Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:12]Br.Cl>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[Br:12][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[N:9][CH:8]=1
Reactant: Clc1cccc2ccncc12
Reactant: BrBr
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: Clc1cccc2c(Br)cncc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 8-chloroisoquinoline (1.0 g, 6.1 mmol) in nitrobenzene (20 mL) at 180° C. was added bromine (0.35 mL, 6.7 mmol) over 10 min. Heating and stirring were continued for 2 hours. The mixture was allowed to cool to about 80° C., then 2M HCl in Et2O (5 mL) was added, followed by Et2O (5 mL) and hexanes (60 mL). The resulting slurry was filtered, washed with hexane and dried. The collected solid was dissolved in water, then the solution was adjusted to pH 9 with Na2CO3 (aq). The solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 9.62 (s, 1H); 8.83 (s, 1H); 8.13 (t, J=5.0 Hz, 1H); 7.74 (d, J=5.0 Hz, 2H). LC6: 4.08 min, (M+H): 242.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15]3)=[CH:3][CH:2]=1.[C:25]1([NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:32][C:22]([C:18]1[C:19]2[C:14](=[CH:13][C:12]([O:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1)=[O:24]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Yield: 87.8 %

Procedure:
The title compound (35.6 mg, 88% yield) was prepared as a brown solid from 6-(quinolin-4-yloxy)-1-naphthoic acid (31.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.3 Hz, 1H, Ar—H), 6.75 (d, J=5.1 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 7.00 (t, J=7.1 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.59 (dd, J=2.3 and 9.2 Hz, 1H, Ar—H), 7.64-7.71 (m, 2H, Ar—H), 7.83-7.92 (m, 3H, Ar—H), 8.08 (d, J=8.4 Hz, 2H, Ar—H), 8.37 (d, J=7.9 Hz, 1H, Ar—H), 8.45 (d, J=9.2 Hz, 1H, Ar—H), 8.73 (d, J=5.1 Hz, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 406 (M+1).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]3)[C:15]2=O)=[CH:11][CH:10]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:8][C:9]1[CH:17]=[C:16]2[C:12](=[CH:11][CH:10]=1)[CH2:13][C:14]1([CH2:19][CH2:20][CH:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]1)[C:15]2=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: O=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
Titanium ethoxide (2.03 mL, 9.85 mmol), 2-methyl-2-propanesulfinamide (0.895 g, 7.39 mmol) and 6′-bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 78, 1.71 g, 4.93 mmol) in dry 2-Me THF (30 mL) were heated to 100° C. to give an azeotrope at 74° C. The azeotropic distillation was continued for 5 h and then the mixture was refluxed for 2 days. The mixture was cooled to r.t. Water (10 mL) and EtOAc (20 mL) were added, under continuous stirring, while a solid formed. The reaction mixture was stirred at r.t. for 2 h, and then the formed solid was left to sediment for 1 h. The mixture was filtered, and the solid was washed with EtOAc. The filtrate was concentrated in vacuo to give a residue that was purified by flash chromatography (eluent heptane/EtOAc 65/35) to give the title compound (400 mg, 18% yield): 1 H NMR (400 MHz, CDCl3) δ ppm 1.34-1.37 (m, 9 H) 1.56 (s, 4 H) 1.73-1.82 (m, 2 H) 2.13 (br. s., 5 H) 2.89 (d, 2 H) 7.22 (d, 1 H) 7.60 (dd, 1 H) 8.53 (d, 1 H); MS (ES+) 451 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17]>ClCCl>[C:2](=[O:3])([O:17][CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC(C)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)COC(=O)OC(C)Cl
Temperature: 0 °C

Procedure:
In 70 ml of dichloromethane are dissolved 13 ml of 2-methyl-1-butanol and 17 g of 1-chloroethyl chloroformate, and the solution is cooled to 0° C. With stirring, a solution of 9.6 ml of pyridine in 30 ml of dichloromethane is added dropwise, and the mixture is stirred for 30 minutes. The salt precipitate is collected by filtration and the filtrate is washed with two 200-ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is further distilled under reduced pressure to give 12.5 g of 1-chloroethyl 2-methylbutyl carbonate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[C:11]C(C)(O)C)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+]>C1(C)C=CC=CC=1>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)#[CH:11]
Reactant: CC(C)(O)C#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1ccc2[nH]ccc2c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(1H-indol-5-yl)-2-methyl-but-3-yn-2-ol (6.6 g, 33.1 mmol), sodiumhydride, 60% in mineral oil (0.13 g, 3.3 mmol) and anhydrous toluene (100 ml) was stirred for 5 hours at 110° C. The crude mixture was evaporated. Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. Yield 3.44 g (74%). Oil.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([C:17]([CH3:19])=[O:18])[CH3:16]>>[OH:18][C:17]([C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][CH:11]=[N:12]3)[N:1]=1)([CH3:19])[CH2:15][CH3:16]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CCC(C)=O
Product: CCC(C)(O)c1ccc2ccc3cccnc3c2n1

Procedure:
The process if claim 1 wherein methyl ethyl ketone is coupled with 1,10-phenanthroline to provide 2-[(1-hydroxy-1-methylpropyl)]-1,10-phenanthroline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:31](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:31][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CN5CCC(O)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN5CCC(O)CC5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 94.1 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]piperid-4-ol is prepared as described in Example 179a starting with 0.045 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]piperid-4-ol instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.44 cm3 of 5N potassium hydroxide. 0.031 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]piperid-4-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: C=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=O)[CH2:8]3)[CH2:5][CH2:4]1.[CH3:24]OC(OC)(C)C.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:22][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][CH2:4][C:3]2=[CH2:2])[CH:11]=1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: C=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Refer to FIG. 190. To 17-methylenandrost-4-en-3-one (9, 2.0000 g, 7.0314 mmol) in 2,2-dimethoxypropane (9.4 ml, 76 mmol) and DMF (9.4 ml) were added 0.37 ml of anh. methanol and 47.0 mg of p-toluenesulfonic acid. After refluxing 4 h the reaction mixture was allowed to cool and then partitioned between 140 ml of hexanes and 90 ml of water. The organic phase was washed with two 90 ml portions of water+90 ml of brine, dried over magnesium sulfate, and flash filtered through a 30 mm dia.×37 mm high column of silica gel (200-400 mesh). Product continued eluting with 200 ml of hexanes. Concentration of the combined filtrates under reduced pressure and recrystallization of the residue from acetone/methanol gave very slightly yellow platelets (1.5291 g, 5.1231 mmol, 73%), m.p. 97-99° C., homogeneous to TLC (25% ethyl acetate/hexanes on silica gel, Rf 0.72).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)cc(Oc2ccccc2)c1
Yield: 6.8 %

Procedure:
Methyl 3,5-dihydroxybenzoate (20 g., 0.12 mole, 1 eq), phenylboronic acid (30 g., 0.25 mole, 2.1 eq.), Copper II acetate (45 g., 0.25 mmole, 2.1 eq.), TEA (90 mL, 0.65 mmole, 5.4 eq.) in dichloromethane (200 mL) and 4 Angstrom molecular sieves (35 g) were stirred at ambient temperature for 24 h under nitrogen gas. The reaction mixture was filtered through silica gel 60 to remove copper acetate to give 8.8 g (30% yield) of crude product. Flash chromatography gave product at 40% ethyl acetate in an ethyl acetate/hexane system. The product is an off-white solid (2.0 g, 7% yield). 1H NMR (400 MHz, chloroform-d3) δ ppm 9.64 (s, 1H), 7.43 (m, 2H), 7.28 (s, 1H), 7.31 (s, 1H), 7.11-7.06 (m, 3H), 6.81 (s, 1H), 3.79s (s, 3H); Calc'd for C14H12O4; m/z (M+H+)=245; found 245.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: C1CNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following Example 156e, 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (1.76 g, 8 mmol), azetidine (550 mg, 9.6 mmol), di-isopropylethylamine (1.75 mL, 10 mmol) and methylene chloride (40 mL) were stirred at room temperature for 3-5 h. Work-up and concentrated under reduced pressure to afford 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole 200a (quant.) as yellow oil, which was used without further purification for the next step. MS (ESI+) m/z 197.1 (M+H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O>C(Cl)Cl>[C:2](=[O:9])([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccn1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Sc1ccccn1)c1ccncc1
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
Following a general procedure (Rao et al., J. Org. Chem. 2000, 65: 1084), to a suspension of isonicotinoyl chloride hydrochloride (4.45 g, 25.0 mmol) in CH2Cl2 (50 mL) was added triethylamine (7 mL, 50 mmol). The mixture was stirred for 5 min under argon. To the resulting solution was added 2-mercaptopyridine (2.77 g, 25.0 mmol) in portions over 5 min with stirring. After 1 h, water was added and the layers were separated. The organic layer was washed (2 N NaOH, then water), dried (Na2SO4) and concentrated to dryness. The solid residue was recrystallized from ethyl acetate/hexanes to afford brown crystals (4.21 g, 77%): mp 115° C.; 1H NMR δ 7.34-7.38 (m, 1H), 7.69-7.38 (m, 4H), 8.69 (m, 1H), 8.83 (m, 2H); 13C NMR δ 120.5, 124.2, 130.8, 137.5, 142.8, 150.1, 150.8, 151.1; HRMS (FAB) obsd 217.0426, calcd 217.0436 (M++H, C11H9N2OS). Anal. Calcd for C11H8N2OS: C, 61.09; H, 3.73; N, 12.95. Found: C, 60.97; H, 3.72; N, 12.95.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[CH:19][N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[CH:19][N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1ccccc1
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.23 g, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.93 mL, 0.93 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1 N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dicloromethane (two times). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the desired compound (0.13 g, 62%). LCMS calculated for C14H14N3OS (M+H)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:20]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (0.5 g) is added portionwise to a stirred suspension of sodium hydride (90 mg, 60% dispersion in mineral oil) in dry DMF (100 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2-chloro-6-fluorophenyl)butanoate (0.62 g) is added in one portion and the reaction stirred for 48 hours at 90° C. The reaction mixture is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-chloro-6-fluorophenyl)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)butanoate (360 mg) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][NH:26]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]2[CH2:29][CH:24]1[CH2:25][N:26]2[CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 401.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]([O-])(=O)=O.[K+].[I-].[K+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[I:12][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: O
Product: Nc1ncc(C(F)(F)F)cc1I
Temperature: 100 °C
Yield: 227.9 %

Procedure:
A mixture of 5-trifluoromethyl-pyridin-2-ylamine (32.4 g, 0.2 mol) and potassium iodate (17.12 g, 0.08 mol) in 2M sulfuric acid (400 mL) was heated at 100° C. and a solution of potassium iodide (33.2 g, 0.2 mol) in water (83 mL) was added dropwise over 1 h. The resulting mixture was heated to reflux for 12 h. After being cooled to room temperature, the mixture was adjusted to pH 7 with careful addition of solid sodium bicarbonate. The mixture was extracted with dichloromethane, washed with a saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-iodo-5-trifluoromethyl-pyridin-2-ylamine (52.5 g, 91%) as yellow solid: LC/MS m/e calcd for C4H3IN2 [M+H]+ 289.01, observed 288.8.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:10]O>C1C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[CH2:5][CH2:6][O:7][CH:8]1[CH:9]([CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: OCCNCCO
Reactant: CCCC(C)CO
Solvent: c1ccccc1
Product: CCCC(C)C1OCCN1CCO
Yield: 104.9 %

Procedure:
A one-liter three-necked flask was charged with 100.1 g diethanol amine and 100 ml benzene, followed by addition in droplets of 100.2 g 2-methylpentanol. The flask was then immersed in an oil bath, and the reaction admixture was allowed to react for 8 hours under reflux condition. Benzene was removed from the admixture thereby providing 187 g N-hydroxyethyl-2-(1-methylbutyl)-1,3-oxazolidine. 100 g of the resulting 2-(1-methylbutyl)-3-oxazolidine ethanol were mixed at room temperature with 51.5 g xylylene diisocyanate and allowed to react at 50° C. for one hour and at 80° C. for 8 hours. The yield was 151 g.
Reaction SMILES: [CH2:1]1[O:24][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=4)=[N:11][NH:10][C:9](=[O:22])[CH2:8][C:7]=3[CH:23]=[C:3]2[O:2]1.O.NN.Cl>C(O)C.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:24][CH2:1][O:2][C:3]4=[CH:23][C:7]=3[CH2:8][C:9](=[O:22])[NH:10][N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Cc2cc3c(cc2C(c2cccc([N+](=O)[O-])c2)=NN1)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(3-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (20 mg, 0.061 mmol) in ethanol (5 ml,) was added Raney Ni (54 mg), hydrazine hydrate (40 μL, 0.71 mmol), and 2N HCl (60 μL, 0.12 mmol). The mixture was stirred at room temperature for 24 h. The solid Ni was filtered out. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (10:1 CHCl3 /EtOH) to afford the title compound as a tan solid (6 mg, 33%), mp: 118°-122° C. 1H NMR (CDCl3) 8.33 (s, 1H), 7.22-7.17 (m, 1H), 6.94 (s, 1H), 6.94-6.88 (m, 1H), 6.81 (s, 1H), 6.79-6.75 (m, 1H), 6.67 (s, 1H), 6.03 (s, 2H), 3.74 (brs, 2H), 3.44 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:23]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1)=O.C(O)=O.[CH:32]([NH2:34])=O>>[N:10]1([C:8]([C:6]2[CH:7]=[C:2]3[C:3]([C:17]([C:19]4[N:23]5[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[N:34][CH:32]=[N:1]3)=[CH:4][CH:5]=2)=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cc(C(=O)N2CCCCCC2)ccc1C(=O)c1cnc2ccc(F)cn12
Reactant: NC=O
Solvent: O=CO
Product: O=C(c1ccc2c(-c3cnc4ccc(F)cn34)ncnc2c1)N1CCCCCC1
Temperature: 170 °C

Procedure:
A solution of example 30 (50 mg) in a mixture of formic acid (160 μL, 32 equiv.) and formamide (640 μL, 122 equiv.), under argon atmosphere, was heated through microwave irradiation for 25 min at 170° C.
Reaction SMILES: [Cl-:1].C([O:9][C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]([O:18][CH2:19][N:20]1[CH2:24][NH+:23]([CH2:25][C@@:26]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=2[F:54])([OH:46])[C@H:27]([N:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH:44]=[N:43][N:42]=[N:41]4)=[CH:36][CH:35]=3)[C:30]2=[O:45])[CH3:28])[N:22]=[CH:21]1)=[O:17])=[O:11])C1C=CC=CC=1.Cl>CO.[C].[Pd]>[Cl-:1].[F:54][C:48]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:47]=1[C@:26]([OH:46])([C@H:27]([N:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([N:40]3[CH:44]=[N:43][N:42]=[N:41]3)=[CH:38][CH:39]=2)[C:30]1=[O:45])[CH3:28])[CH2:25][NH+:23]1[CH2:24][N:20]([CH2:19][O:18][C:16]([O:15][CH2:14][CH2:13][CH2:12][C:10]([OH:11])=[O:9])=[O:17])[CH:21]=[N:22]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCCCC(=O)OCc2ccccc2)C=N1)c1ccc(F)cc1F
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCCCC(=O)O)C=N1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
4-[(3-Benzyloxycarbonylpropoxy)carbonyloxymethyl]-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (Compound 29, 155 mg) was dissolved in methanol (6 ml). To the solution were added 1N hydrochloric acid solution (0.2 ml) and 10% palladium-carbon (50% wet, 77 mg). The mixture was stirred for 0.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and to the filtrate was added distilled water. The mixture was concentrated under reduced pressure, and the concentrate was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(3-carboxypropoxy)carbonyloxymethyl]-1H-1,2,4-triazolium chloride (Compound 33, 122 mg) as a white powder.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])=[O:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 146.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (155 mg, 0.53 mmol, 1.0 eq), L-norvaline N-benzylamide (220 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 372 mg (70%) of L-norvaline, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.