated to recover the oily layer. After that, ether and tetrahydrofuran were evaporated off under a reduced pressure to obtain 1-(3-vinylphenyl)-1-phenylethane in a yield of 74%.