Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:41])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@H:16]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:17][C:18](=[O:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].Cl.ClCCC12O[C@@H]3[C@@]45[CH2:60][CH2:61][N:62](C)[C@@H]([C@@H]4C=C[C@@H]3O)CC(=C51)C=CC2O.O1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(=O)([O-])[O-].[Cs+].[Cs+]>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:41])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:60][CH2:61][N:62]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@H:16]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:17][C:18](=[O:24])[CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN1CC[C@]23C4=C5C=CC(O)C4(CCCl)O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: CC(C)(C)CC(=O)C[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)CC(=O)C[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCCN2CCOCC2)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O

Procedure:
The product of Step 1 above is alkylated with 4-(2-chloroethyl)morphine hydrochloride in dioxane and cesium carbonate. The reaction mixture is concentrated and purified via flash column chromatography to provide the title product.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)[NH2:2].COC(OC)[N:22]([CH3:24])C.[NH2:27]N>C(O)(=O)C>[CH:15]1([C:5]2[C:4]([C:1]3[NH:22][CH:24]=[N:27][N:2]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:14])[CH:6]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(C(N)=O)c(C2CCC2)cc1C
Reactant: NN
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2nnc[nH]2)c(C2CCC2)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a vial was added methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate (compound 202.1, 59 mg, 0.24 mmol, 1.0 equiv) and N,N-dimethylformamide dimethyl acetal (1 mL) was added. The mixture was heated at 80° C. for 5 hours then the solvents were removed in vacuo. To the residue was added acetic acid (400 μL) and a solution of anhydrous hydrazine (8.2 μL, 0.26 mmol, 1.1 equiv) in acetic acid (100.4). To the resulting thick suspension was added additional acetic acid (500 μL) and the mixture was stirred at 80° C. for 1.5 hours then the solvents removed in vacuo. Ethyl acetate (5 mL) and DCM (5 mL) was added (some undissolved solids). The organics was washed with saturated NaHCO3 (10 mL) and brine (5 mL) and removed in vacuo to obtain the title compound as a white solid (theoretical yield). m/z (ES+) 272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C@@H:19]1([NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH2:25]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][CH:19]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CCO
Product: Fc1ccc(C2=NC3CCCCC3N=C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
First, 12.07 g of 4,4′-difluorobenzil (manufactured by Tokyo Kasei Kogyo Co., Ltd) was mixed with 5.60 g of trans-1,2-cyclohexanediamine (manufactured by Kanto Kasei Co., Ltd) by using 300 mL of ethanol as a solvent, and then the mixed solution was refluxed under a nitrogen atmosphere for 3 hours. By leaving a the refluxed solution to be cooled to a room temperature and taking out a deposited crystal by filtration, 2,3-bis(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydroquinoxaline was obtained (light yellow plate-like crystal, yield: 94%). Subsequently, 6.90 g of 2,3-bis(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydroquinoxaline which was obtained in the above step was mixed with 6.90 g of iron chloride (III) using 150 mL of ethanol as a solvent to gently stir with heat for 3 hours at 50° C. After the stirring, a deposition was caused by adding water to the stirred solution. A deposit was taken out by filtering and was washed with ethanol. Then, by recrystallizing the deposit with ethanol, a ligand 2,3-bis(4-fluorophenyl)-5,6,7,8-tetrahydroquinoxaline (abbreviation: HfdpqtH) was obtained (milky white powder, yield: 68%). Synthesis scheme of Step 1 (e-1) is shown next.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.Cl(O)(=O)(=O)=O>[Cl:1][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]#[N:16]
Reactant: N#CCc1ccsc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccsc1Cl
Reaction time: 3 h
Yield: 33 %

Procedure:
Perchloric acid (0.070 mL, 0.81 mmol) was added to a rapidly stirring suspension of N-chlorosuccinimide (10.8 g, 81.2 mmol) and 2-(thiophen-3-yl)acetonitrile (10.0 g, 81.2 mmol) in carbon tetrachloride (40 mL). After 3 h at room temperature, the reaction mixture was treated with solid NaHCO3 (300 mg, 3.6 mmol), then filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 5-15% EtOAc/hexanes to afford pure 2-(2-chlorothiophen-3-yl)acetonitrile as a pale yellow oil (4.23 g, 26.8 mmol, 33% yield). MS (M+H)+ 158/160.
Reaction SMILES: [CH2:1]([C@H:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:30][CH3:31])CC)C.C([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])=C>ClCCl>[CH2:1]([C@H:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C@H:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:40]([C:35]1[CH:36]=[CH:37][C:38]([CH:30]=[CH2:31])=[CH:39][CH:34]=1)(=[O:42])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: C=Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 54 %

Procedure:
To a solution of Example 1 (11.86 g) in dichloromethane (100 mL) was added triethylamine (TEA) (19.6 mL, 4 equivalents) followed by dropwise addition of vinylbenzenesulfonyl chloride (8.36 g, 1.2 equivalents) at 25° C. for 3 hrs. The mixture was partitioned in 1N sodium bicarbonate (NaHCO3) and ethyl acetate (EtOAc). The organic extract was concentrated, and the residue was chromatographed on silica gel, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (9.6 g, 54%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (d, J=6.44 Hz, 3H), 0.90 (d, J=6.78 Hz, 3H), 1.34 (s, 9H), 1.86 (m, 1H), 2.84 (dd, J=13.39, 6.61 Hz, 2H), 2.97 (m, 3H), 3.11 (m, 3H), 3.79 (s, 1H), 4.61 (s, 1H), 5.44 (d, J=10.85 Hz, 1H), 5.88 (d, J=17.63 Hz, 1H), 6.75 (dd, J=17.63, 10.85 Hz, 1H), 7.25 (m, 5H), 7.51 (d, J=8.48 Hz, 2H), 7.72 (d, J=8.48 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)#[N:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:54]3[CH:55]=[CH:56][C:51]([C:49]#[N:50])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C#N)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-cyanophenylboronic acid to give 33 on a 0.1 mmol scale via General Procedure H (73 mg, 71%): δH (400 MHz, CDCl3) 2.39 (s, 3H, CH3), 2.82 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.85 (s, 2H, CH2), 5.05 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.67 (s, 1H, CH), 6.69 (d, J=1.2 Hz, 1H, CH), 7.22-7.34 (m, 13H, CH), 7.38-7.40 (m, 2H, CH), 7.61 (d, J=8.0 Hz, 2H, CH), 7.64 (d, J=8.4 Hz, 2H, CH), 7.70-7.72 (m, 3H, CH), 7.84 (d, J=8.4 Hz, 1H, CH); δC (100 MHz, CDCl3) 21.4, 36.0, 51.4, 52.7, 67.0, 70.7, 111.0, 114.0, 118.7, 119.9, 120.8, 126.9, 127.3, 127.4, 127.5, 128.0, 128.2, 128.2, 128.5, 128.5, 128.7, 129.5, 130.8, 132.4, 132.5, 133.1, 135.6, 135.7, 137.1, 138.4, 143.3, 144.8, 158.8, 165.2, 167.1, 167.6; LRMS (ES+) calcd for [C45H39N3O6S+H] 750.26 found 750.26.
Reaction SMILES: [C:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:19])=[O:6])(=[O:3])[CH3:2].C(NC(N1C2[C:32](=[CH:33][C:34](C(=O)C)=CC=2)[CH2:31][C:30]1=O)=O)(=O)C(C)(C)C.C(NC(N1C2C(=CC(C(=O)C)=CC=2)CC1=O)=O)(=O)CC>>[C:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:19])=[O:6])(=[O:3])[C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)NC(=O)N1C(=O)Cc2cc(C(C)=O)ccc21
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(=O)NC(=O)C(C)(C)C
Agent: CCC(=O)NC(=O)N1C(=O)Cc2cc(C(C)=O)ccc21
Product: CC(=O)c1ccc2c(c1)CC(=O)N2C(=O)NC(=O)c1ccccc1

Procedure:
In a similar manner 1-(N-acetylcarbamoyl)-5-acetyloxindole, 1-(N-s-butyrylcarbamoyl)-5-acetyloxindole, 1-(N-pivaloylcarbamoyl)-5-acetyloxindole and 1-(N-propionylcarbamoyl)-5-acetyloxindole are prepared.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5]O.CCCCCC.C1(C)C=CC=CC=1.O>P(OP(O)(O)=O)(O)(O)=O>[CH3:1][O:2][C:3]([C:4]1[C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:5]=1)=[O:21]
Reactant: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A slurry of 2-(5-chloro-2-phenoxy-phenyl)-3-hydroxy-acrylic acid methyl ester (210 g, 691 mmol) was heated in pyrophosphoric acid (420 g) to 60° C. After two hours, the reaction was cooled to 20° C. and hexane (250 mL), toluene (500 mL), and water (500 mL) were added to quench the reaction. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (500 mL) and saturated brine (500 mL). The organic fraction was concentrated and the resulting oil was crystallized from n-butanol (500 mL; 20° C. for one hour and −10° C. for two hours), which provided the titled compound as off-white crystals (172 g, 85% yield for steps A and B). 1H NMR (400 MHz, CDCl3) 3.9 (s, 3H), 7.1-7.2 (m, 3H), 7.3 (m, 2H), 7.4 (t, 1H), 7.6 (d, 1H), 8.0 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[NH2:30][CH2:31][CH:32]1[CH2:35][CH2:34][O:33]1>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:30][CH2:31][CH:32]2[CH2:35][CH2:34][O:33]2)=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:25])([F:24])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: NCC1CCO1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NCC2CCO2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (200 mg, 0.45 mmol) (prepared according to WO 02/48115, example 2D) in tetrahydrofurane (4 ml), is added 2-aminomethyloxetane (the product of step 2) (79 mg, 0.91 mmol), and the mixture is heated to reflux for 30 minutes. The solution is allowed to cool to ambient temperature and the solvent evaporated in vacuo. The residue is purified by prep. HPLC (hexane/ethyl acetate gradient on LiChrospher Si 60, Merck NW25 column) to afford 180 mg (71%) of the title compound as a white solid. [1H-NMR (CDCl3): 10.21 (s, 1H), 8.48 (d, 1H), 7.88 (d, 1H), 7.41 (m, 1H), 7.32 (s, 1H), 7.29 (m, 2H), 6.63 (m, 1H), 4.98 (m, 1H), 4.68 (m, 1H), 4.48 (m, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 2.68 (m, 1H), 2.43 (m, 1H), 2.19 (s, 3H); MS (electrospray ES+): 528, 530 ((M+H)+)].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.C(Cl)Cl.C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([N:2]1[CH:3]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:26])([F:25])[F:27])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 40 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
To a round bottom flask containing 8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.000478 mol) in methylene chloride (3 mL, 0.05 mol) and chloroform (2 mL, 0.02 mol) was added triethylamine (0.080 mL, 0.00057 mol) and methanesulfonyl chloride (0.088 mL, 0.00114 mol). The reaction was stirred at 40° C. for 6 h. The mixture was washed with water followed by brine, dried with MgSO4 and concentrated. The crude was loaded as a solid onto silica gel and purified by flash chromatography (1-10% MeOH in DCM) followed by reverse-phase HPLC to give 238 (16.5 mg) as a colorless solid. MS(ESI+) 497.0. 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.56 (s, 1H), 8.33 (d, J=8.3, 1H), 8.30 (s, 1H), 7.65 (dd, J=8.3, 1.6, 1H), 7.55 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.42 (t, J=4.9, 2H), 3.58 (s, 3H), 3.49 (t, J=4.9, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:27]([O-:29])=[O:28])[CH2:13][CH2:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:41](O)[CH2:42][OH:43].C1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:27]([O-:29])=[O:28])[CH2:13][CH2:14][C:15]2([O:43][CH2:42][CH2:41][O:26]2)[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCC(=O)CCC(Cc2ccc(OC)c(OC)c2)[N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CCC2(CCC(Cc3ccc(OC)c(OC)c3)[N+](=O)[O-])OCCO2)cc1
Temperature: 25 °C

Procedure:
Into a 1 l. r.b. flask equipped with a Dean-Stark trap was placed 22 g. (0.055 mole) of 1-(3,4-dimethoxyphenyl)-7-(4-methoxyphenyl)-2-nitro-5-heptanone, 2 g. of p-toluenesulfonic acid, 25 ml. of ethylene glycol, and 500 ml. of benzene, the mixture was refluxed until no more water was separated, and then cooled to room temperature. The dark solution was poured into cold dil. NaHCO3 solution and extracted with ethyl acetate. The organic layer was backwashed with water and dried over anhydrous MgSO4. Upon removing solvent by distillation a gray solid was obtained from trituration with ether. Recrystallization from 80% ethanol yielded 25 g. of product as a white solid; m.p. 98°-100° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2ncccc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetate (0.205 g, 0.939 mmol) in THF (5 mL) was added sodium hydroxide (0.939 mL of a 3 N aqueous solution, 2.818 mmol) and the reaction mixture was stirred at 70° C. for 0.5 h. The resulting solution was concentrated under vacuum and co-evaporated from toluene to give 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=1.033, method [3], MS (ESI) 205.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[O-:30][CH2:31][CH3:32].[Na+]>C(O)C>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([O:30][CH2:31][CH3:32])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 56 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and sodium ethoxide (5 mL of a 0.5M solution in ethanol). Yield 0.1 g.
Reaction SMILES: Br[C:2]([F:14])([CH:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[F:14][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:9]2[CH:8]1[CH2:12][CH2:11][C:10]2=[O:13]
Reactant: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2SR)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate in an amount of 1.00 g was dissolved in 5.0 mL of N,N-dimethylformamide, and 0.84 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring for 5 hours at room temperature. The reaction mixture was poured into 1M hydrochloric acid, followed by extractions with ethyl acetate twice. The organic layers were combined, and the combined organic layer was subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1), thereby yielding 0.68 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:37][CH:19]1[CH2:20][O:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH:34]1[O:36][CH2:35]1)=[O:31])=[O:23].[OH-:38].[K+]>CO>[OH:18][CH:19]([CH2:37][N:6]1[C:5](=[O:38])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH:34]([OH:36])[CH2:35][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])=[O:31])=[O:23]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: [OH-]
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Agent: [K+]
Solvent: CO
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
27.0 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 14.0 g of bis(2,3-epoxypropyl)1,2-cyclohexanedicarboxylate and 0.2 g of potassium hydroxide were reacted in 300 ml of methanol, following substantially the same procedure as in Example 1. The desired Compound No. 147 was obtained in the form of white crystals melting at 119°-122° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH:31]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(=O)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), morpholine (35 μL), and 1,2-dichloroethane (1.94 mL) was added sodium triacetoxyborohydride (100 mg), followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and water, followed by extraction with chloroform twice. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0-99:1-97:3) to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-({3-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (55 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:15]([Mg]Br)[CH:16]=[CH2:17].Cl>C1COCC1.CCOCC>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CC[Mg]Br
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A stirred solution of 8.77 g (44.7 mmol) of 2,3,4-trimethoxybenzaldehyde in 100 mL of THF was cooled in an ice bath and 55 mL of 1.0 molar (55.0 mmol) allylmagnesium bromide in ether was added dropwise over 0.5 h. The cooling bath was allowed to warm up and the mixture was stirred overnight at room temperature. A 200 mL portion of 5% aqueous HCl was added and the mixture was extracted with two 200 mL portions of ether. The combined ether extracts were washed with 50 mL of saturated aqueous NaHCO3, dried over MgSO4 and the solvent removed in vacuo to leave 10.30 g of 4-hydroxy-4-(2,3,4-trimethoxyphenyl)butene as an oil. 1H NMR (CDCl3) d 2.5 (m, 2H), 3.8 (s, 6H), 3.9 (s, 3H), 4.9 (t, 1H), 5.1 (m, 2H), 5.85 (m, 1H), 6.65 (d, 1H), 7.05 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.ClC1C=CN=C2C=C(C3SC=CN=3)SC=12.BrC1SC=CN=1.Br[C:46]1[N:47]([CH3:55])[C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:50]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:46]3[N:47]([CH3:55])[C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:50]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: COC(=O)c1cnc(Br)n1C
Agent: Brc1nccs1
Agent: Clc1ccnc2cc(-c3nccs3)sc12
Product: COC(=O)c1cnc(-c2cc3nccc(Cl)c3s2)n1C

Procedure:
Starting from the compound 98 (scheme 19) and following the procedure described above for the synthesis of compound 10 (example 12, scheme 2) but substituting 2-bromothiazole in the step 2 for the bromide 118, title compound 119 was obtained as a white solid (580 mg, 100% yield). MS (m/z) 308.1/310.0 (M+H).