Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12]C)=O.[CH2:14]([N:17]=[C:18]=[S:19])[CH2:15][CH3:16]>C(N(CC)CC)C>[CH2:14]([N:17]1[C:10](=[O:12])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[NH:4][C:18]1=[S:19])[CH2:15][CH3:16]
Reactant: COC(=O)c1sccc1N
Reactant: CCCN=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2ccsc2c1=O
Temperature: 25 °C

Procedure:
To a suspension of 150 mL of ethanol containing 9.5 g of methyl 3-amino-2-thiophenecarboxylate was added dropwise 9.3 mL of n-propyl isothiocyanate with stirring. To this reaction mixture was added 12.64 mL of triethylamine. The reaction mixture was heated at reflux for 3 h, allowed to cool to room temperature and then stirred for approximately 24 h. The mixture was then heated at reflux for an additional 32 h, cooled to approximately 5° C. and filtered to obtain 5.5 g of the title compound of Step A as an off-white solid melting at 246-249° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[NH:17][C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[N:17]([CH3:28])[C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: COc1c2c(c(NC(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide (0.073 g, 0.196 mmol) in 2 mL DMF was added Cs2CO3 (0.084 g, 0.25 mmol) and methyl iodide (0.044 mL, 0.7 mmole) and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was partitioned between CHCl3 and 10% KHSO4, the organic was dried with Na2SO4, filtered and evaporated to give the crude product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br-].[CH:12]1([Zn+])[CH2:16][CH2:15][CH2:14][CH2:13]1.O1CCOCC1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CO>[CH:12]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: [Zn+]C1CCCC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CO
Product: c1nc(C2CCCC2)c2cc[nH]c2n1
Temperature: 110 °C
Yield: 16.4 %

Procedure:
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.503 g, 3.28 mmol), cyclopentylzinc bromide (47, 29.5 mL, 0.500 M in tetrahydrofuran, 14.7 mmol), [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (0.178 g, 0.328 mmol) and 9.3 mL of 1,4-dioxane were combined. The reaction mixture was heated at 110° C. overnight. Methanol was added and the reaction was concentrated under vacuum. Ethyl acetate and water were added to the residue, filtered through a bed of celite, and the celite washed with ethyl acetate. The filtrate layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (48, 0.101 g). MS(ESI) [M+H+]+=188.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:18])[N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:18])[N:14]([CH2:15][CH2:16][O:17][CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CCO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(Cl)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
A round bottom flask was charge with a stir bar, 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (3.9 g, 14.9 mmol), dichloromethane (125 mL), aqueous sodium hydroxide (50%, 125 mL), benzyltrimethylammonium chloride (0.55 g, 0.003 mmol) and stirred vigorously at ambient temperature. To this mixture was added cinnamyl bromide (8.8 g, 44.71 mmol) as a solid. After 45 minutes the solution was clear and the reaction was judged complete. The solution was poured into ice water (200 mL), the organic layer separated and was drawn off. The aqueous solution was extracted with dichloromethane (4×). The organic layers were combined, washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting orange oil was purified by chromatography over silica gel (dichloromethane, followed by 98/2 dichloromethane/methanol). The resulting oil was triturated with ethyl ether and the resulting solid was collected by filtration and dried to provide 4.22 g of 4-chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 1,4-dibromobenzene (1.00 g, 4.24 mmol) at −78° C. in ether (20 ml) was added n-BuLi (2.65 ml, 1.6 M solution in hexane, 4.24 mmol) and the reaction mixture was stirred at −78° C. for 30 min. Cyclobutanone (348 μl, 4.66 mmol) was then added and the reaction mixture was stirred at −78° C. for 15 min. The reaction mixture was then slowly (over 2 h) warmed to 0° C. and stirred for a further 1 h. Water was added followed by sat. NH4Cl and the reaction mixture was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether/pentane) to give 1-(4-bromophenyl)-cyclobutanol (330 mg, 34%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 2.57-2.48 (m, 2H), 2.41-2.31 (m, 2H), 2.02 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.C([N:20](CC)CC)C.C(Cl)(Cl)Cl>C1COCC1>[NH2:20][C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CCN(CC)CC
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(N)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-Chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (13 mg, 0.050 mmol) [Compound (AC) in which Q is a chlorine atom, R2B is methylthio, and —X—Y—Z— is —O—C(c-C3H5)═N—] obtained in Reference Example 3 was dissolved in THF (0.50 mL), then triethylamine (0.007 mL) and a chloroform solution (1.0 mol/L, 0.20 mL) of R1—H [wherein R1 has the same definition as described above: Compound (B)] were added thereto, followed by stirring at 60° C. for 12 hours with hermetic sealing. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated and dried. The residue was dissolved in chloroform/methanol (chloroform:methanol=3:1, 0.50 mL), then benzoyl chloride polymer-bound [about 2.5 mmol/g, 46 mg, Canadian Journal of Chemistry, vol. 55, p. 3351 (1977)], and poly(4-vinylpyridine) (46 mg) were added thereto, followed by further stirring at room temperature for 12 hours. The resin was filtered off from the reaction mixture, and the filtrate was concentrated and dried to give 4-amino-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine [Compound (AD) in which —X—Y—Z— is —O—C(c-C3H5)═N—].
Reaction SMILES: [C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH2:15])=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>CO.C(Cl)Cl>[C:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([O:16][CH3:17])[C:13]([NH:15][C:20]3[N:25]=[C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]4[NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:23]([Cl:38])=[CH:22][N:21]=3)=[CH:14][C:8]=2[NH:7][C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1N)NC(=O)CN(C(C)=O)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(C(C)=O)C2
Yield: 10.6 %

Procedure:
In an analogous manner to procedure 1656g, 4-acetyl-8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.24 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (82 mg, 0.24 mmol) were coupled to provide N-{(1R,2R)-2-[2-(4-Acetyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]di-azepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (14 mg, 10%) as a pale yellow solid following preparative tlc (10% MeOH-DCM); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.63 (d, J=7 Hz, 1H), 5.46 (d, J=7 Hz, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.53 (s, 2H), 3.29 (m, 1H), 2.89 (s, 3H), 2.21 (m, 2H), 2.17 (s, 3H), 1.83 (m, 2H), 1.65 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 553 (M+1); mp 167° C. (dec.).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.Br[C:19]1C=C2C(C=CN2)=C[CH:20]=1.[Li]C(C)(C)C.CN1CCC(=O)CC1>>[OH:1][C:2]1([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH2:7][CH:6]2[N:5]([CH2:8][CH2:19][CH2:20]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(c2ccc3cc[nH]c3c2)CC1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CN1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Product: OC1(c2ccc3cc[nH]c3c2)CCN2CCCC2C1

Procedure:
In a similar fashion, 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-indole was prepared from 6-bromoindole (1.0 g, 5 mmol); KH (0.225 g, 5.6 mmol), 1.7M tBuLi (7.5 ml, 12.7 mmol) and N-methyl-4-piperidone (1.246 g, 10.9 mmol). Yield 0.382 g (35%).
Reaction SMILES: [C:1]1([CH2:7]/[C:8](=[N:16]/[NH:17]C(OC)=O)/[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22](Cl)(Cl)=O>ClCCl>[C:1]1([C:7]2[S:22][N:17]=[N:16][C:8]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)N/N=C(/Cc1ccccc1)Sc1ccccc1
Solvent: ClCCl
Product: c1ccc(Sc2nnsc2-c2ccccc2)cc1

Procedure:
A solution of (Z)-[2-phenyl-1-(phenylthio)ethylidene]hydrazinecarboxylic acid, methyl ester in 450 ml of dry dichloromethane was treated with 29.7 g of thionyl chloride. This mixture ws refluxed for one hour, then poured into chipped ice and extracted three times with ether. The extracts were combined, washed with 0.1N sodium hydroxide twice, water and saturated sodium chloride and dried. This material was evaporated onto 100 g of silica gel which was then poured onto a column of silica gel packed in petroleum ether. The column was eluted with a gradient of 20°-60% dichloromethane in petroleum ether, giving 35 g of the desired compound as an orange oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 7.28 (bs, 5H, C6H5); 7.30-7.65 (m, 5H, C6H5). Infrared absorption spectrum (neat): 1580(m); 1475(s); 1440(s); 1286(w); 1265(m); 1255(m); 1240(w); 1025(w); 1005(w); 985(w); 935(m); 915(m); 805(m); 765(m); 745(s); 695(s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC.CCOCC.CO>C(Cl)Cl>[C:7]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[C@H](N)CO
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 88.8 %

Procedure:
To a stirred solution of (S)-(+)-2-aminobutan-1-ol (10 g, 112.18 mmol) in CH2Cl2 (500 mL) under Ar at RT, was added Pri2NEt (30 mL, 172.22 mmol) followed by trityl chloride (35.4 mL, 126.98 mmol). The reaction mixture was stirred at this temperature for 48 h, when TLC (55:40:5 hexane/Et2O/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue precipitated from Me2CO (50 mL) with hexane (900 mL) with stirring, the precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (1 L), filtered, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil (33 g, 89%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.58 (t, 3H, J=7.26, —NHCH(CH2CH3)CH2OH), 1.10 (m, 2H, —NHCH(CH2CH3)CH2OH), 2.24 (m, 1H, —NHCH(CH2CH3)CH2OH), 2.76+3.03 (2×m, 2H, —NHCH(CH2CH3)CH2OH), 4.32 (t, 1H, J=4.97 Hz, —NHCH(CH2CH3)CH2OH), 7.15-7.52 (m, 15H, 3×Bz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12](O)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]([F:16])([F:15])[F:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9](/[N:11]=[C:12](/[C:13]([F:14])([F:16])[F:15])\[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@](O)(NC(=O)OCc1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)/C(=N\C(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-hydroxyalaninate (2690 g, 8.39 mol) in diethyl ether (18 L) under an atmosphere of nitrogen was added dropwise 2,2,2-trifluoroacetyl 2,2,2-trifluoroacetate (1937 g, 9.22 mol) at 0° C. followed by the addition of pyridine dropwise (1457 g, 18.44 mol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 6 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford ethyl (2E)-2-{[(benzyloxy)carbonyl]imino}-3,3,3-trifluoropropanoate.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]([C:24]1([NH2:33])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:19]([O:21][C:22]([C:24]1([NH:33][C:10]([C:6]2[C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-7-carboxylic acid (394 mg, 2.4 mmol) in DCM (10 mL) is added oxalyl chloride (0.85 mL, 9.6 mmol). The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol) and DIPEA (3.17 mL, 19.2 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (39) as white solid (635 mg, 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13](OCC)=[O:14])[C@H:10]([C:18](OCC)=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(Cl)(Cl)Cl>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 93.9 %

Procedure:
trans-Diethyl 1-benzylpyrrolidine-3,4-dicarboxylate (830 mg, 2.72 mmol) synthesized by using WO2009/027820 as a reference was dissolved in THF (24 mL). After adding lithium aluminum hydride (206 mg, 5.44 mmol) at 0° C., the solution was stirred at room temperature for 1.3 hours. The reaction mixture was further stirred at room temperature after adding sodium sulfate decahydrate, chloroform, and Celite. The mixture was filtered after adding anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Hexane was added, and the solid was removed by filtration to give (trans-1-benzylpyrrolidine-3,4-diyl)dimethanol (565 mg, 93.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH2:11][CH3:12].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH2:11][CH3:12])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccccc1N
Reactant: CCOC(=O)CC(=O)CC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(CC)Nc1ccccc1OC
Yield: 49.4 %

Procedure:
A mixture of o-anisidine (15.11 g), ethyl propionylacetate (17.69 g) and acetic acid (0.5 ml) in benzene (30 ml) was refluxed removing water for 24 hours. The solvent was removed in vacuo, and the residue was dissolved in toluene (30 ml). The reaction mixture was refluxed for an additional 8 hours. The solvent was removed in vacuo. The residue was purified by column chromatography (hexane-ethyl acetate) to give ethyl 3-(2-methoxyanilino)-2-pentenoate (15.11 g) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](OC)=[O:10])=[C:5]([N+:15]([O-])=O)[CH:4]=1)=[O:2]>CC(O)=O.O.[Fe]>[O:10]=[C:9]1[CH2:8][O:7][C:6]2[CH:13]=[CH:14][C:3]([CH:1]=[O:2])=[CH:4][C:5]=2[NH:15]1
Reactant: COC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)NC(=O)CO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 2-(4-formyl-2-nitrophenoxy)acetate (1) (1.381 g, 5.77 mmol) and iron (1.612 g, 28.9 mmol) in AcOH (23 mL). The reaction was stirred at 80° C. for 1 hr. The reaction was concentrated in vacuo and taken up in DCM/MeOH (1:1, 100 mL), filtered and the filtrate was concentrated in vacuo to give 4.3 g crude of a brown solid. The solid was taken up in water and filtered; the solid was washed with water and dried in vacuo to give a light brown solid (0.712 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.72 (s, 2 H) 7.14 (d, J=8.34 Hz, 1H) 7.38 (d, J=1.77 Hz, 1H) 7.54 (dd, J=8.21, 1.89 Hz, 1H) 9.84 (s, 1 H) 10.99 (s, 1H). ESI-MS: m/z 178.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)o2)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nc(-c3ccc(N)cc3)c(-c3ccc(N)cc3)o2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
13 g (0.03 mol) of the 2,4,5-tris(4'-nitrophenyl)oxazole was mixed with 500 ml of N,N-dimethylformamide and 26 g of iron powder. The mixture thus obtained was admixed with 10 ml of concentrated sulfuric acid and 30 ml of water, and then heated to a temperature of 100° C. with stirring. After 1 hour passed, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate with the reaction temperature kept at a temperature of 100° C. The pH of the solution after the reaction was adjusted to 8. The reaction solution was hot-filtered, and the filtrate was then poured into 3 l of ice water to produce a light yellow precipitate of 2,4,5-tris(4'-aminophenyl)oxazole which was then filtered off and dried to obtain 4.47 g of the product (yield: 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CO)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 8 (9.21 g, 0.030 mol) in MeOH (150 mL) was added slowly NaBH4 (2.3 g, 0.061 mol) at 0° C. After the mixture was stirred at 20° C. for 3 hours, 12 mL of 6 N HCl was added, and the mixture was stirred for an additional 30 minutes. The solution was then concentrated to about one-quarter of the original volume and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried with Na2SO4, filtered, and then concentrated in vacuo to afford compound 9 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 7.47 (m), δ 7.42 (m), δ 7.34 (m), δ 7.28 (m), δ 7.16 (m), δ 6.94 (m), δ 5.08 (s), δ 4.45 (t), δ 3.64 (d), δ 1.28 (s), δ 1.25 (s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:15][C:16]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:18]([C:17]3[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:16]=3[F:15])=[O:19])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C)c1
Yield: 80.8 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine (1.44 g) described in Preparation Example 79 and 2-fluoro-4-iodobenzoic acid (2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.67 g) was obtained.