Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:19]=[C:18]2[C:5](=[N:6][CH2:7][N:8]2[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:4]([NH:21][CH3:22])(N)[N:3]=1.[CH2:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]#[CH:25].C(N(CC)CC)C>CN(C)C=O.[Cu](I)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>[OH:16][CH2:15][C@H:14]1[O:17][C@@H:9]([N:8]2[CH:7]=[N:6][C:5]3[C:18]2=[N:19][C:2]([C:25]#[C:24][CH2:23][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3][C:4]=3[NH:21][CH3:22])[C@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: C#CCOc1ccccc1
Reactant: CNC1(N)N=C(I)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1nc(C#CCOc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 2-iodo-6-methylamino adenosine (50 mg) and prop-2-ynyloxybenzene (0.022 mL, 0.16 mmol) in N,N-dimethylformamide (1 ml) and triethylamine (0.021 mL, 0.16 mmol) at 23 C was added copper iodide (5 mg, 0.026 mmol) and dichlorobis-(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) catalyst. After being stirred in a sealed reaction-vial at 80° C. for 6 hours, the reaction was concentrated in vacuo, and the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1) to afford (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I. MS: 412.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.N[C:13]([NH2:15])=O.P(Cl)(Cl)([Cl:18])=O>CCOC(C)=O.O>[Cl:18][C:13]1[N:15]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([Cl:10])=[C:7]([F:11])[CH:6]=2)[N:1]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(F)cc1C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc2cnc(Cl)nc2cc1Cl
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 12.3 %

Procedure:
A mixture of 2-amino-4-chloro-5-fluorobenzaldehyde (0.30 g, 1.73 mmol) and urea (1.04 g, 17.3 mmol) was heated to 180° C. for 1 h, then cooled to RT. The solid was then suspended in a mixture of EtOAc and water and then it was filtered and the collected solid was washed with water several times, then air-dried. This intermediate quinazolinone was then suspended in phosphorus oxychloride (3.0 mL, 32.2 mmol) and then heated to 100° C. for 1 h. After cooling to RT, the mixture was added dropwise to an ice-water mixture. The mixture was stirred for 5 minutes and then the product was extracted into EtOAc (3×). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 2,7-dichloro-6-fluoroquinazoline as a white solid (46 mg, 12% yield). m/z=217 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:61][C:58]1[S:59][C:60]2[C:52]([CH:47]3[CH2:48][O:49][CH2:50][CH2:51][O:46]3)=[CH:53][CH:54]=[C:55]([O:62][CH3:63])[C:56]=2[N:57]=1)=[O:8]
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(N(C)C)c3)nc12

Procedure:
From 3-dimethylaminobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+18.7° (c=1.06, CHCl3), ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: C1(O)C=CC=CC=1.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](C(C)C)[C:12]=1[OH:20])([CH3:10])[CH3:9]>[O-]C1C=CC=CC=1.[Al+3].[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1>[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:20])([CH3:10])[CH3:9]
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [Al+3]
Agent: [O-]c1ccccc1
Solvent: Oc1ccccc1
Product: CC(C)c1ccccc1O
Yield: 11.3 %

Procedure:
For example, U.S. Pat. No. 2,831,898 discloses a process for producing 2,6-diisopropyl phenol from propylene gas and phenol by Friedel-Crafts reaction at high pressure of 21-35 atm, high temperature of 200°-210° C. and under nitrogen atmosphere with aluminum phenoxide, as a catalyst, prepared from alumina and phenol. But there is a defect that 2,6-diisopropyl phenol desired was obtained only with 11.3% yield even though 2-isopropyl phenol which is a by-product was obtained with 31.4% yield.
Reaction SMILES: O[CH:2]([C@H:5]1[O:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:3]C.[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.CN([CH:37]=[O:38])C>O>[Si:15]([O:9][CH:5]([CH:6]1[CH2:7][CH2:8][O:10][C:37]1=[O:38])[CH2:2][CH3:3])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(O)[C@@H]1CCC(=O)O1
Agent: c1c[nH]cn1
Solvent: O
Product: CCC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C1CCOC1=O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of (5S)-5-(1-hydroxypropyl)tetrahydrofuran-2-one (compound 28d, 9 g, 62.5 mmol) in DMF (100 mL) was added tert-butylchlorodiphenylsilane (42.8 g, 156 mmol) and imidazole (10.6 g, 156 mmol) under N2. After being stirred at 50° C. for 12 hours, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine (100 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:3 EtOAc in petroleum ether) to afford 18 g of (5S)-5-[(1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one. 10 g of the mixture was further purified and separated by SFC to afford 5.6 g of (5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one (compound 28e-S) and 2 g of (5S)-5-[(1R)-1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one (compound 28e-R). (Refer to Tetrahedron. 1997, 53, 6281-6294).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:22]=[C:23]([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1.[Br-].[K+]>C(#N)C1C=CC=CC=1.[Ni](Br)Br>[Br-:20].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[C:12]([P+:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]3[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=3)[CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Br[Ni]Br
Agent: [Br-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: c1ccc(P(c2ccccc2)c2cccc([P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of nickel (II) bromide (dry under vacuum for 2 h at 140° C.) (3.6 g, 16 mmol, 0.5 equiv) in benzonitrile (dry overnight on activated 4 A molecular sieves) (250 mL) was added triphenylphosphine (26.0 g, 49 mmol, 3 equiv). The solution was heated under reflux for 15 min and then cooled to room temperature. (3-bromophenyl)diphenylphosphine (2) (11.1 g, 32.5 mmol, 1.0 equiv) in benzonitrile (20 mL plus rinse 5 mL) was added to the solution. The resulting solution was heated under reflux for 4 h then cooled to room temperature. A 10% (w/w) aqueous solution of potassium bromide (250 mL) was added. The layers were separated, and the aqueous layer was washed two times with CH2Cl2 (250 mL). The organic layer was washed three times with water (100 mL) and dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. To the resulting solution was added hexane (750 mL) to precipitate the crude product. The precipitate was filtered and washed with hexane and then dissolved in CH2Cl2 (20 mL). Et2O (150 mL) was then added and the mixture was filtered. The resulting solid was purified by flash chromatography (MeOH/CH2Cl2, 0:100-10:90) to afford (3-diphenylphosphinophenyl)triphenylphosphonium bromide (3) (>95% purity) as a white solid (15.3 g, 78%), which was characterized as follows:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[N:17]([CH2:36][CH2:37][C:38]4[S:39][CH:40]=[CH:41][CH:42]=4)[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reactant: c1ccc(CCN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1ccc(CCN2CCC(Nc3nc4ccccc4n3CCc3cccs3)CC2)cc1
Yield: 23.2 %

Procedure:
A mixture of 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.9 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 1 part of sodium carbonate and 135 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone, yielding 1 part (23.2%) of N-[1-(2-phenylethyl)-4-piperidinyl]-1-[2-(2-thienyl)ethyl]-1H-benzimidazol-2-amine; mp. 118.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.[Ni]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1

Procedure:
92 g (0.408 mol) of 5-chloro-3-trifluoromethyl-nitrobenzene in 1 l of methanol are hydrogenated in the presence of 10.17 g of Raney nickel. The reaction mixture is filtered through Celite/activated carbon and the residue washed with methanol. Concentration of the filtrate by evaporation yields the oily 5-amino-3-chloro-benzotrifluoride; 1H-NMR (DMSO-d6) δ6.80 (m, 3H), 5.92 (s, H2N).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:23][NH2:24]>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH:24][CH3:23])=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CN
Solvent: O
Product: CNC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A mixture of 500 mg of [4(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester [Example 1b)] and 2 ml of methylamine (about 8 M in ethanol) was stirred at 80° C. during 18 h. For the working-up, the solution was cooled to room temperature and treated with water. The pure product precipitated and was collected on a filter funnel. After drying there were obtained 398 mg (86% of theory) of 2-[4-(4-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17]C[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=[C:21](C4C=C(F)C=C(N5CCN6C7CCCCC=7C=C6C5=O)C=4COC(=O)C)[N:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=C2C(=CC=1)CN(C(OC(C)(C)C)=O)C2.[Br:70]C1C(=O)N(C)C=C(Br)N=1>>[Br:70][C:21]1[N:20]=[C:19]([NH:18][C:13]2[CH:12]=[C:11]3[C:10](=[CH:15][CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]3)[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)c1=O

Procedure:
Following the procedures as described for 129a and starting with 600 mg of tert-butyl 5-aminoisoindoline-2-carboxylate (231c) and 685 mg of 3,5-dibromo-1-methylpyrazin-2(1H)-one, 231d was obtained as a yellow solid (732 mg, 68%). MS: [M+H]+ 421.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[CH:9]([S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Br
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Sc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
A mixture of 4-mercaptopyridine (7 g, 63 mmol), 2-bromopropane (7.0 ml, 75.6 mmol), and potassium carbonate (10.2 g, 73.7 mmol) was stirred at room temperature for 6 hours and left overnight. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (i-hexane:ethyl acetate) to give the title product (7.4 g, 63%). The hydrochloride salt was prepared by treatment of the title compound with ethereal HCl.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[Cl-].[CH:14](=[N+:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][N:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11])[CH3:23]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [C:1]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O.NN>C(O)CO>[CH2:1]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCCc1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 2-butyrylfluorene (11.3 g.), powdered potassium hydroxide (4.16 g.) and 100% hydrazine hydrate (9 ml.) in ethylene glycol (104 ml.) was refluxed for 1 hour with stirring. The mixture was then slowly distilled until the boiling-point reached 185° and then heated to reflux for 3 hours. The cooled mixture was treated with water (ca. 300 ml.) and the product was isolated with ether in the usual manner. Recrystallisation from methanol gave 2-butylfluorene, m.p. 65°-66.5°.
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:7][C@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1)[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([N:7]1[C@@H:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C@H:6]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CC[C@H](CC)N1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@H](CC)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of ethyl (5S)-5-ethyl-L-prolinate (2.5 mmol), 2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.00 g, 3.13 mmol) and N-(tert-butoxycarbonyl)-L-leucine hydrate (0.779 g, 3.12 mmol) were mixed in 4 mL of dimethylformamide. Triethylamine (approx 1.1 mL) was added until the pH reached about 6 (wet pH paper). After stirring for 16 hours, the mixture was concentrated under reduced pressure and the residue partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with saturated NaHCO3, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash chromatography (30% to 50% ethyl acetate/hexane) to provide the titled compound. MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:2].S(C)C.CO>C1COCC1>[NH2:2][CH2:1][CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: Cc1cccc([C@H](OCC#N)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cccc([C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C

Procedure:
(R)-tert-Butyl 3-((R)-(cyanomethoxy)(m-tolyl)methyl)piperidine-1-carboxylate (20 g, 0.04 mol) was dissolved in anhydrous THF (300 mL), and the solution was heated to reflux under nitrogen. A solution of BH3.Me2S (12 mL, 0.12 mol) in THF was added dropwise, and stirring was continued under reflux overnight. The resulting solution was cooled to rt and MeOH was added dropwise to quench the excess borane. After evaporation of the solution, the crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(m-tolyl)methyl)piperidine-1-carboxylate was obtained and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:44])[C@H:16]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2C(OC(C)(C)C)=O)=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][C@@H:27]([C:25]([NH:24][C@H:16]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[O:44])=[O:26])[NH:28]1
Reactant: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl (3S)-3-(N-((1R)-2-[4-(2-methoxyphenyl)piperidyl]-2-oxo-1-benzylethyl]carbamoyl)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Step b) (1.4 g, 2.34 mmol) and 50% TFA in CH2Cl2 (80 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 10U % CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (0.5 g). MS (ESI, pos. ion) m/z: 498 (M+1). Calc'd for C31H35N3O3: 497.27.
Reaction SMILES: [CH2:1]([O:7][N:8]=[C:9]([C:15](=O)[CH2:16]Cl)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:19][C:20]([NH2:22])=[S:21].C(O)C>O>[NH2:22][C:20]1[S:21][CH:16]=[C:15]([C:9](=[N:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:19]=1
Reactant: NC(N)=S
Reactant: CCCCCCON=C(C(=O)CCl)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 49 %

Procedure:
Ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.), thiourea (15.2 g.), sodium acetate 3-hydrate (27.2 g.), ethanol (280 ml.) and water (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer, 29.3 g.), mp 77° to 78° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:23]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[N:7][CH:6]=[CH:5]2.C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23]
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Temperature: 90 °C
Reaction time: 5 h
Yield: 30.9 %

Procedure:
6-Methyl-5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinoline-1-amine (1.49 g, 4.29 mmol) obtained in Step (1) above was stirred in a solvent of ethanol (10 mL). The reaction solution was added with tin chloride (II) dihydrate (4.06 g, 21.46 mmol), and stirred for about 5 hours at 90° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.42 g, 31%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>CC#N>[Br-:23].[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: BrCC1OCCO1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CC3OCCO3)(CC1)CC2
Product: [Br-]
Yield: 12.4 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0574 g, 0.196 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.040 mL, 0.386 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0112 g, 12.4%). EI-MS m/z 380(M+) Rt (1.64 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15].I[C:17]1[CH:18]=[C:19]([C:23]2[C:28]3[S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:21]1[CH:22]=[CH:17][CH:18]=[C:19]([C:23]2[C:28]3[S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH:20]=1
Reactant: Brc1ccccc1Nc1ccccc1Br
Reactant: Ic1cccc(-c2cccc3c2sc2ccccc23)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1ccccc1N(c1cccc(-c2cccc3c2sc2ccccc23)c1)c1ccccc1Br
Temperature: 200 °C
Yield: 46.9 %

Procedure:
Bis(2-bromophenyl)amine (7.15 g, 21.86 mmol), 4-(3-iodophenyl)dibenzo[b,d]thiophene (9.29 g, 24.05 mmol), copper (0.695 g, 10.93 mmol), and K2CO3 (6.04 g, 43.7 mmol) were added into a 50 mL flask. The neat solids were heated at 200° C. for 36 hours. The mixture was then cooled. DCM (250 mL) was added to solubilize the organic products. The solution was filtered through a pad of Celite® and washed several times with DCM. The crude material was purified via column chromatography using hexane/DCM (85/15). The product collected from the column was triturated with methanol and filtered to afford 2-bromo-N-(2-bromophenyl)-N-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)aniline (6.0 g, 10.25 mmol, 46.9% yield) as a yellowish powder.