Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1.C(=O)([O-])N.[K+]>CN(C=O)C>[C:22]([O:21][C:20](=[O:26])[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:14][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
A mixture of 2,3-dichloro-5-(trifluoromethyl)pyridine (2.0 g, 9.26 mmol), tert-butyl piperidine-4-ylcarbamate (2.2 g, 111.1 mmol) and anhydrous potassium carbamate (3.8 g, 27.78 mmol) in DMF (15 ml) was heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated, water and EtOAc were added to the residue and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (hexane/EtOAc 90:10) to yield the title compound (2.5 g, 70%). 1H NMR (500 MHz, CDCl3): δ 1.47 s, 9H), 1.53-1.60 (m, 2H), 2.07-2.09 (m, 2H), 3.01-3.06 (m, 2H), 3.72 (br.s., 1H), 3.97-4.00 (m, 2H, 4.54 (br.s., 1H), 7.75 (s, 1H), 8.38 (s, 1H); Mass Spectrum: M+H+ 380.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[Cl:9])[CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(C=O)ccc1O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OCc1ccc(Cl)c(Cl)c1
Yield: 99.8 %

Procedure:
0.5M solution of 4-chloromethyl-1,2-dichloro-benzene (1.55 g, 8.0 mmol) in DMF was added dropwise to a suspension of 4-hydroxy-3-methyl-benzaldehyde (990 mg, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was treated as described in Example 6. The residue was purified on silica gel, obtaining 2.15 g of the title compound in a quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=O.CN.CO.CC(O)=O.[C:22]([BH3-])#[N:23].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:23][CH3:22]
Reactant: [BH3-]C#N
Reactant: Cc1c(C=O)n(C)c2ccccc12
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) was added a solution of 2.0 M methylamine in methanol (150 mL, 300 mmole) and HOAc (4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr, then was cooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole) was added portionwise over 5 min. The reaction was then allowed to warm to RT. After 16 hr, the reaction was concentrated under vacuum and the residue was taken up in Et2O. The solution was washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Flash chromatography on silica gel (95:5 CHCl3/methanol containing 5% NH4OH) gave the title compound (7.34 g, 52%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 1 H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (t, 1 H), 7.09 (t, 1 H), 3.88 (s, 2 H), 3.76 (s, 3 H), 2.46 (s, 3 H), 2.32 (s, 3 H), 1.36 (br s, 1 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br-:31].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 45.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-2-thienyl)methanol (0.0578 g, 0.189 mmol) and 3-bromopropyl phenyl ether (0.033 mL, 0.209 mmol) in 1MeOH/1CHCl3 (4.0 mL) were reacted to give the desired product (0.0448 g, 45.4%). EI-MS m/z 440(M+) Rt (1.94 min).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].N(C(C)C)C(C)C.[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.C([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](OS(C(F)(F)F)(=O)=O)[CH2:28][CH2:27]1)=[O:25])(C)(C)C>CCCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH2:2]([O:25][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:18]2[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=2)[CH2:30][CH2:31]1)=[O:23])[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cn1cccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCCOC(=O)N1CC=C(c2ccnn2C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 931.4 %

Procedure:
A solution of BuLi (13.3 mmol) in hexane (1.6 M, 8.3 mL) was added to a stirred solution of iPr2NH (1.87 mL, 13.3 mmol) in THF (15 mL) at 0° C. under N2. The resulting solution was stirred for 20 min and then cooled to −78° C. and N-methyl pyrazole (0.99 g, 12.1 mmol) was added. The mixture was stirred for 1 h at −78° C. and then a solution of ZnCl2 (1.8 g, 13.3 mmol) in THF (10 mL) was added and the reaction was allowed to warm to RT and stirred for a further 20 min. A solution of 1-(tert-butoxycarbonyl)-4-[(trifluoromethanesulfonyl)oxy]-1,2,3,6-tetrahydropyridine (Synthesis 1991, 11, 993–5) (150 mg, 0.53 mmol) in THF (5 mL) and Pd(PPh3)4 (347 mg, 5 mol %) were added and the reaction was heated at reflux for 3 h. The mixture was partitioned between EtOAc (75 mL) and NH4Cl solution (75 mL), separated and the organics were washed with H2O (75 mL) and brine (50 mL). After concentrating under reduced pressure, the residue was purified by column chromatography on silica eluting with 100% EtOAc to yield the pyrazole (1.30 g, 82%). 1H NMR (CDCl3, 360 MHz) δ 7.41 (1H, d, J=1.9 Hz), 6.13 (1H, d, J=1.9 Hz), 5.83 (1H, broad s), 4.10–4.00 (2H, m), 3.88 (3H, s), 3.62 (2H, t, J=5.7 Hz), 2.45–2.37 (2H, m), 1.49 (9H, s). MS (ES+) C14H21N3O2 requires: 263, found: 264 (M+H+, 100%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([NH:29][CH2:28][CH2:27][CH:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:31])=[CH:9][CH:8]=2)[CH2:25][CH2:24]1)[CH3:30])=[O:36]
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: Cc1cccc(Cl)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 164) (73 mg, 0.17 mmol) and 2-chloro-6-methylbenzoic acid (43 mg, 0.25 mmol) followed by general procedure K with the resulting ester gave 4-[{1-[3-(2-chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-(3-cyano-benzyl)-amino]-benzoic acid as a beige solid (44.5 mg, 46% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:20])[C:18]=1[OH:19])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6].[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:20][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([CH3:1])[C:18]=1[O:19][CH3:21])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1C
Yield: 94.3 %

Procedure:
A solution containing compound 1 (15.0 g, 55.4 mmol), K2CO3 (20.0 g, 0.145 mol) and CH3I (30 mL, 0.48 mol) in 250 mL acetone was refluxed for 6 hours. The solvent was evaporated and the residue partitioned between CH2Cl2 and H2O. The organic layer was dried over Na2SO4, filtered and evaporated to leave a yellow-white powder. Recrystallization from CH3OH/pet ether at -20° C. gave 14.9 g of white crystals (94%). The material was characterized by NMR, TLC, mass spectroscopy, IR and elemental analysis, m.p. 131°-132.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[N:13]([O-])=O.[Na+].[O:17]=[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1C(O)=O>O.Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:13]=[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]2=[O:17])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: O=C(O)C1CCCCC1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCCCC1=NNc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
To 4-bromo-2-(trifluoromethyl)aniline (4.61 g, 19.21 mmol) in H2O (24 mL), conc. HCl (4 mL) was added and stirred at 0° C. for 10 min. NaNO2 (1.32 g, 19.21 mmol), dissolved in water (10 mL), was added to the reaction mixture and allowed to stir at 0° C. for 30 min. The solid obtained was filtered, the filtrate was cooled to 0° C. and 2-oxocyclohexanecarboxylic acid (2.46 g, 19.21 mmol) was added while maintaining the temperature at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 1 h. The solid obtained was filtered and air dried to afford the title compound (2 g, 30%). 1H NMR (200 MHz, CDCl3, δ in ppm) 14.05 (br s, 1H), 7.80-7.75 (d, J=8.8 Hz, 1H), 7.64-7.54 (m, 2H), 2.76-2.69 (m, 2H), 2.60-2.53 (m, 2H), 1.91-1.84 (m, 4H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].Cl.C([O-])(=O)C.[Na+]>O.CC(=O)CC>[C:13]([CH2:14][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:15])[CH3:12]
Reactant: CC(=O)CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)CSc1nc2ccccc2[nH]1

Procedure:
2-Mercaptobenzimidazole (14.6 g, 0.1 mole) and chloroacetone (9.25 g, 0.1 mole) were added to 2-butanone (400 ml) and refluxed for 5 hrs. On cooling the product hydrochloride, 21.24 g, 88% was isolated by filtration, washed with acetone and air dried. The salt was dissolved in water (150 ml) and added to a solution of sodium acetate (7.2 g, 0.088 mole) in water (100 ml). The oil obtained was extracted into ethyl acetate, filtered to remove some insoluble material (0.4 g), dried and evaporated to dryness. The residue was crystallised from ethanol to give three crops of 2-(acetylmethylthio)benzimidazole (2), as colourless crystals, 15.0 g, 73%, mp. 112°-113° C. PMR was consistent with a tautomeric mixture of the open chain and ring closed forms.
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[NH2:41][C:42]1[N:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[ClH:27].[ClH:27].[NH2:41][C:42]1[N:47]=[CH:46][C:45]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:44][N:43]=1
Reactant: Nc1ncc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cnc(N)nc3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 5 (25 mg, 43 μmol) and 2-amino-5-bromopyrimidine (6.2 mg, 36 mmol) in accordance with Method L2.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1.O>CCO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18]([C:16]1[S:15][C:14]2[C:8]3[CH:7]=[CH:6][C:5]([CH2:4][NH:2][CH3:1])=[CH:29][C:9]=3[O:10][CH2:11][CH2:12][C:13]=2[CH:17]=1)=[O:19]
Reactant: CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of CH3NH2 in EtOH (0.25 mL) was added TEA (0.5 mL) and 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (250 mg). The reaction mixture was stirred for 2 h at 60° C. before added water. The mixture was extracted with EtOAc (20 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (CH2Cl2: MeOH=10:1) to afford 243 as a light yellow solid (95.6 mg, 42.8%). MS: (ESI+) 412.9
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:10]1[N:20]2[C@@H:14]([S:15][CH2:16][CH2:17][C@H:18]([NH:22]C(=O)OC(C)(C)C)[C:19]2=[O:21])[CH2:13][CH2:12][CH2:11]1)#[N:9]>C(Cl)Cl>[NH2:22][C@H:18]1[CH2:17][CH2:16][S:15][C@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:8]#[N:9])[N:20]2[C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (0.15 mL) was added to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (36 mg, 0.11 mmol) in DCM (0.35 mL). The reaction mixture was then stirred at rt for 45 min. The reaction mixture was concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc was isolated, dried over MgSO4, filtered and concentrated give (4S,7S,10aS)-4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carbonitrile (15 mg, 0.067 mmol, 60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(O[C:15](=[O:24])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17])(=O)O.[Cl:25][CH2:26][C:27](Cl)=[O:28].Cl>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:15](=[O:24])[CH:16]([O:17][C:27](=[O:28])[CH2:26][Cl:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:4]
Reactant: O=C(O)OC(=O)C(O)c1ccccc1
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)C(OC(=O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 2 ml of N,N-dimethylacetamide, which is stirred under ice-cooling beforehand, is added 534 mg of mandelic-carbonic anhydride, followed by stirring at room temperature for 30 minutes. The mixture is stirred beforehand under ice-cooling, to which is added dropwise 1.05 ml of chloroacetyl chloride, followed by stirring at room temperature for 3 hours. The reaction mixture is shaken with 1000 ml of ethyl acetate and 20 ml of 1N-HCl, then the organic layer is separated. The organic layer is washed with a saturated aqueous solution of sodium chloride (30 ml×3), 20 ml of 1N-NaHCO3 aqueous solution and a saturated aqueous solution of sodium chloride (30 ml×3), successively, dried, and the solvent is evaporated under reduced pressure. The residue is purified by column-chromatography on silica-gel to afford cis-3-(2-chloroacetyloxy-2-phenylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:5]2=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=[C:4]2[C:3]=1[CH3:14].[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][C:2]1[NH:13][C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[C:3]=1[CH3:14]
Reactant: Cc1[nH]c2ncc([N+](=O)[O-])cc2c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c2ncc(N)cc2c1C
Temperature: 110 °C
Yield: 99.9 %

Procedure:
2,3-Dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.11 g, 0.596 mmol), iron (0.40 g, 7.16 mmol) and ammonium chloride (0.13 g, 2.39 mmol) were combined with ethanol (2.8 mL) and water (0.65 mL) in a microwave vessel and heated in a microwave reactor to 110° C. for 15 minutes. The reaction mixture was filtered, saturated aqueous sodium bicarbonate was added, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to afford 2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.096 g, 100%), which was carried to the next step without further purification.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[CH2:8]Cl.II.[CH2:15]([N:22]1[CH2:27][CH2:26][O:25][CH:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH2:27][CH2:26][O:25][CH:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:29])[CH2:8][C:7]2[CH:10]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=2[O:11][CH3:12])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccc(F)cc1CCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Yield: 106.8 %

Procedure:
Alternatively, the following method may be used. Magnesium turnings (21.6 g, 0.888 mole, 2 eq.) and diethyl ether (300 ml) were loaded in a reactor under N2. A solution of 5-fluoro-2-methoxybenzyl chloride (116 g, 0.664 mole, 1.5 eq.) in diethyl ether (200 ml) was loaded in an addition funnel. Iodine crystals and a small amount of the 5-fluoro-2-methoxybenzyl chloride solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 5-fluoro-2 methoxybenzyl chloride solution was then added drop-wise maintaining the temperature of the reaction mixture below 28° C. The mixture was stirred for another 5 minutes at 19° C. after completion of the addition and a white suspension was formed. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (125 g, 0.444 mole) in diethyl ether (1.8 L) was added drop-wise, maintaining the temperature of the reaction mixture below 25° C. The suspension obtained was stirred for 2 hours. The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (625 ml) and water (500 ml), maintaining the temperature below 20° C. The mixture was stirred for 30 minutes and the solids were filtered, washed with water (125 ml) and diethyl ether (200 ml). The filtrates were loaded into a separation funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (1 L). The organic layers were combined and dried over MgSO4, filtered and the filter cake was washed with diethyl ether (100 ml). The filtrates were concentrated under vacuum. The yield of title compound was 201 g as a yellow solid (107%). Title compound (200 g, 0.474 mole) was then suspended in isopropanol (400 ml) under N2. The suspension was heated under reflux until all solids were dissolved. The solution is allowed to cool to 20° C. over 4 hours under stirring. The solid is filtered, washed with isopropanol (100 ml) and dried at 40° C. under vacuum. The yield of pure title compound is 158 g (79%). 1H-NMR (CDCl3): 6.99-7.26 ppm, 10H, mp; 6.60-6.71 ppm, 1H, dt; 6.49-6.60 ppm, 1H, dd; 6.31-6.44 ppm, 1H, dd; 3.92-4.01 ppm, 1H, dt; 3.80-3.90 ppm, 1H, dd; 3.64-3.73 ppm, 1H, dd; 3.59-3.64 ppm, 1H, d; 3.52-3.59 ppm, 3+1 H, 2s; 3.37-3.45 ppm, 1H, d; 3.07-3.17 ppm, 1H, d; 2.84-2.92 ppm, 1H, d; 2.43-2.53 ppm, 1H, d; 2.20-2.28 ppm, 1H, d; 1.98-2.11 ppm, 2H, mp.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]2[CH3:37])=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH3:39][Mg]Br.C(OCC)(=O)C.O>O1CCCC1>[OH:4][CH:3]([CH3:39])[C:2]([CH3:38])([CH3:1])[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]2[CH3:37])=[CH:10][CH:11]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4′-({1-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.15 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (3.0 M diethyl ether solution, 0.78 mL) at −78° C., and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.60 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:27]12CC(C=C1)C=[CH:28]2.C1(C)C(C)=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(-c2nnc(-c3ccccn3)nc2-c2ccc(Br)cc2)cc1
Reactant: C1=CC2C=CC1C2
Solvent: Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2ccc(-c3ccccn3)nc2-c2ccc(Br)cc2)cc1
Temperature: 140 °C
Yield: 59.6 %

Procedure:
In a 500 mL three-neck flask were put 13 g (27 mmol) of 5,6-bis(4-bromophenyl)-3-(2-pyridyl)-1,2,4-triazine, 9.0 mL (83 mmol) of 2,5-Norbornadiene, and 150 mL of xylene. This mixture was refluxed at 140° C. for 5 hours under a nitrogen stream. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The extract was washed with a saturated saline together with the organic layer, and the organic layer was then dried with magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The solid was refined with silica gel column chromatography (toluene), so that a target substance, 7.5 g of light-yellow powder was obtained in a yield of 59%.