Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C:5]1([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:14](=[O:16])[O-:15])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)(C)C.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][CH:5]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:27]([O:26][CH3:25])=[O:28])[CH:30]=3)=[CH:20][CH:19]=2)[C:14]([O:15][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:16])[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)CCC(N(Cc2ccc(Br)cc2)C(=O)[O-])(C(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cccc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCC(C)(C)CC3)cc2)c1

Procedure:
A flask equipped with a septum-sealed reflux condenser was charged with 1,1-dimethylethyl[(4-bromophenyl)methyl](4,4-dimethylcyclohexyl)carbamate (0.988 g; 2.49 mmol; Example V-11), {3-[(methyloxy)carbonyl]phenyl}boronic acid (0.493 g; 2.74 mmol), Pd(OAc)2 (0.0028 g; 0.012 mmol) and 2-(2′,6′-dimethoxybiphenyl)di-cyclohexylphosphine (S-Phos; 0.010 g; 0.025 mmol) was evacuated and back-filled with N2 several times. PhMe/EtOH (4:1 v/v, 7.5 mL), and 2M Na2CO3 were added via syringe through the condenser's septum and the mixture was heated under reflux for 2 h (until consumption of the aryl bromide was observed). Upon cooling, the mixture was poured into EtOAc/water, the whole was filtered through a 0.45 μm PTFE membrane filter and the layers were separated. The aqueous layer was extracted with EtOAc, combined organics were washed (brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum/syrup. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (s, 6H), 1.07-1.79 (m, 18H), 3.89 (s, 3H), 4.42 (br. s., 2H), 7.36 (d, J=8.03 Hz, 2H), 7.62 (t, J=7.85 Hz, 1H), 7.67 (d, J=8.03 Hz, 2H), 7.95 (t, J=6.96 Hz, 2H), 8.18 (s, 1H).
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:27]([OH:29])=O)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[B-](F)(F)(F)F.CN(C([O:42][N:43]1C(=O)C=CC=C1)=[N+](C)C)C.C(N(C(C)C)C(C)C)C.ClCCl.N1CCCCC1>ClCCl.CC(N(C)C)=O>[NH2:18][C@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]([NH:43][OH:42])=[O:29]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: N[C@H](Cc1ccccc1)C(=O)NO
Reaction time: 0.08 h

Procedure:
To a solution of N-(9-fluorenylmethoxycarbonyl)-D-phenylalanine (2.09 g, 5.4 mmol) in dry dichloromethane/DMA 1:1 (20 ml) are added TPTU (1.76 g, 5.94 mmol) and N-ethyldiiso-propylamine (1.02 ml, 5.94 mmol). After stirring for 5 min the mixture is added to aminooxy-2-chlorotrityl polystyrene resin (2.8 g, 2.7 mmol; Tetrahedron Lett. 1997, 38, 3311–3314) and the resulting suspension shaken at r.t. for 16 h. The mixture is filtered and the resin washed alternating with DMA and dichloromethane (3×). The described coupling procedure is repeated with a freshly prepared mixture of N-(9-fluorenylmethoxycarbonyl)-D-phenylalanine (2.09 g, 5.4 mmol), TPTU (1.76 g, 5.94 mmol) and N-ethyldiisopropylamine (1.02 ml, 5.94 mmol) in dichloromethane/DMA 1:1 (20 ml). After 16 h the suspension is filtered and the resin washed with DMA (2×), alternating with H2O and DMA (2×), alternating with 2-propanol and THF (3×), THF (2×) and dichloromethane (3×). The resin thus obtained is shaken for 30 min with a freshly prepared solution of dichloromethane/piperidine 8:2 (25 ml). After filtration, this process is repeated twice with fresh dichloromethane/piperidine solutions. The suspension is filtered, the resin washed with dichloromethane (2×), alternating with 2-propanol and dichloromethane (2×), dichloromethane (3×) and dried in vacuo, thus providing polymer-bound (R)-2-amino-N-hydroxy-3-phenyl-propionamide.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OCCCC)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:35]1[CH:36]=[N:37]C(Br)=[N:39][CH:40]=1)[CH3:34]>>[CH2:33]([C:35]1[CH:36]=[N:37][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:31]=[CH:32][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)=[N:13][CH:14]=3)[CH2:23][CH2:22]2)=[N:39][CH:40]=1)[CH3:34]
Reactant: CCCCOC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Reactant: CCc1cnc(Br)nc1
Product: CCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tort-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (26 mg, 0.06 mmol) and 5-ethyl-2-bromopyrimidine (14 μL, 0.12 mmol) following a procedure analogous to that in Example 48 as a white crystal (10 mg, yield 38%).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH3:13]>C(O)C>[CH3:13][C:12]1[N:9]=[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8][CH:11]=1
Reactant: NC(=S)c1cccnc1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc(-c2cccnc2)n1
Reaction time: 48 h
Yield: 12.9 %

Procedure:
(See FIG. 10.) To a solution/slurry of thionicotinamide (3.3 g, 23.9 mmol) in ethanol (100 mL) is added chloroacetone (2.28 mL, 28.7 mmol) and the resultant slurry is heated to reflux and stirred for 48 h. The solvent was removed in vacuo and the crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.34) to afford the title compound 26 (543 mg, 13% yield) as a brown solid: mp=42-43° C.; 1H NMR (CDCl3) δ 9.09 (m, 1H), 8.57 (m, 1H), 8.15 (m, 1H), 7.31 (m, 1H), 6.89 (m, 1H), 2.47 (s, 3E1); LRMS (ESI) calcd for C9H8N2S [M+H]+ 177. found 177.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[N:20]1([CH2:26][CH2:27][O:28][C:29]2[C:37]([CH3:38])=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=2[CH3:39])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:33]([C:32]2[CH:36]=[C:37]([CH3:38])[C:29]([O:28][CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:30]([CH3:39])[CH:31]=2)=[O:34])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: Cc1cc(C(=O)O)cc(C)c1OCCN1CCCCC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(C)c(OCCN3CCCCC3)c(C)c2)cc1

Procedure:
2.9 g of the title compound was prepared from 2 g of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and 4-[2-(1-piperidinyl)ethoxy]-3,5,-dimethylbenzoic acid in a manner similar to that used in Preparation 15.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[N:6][C:7]=1[CH3:8].N1C=CC=CC=1.[CH3:21][C:22]1[C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[C:25]([CH3:39])[O:24][N:23]=1>ClCCl>[CH3:21][C:22]1[C:26]([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]3[C:7]([CH3:8])=[N:6][C:5]([N:9]4[CH2:13][CH2:12][O:11][C:10]4=[O:14])=[CH:4][CH:3]=3)(=[O:37])=[O:36])=[CH:33][CH:34]=2)=[C:25]([CH3:39])[O:24][N:23]=1
Reactant: Cc1nc(N2CCOC2=O)ccc1N
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CCOC2=O)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 72.2 %

Procedure:
To a solution of 3-(5-amino-6-methyl-2-pyridinyl)-1,3-oxazolidin-2-one (80 mg, 0.414 mmol) in dichloromethane (3 mL) and pyridine (0.033 mL, 0.414 mmol) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (125 mg, 0.414 mmol). The reaction vessel was sealed and heated at 65° C. for 6 hours. The reaction mixture was then allowed to cool and separated between dichloromethane (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic phase was separated using a hydrophobic frit and evaporated in vacuo. The crude was then purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (137 mg) as a colourless glassy solid. LCMS (2 min, formic) Rt 0.92 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:20]([OH:39])[C@:21]4([OH:38])[C:29](=[O:30])[C:28]([C:31]([NH2:33])=[O:32])=[C:27]([OH:34])[C@@H:26]([N:35]([CH3:37])[CH3:36])[C@@H:22]4[CH2:23]3)[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16])=[O:8])([CH3:4])[CH3:3].[ClH:43]>C(#N)C>[CH3:4][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:17]([OH:18])[C:14]=2[C:15]=1[OH:16])[C:20](=[O:39])[C@@:21]1([OH:38])[C@H:22]([C@H:26]([N:35]([CH3:36])[CH3:37])[C:27]([C:28]([C:31]([NH2:33])=[O:32])=[C:29]1[OH:30])=[O:34])[CH2:23]3)=[O:8])([CH3:1])[CH3:3].[ClH:43]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CC#N
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Reaction time: 20 h

Procedure:
A suspension of Tigecycline was prepared by mixing a solid Tigecycline sample and acetonitrile in amounts as shown in Table A. The mixture was than stirred for 1 hour at room temperature before 5 N hydrochloric acid was added in amounts corresponding to Table A. After stirring for about 20 hours the solid was filtered off and dried at room temperature under vacuum to obtain crystalline form A of Tigecycline hydrochloride.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]1([N:6]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[C:14]([Cl:13])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1csc(CNC2CCCC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N(Cc1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 147.5 %

Procedure:
To a solution of 5.0 g (27.58 mmol) of cyclopentylthiophen-2-ylmethylamine in 40 ml of methylene chloride at 10° C. was added slowly with stirring 4.09 g (13.79 mmol) of triphosgene in 35 ml of methylene chloride. The reaction was allowed to continue stirring at room temperature for 64 hours, refluxed for 4 hours and 25 hours more at room temperature. The solvent was evaporated and the residue extracted with n-hexane. The organic solution was concentrated to yield 4.96 g (20.34 mmol) of a brown oil (74%). 1H-NMR (CDCl3):δ 1,4 (m, 8H), 4,2 (bs, 1H), 4,5 (m, 2H), 6,8–7,3 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:24](OC)[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C>[CH2:12]([O:11][CH2:10][C@@H:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:24]=[CH:25][N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)=[CH:32][CH:33]=2)[C:19]1=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CN(Cc2ccc(-n3ccnc3)cc2)C(=O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of N-tert-butoxycarbonyl-O-benzyl-L-serine (1.48 g) and 2,2-dimethoxyethyl[4-(1H-imidazol-1-yl)benzyl]amine (1.31 g) in acetonitrile (50 ml) were added HOBt (842 mg) and WSC hydrochloride (1.05 g), under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the mixture was added N, N-dimethylaminopyridine (catalytic amount), and the mixture was stirred overnight. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate methanol=20:1). To the obtained product were added p-toluene sulfonic acid (856 mg) and toluene (60 ml), and the mixture was refluxed for 30 minutes and cooled. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1) to give amorphous of the title compound (1.14 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[OH-].[Na+].[N:36]1([CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH:40]=[CH:39][N:38]=[N:37]1>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:1][C:48]3[CH:47]=[CH:46][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][N:36]4[CH:40]=[CH:39][N:38]=[N:37]4)=[CH:50][CH:49]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
The obtained 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (567 g, 2.11 mol) and diisopropylethylamine (340 g, 2.63 mol) were added to THF (3.4 L). A solution of methanesulfonyl chloride (302 g, 2.63 mol) in THF (567 ml) was added dropwise under ice-cooling. The mixture was stirred at the same temperature for 1 hour and diisopropylethylamine (27.3 g, 0.21 mol), methanesulfonyl chloride (24.2 g, 0.21 mol) and THF (57 ml) solution were added. The mixture was stirred under reflux for 1.5 hours. After allowing to cool to room temperature, 15% aqueous sodium hydroxide (1.96 kg, 7.35 mol) was added dropwise. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (503 g, 2.32 mol) and tetra(n-butyl) ammonium bromide (68.0 g, 0.21 mol) were added at the same temperature, and the mixture was refluxed for 4 hours under stirring. Water (3.1 L) and methanol (7.4 L) were added dropwise at the same temperature. After allowing to cool to room temperature, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with THF/methanol/water (1:1:2) (2.8 L), water (2.8 L) and cold-methanol (2.8 L) and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (883 g, 1.88 mol, yield 85%).
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.[I-].[I-].[Sm+2].[CH2:18]([C:20]([CH3:22])=[O:21])[CH3:19]>O1CCCC1>[OH:21][C:20]([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)([CH3:22])[CH2:18][CH3:19]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CCC(C)=O
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CCC(C)(O)c1ccc2ccc3cccnc3c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
An embodiment of the process comprises mixing a stirred solution of 1,10-phenanthroline in tetrahydrofuran (THF) with a solution of the lanthanideII, samarium diiodide, in THF at a temperature of about 25° C. To the mixed solutions is added a solution of the ketone, methyl ethyl ketone, and the reaction mixture is stirred at about 25° C. for about 12 hours. The reaction is then quenched by the addition of a saturated aqueous solution of ammonium chloride and the mixture extracted with methylene chloride. The extract is washed with brine, dried and concentrated in vacao. The concentrate of product is purified by flash chromatography using alumina and ethyl acetate-hexanes as a gradient to provide racemic 2-[(1-hydroxy-1-methylpropyl)]-1,10-phenanthroline. (Formula 1, R=H, R1=ethyl, R2=methyl) This embodiment is depicted in the following reaction scheme wherein MEK is methyl ethyl ketone.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[O:12])[CH:7]=[C:8]([CH3:11])[NH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:12][CH2:20][CH2:21][OH:22])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1
Reactant: OCCBr
Reactant: COCOc1c[nH]c(C)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cnc(C)cc1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 5-(methoxymethoxy)-2-methylpyridin-4(1H)-on (1.28 g, 7.56 mmol) in N,N′-dimethylformamide (19 mL), potassium carbonate (2.10 g, 15.1 mmol) and 2-bromoethanol (804 μL, 11.3 mmol) were added sequentially, and the mixture was stirred at 90° C. overnight. After the reaction has terminated, the reaction solution was concentrated in vacuo. The obtained residue was dissolved in chloroform/methanol, the solids were filtered, and the filtrate was concentrated in vacuo. The obtained residue was purified by column chromatography (hexane/acetone) and 2-(5-(methoxymethoxy)-2-methylpyridin-4-yloxy)ethanol (900 mg, yield 56%) was obtained as an orange oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27].C(N(CC)CC)C>CS(C)=O>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@H](CN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN1CC[C@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 140 °C
Yield: 22 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.105 g), ((R)-1-ethylpyrrolidin-3-yl)methyl-amine (Intermediate 163, 0.5 g) and triethylamine (0.5 g) in DMSO (1 mL) was stirred and heated at 140° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatogrpahy on silica, eluting with a mixture of methanol and DCM (5%). The product was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid,
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:24]=2)(=[O:18])=[O:17])[CH:7]=1.[Li+].[OH-].CCCCCC.C(OCC)(=O)C.Cl>O1CCCC1>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH:24]=1)(=[O:17])=[O:18])[CH:7]=[C:6]2[CH2:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2cncc(-c3ccc(C(F)(F)F)cc3)c2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CCc1cn(S(=O)(=O)c2cncc(-c3ccc(C(F)(F)F)cc3)c2)c2ccc(Cl)cc12

Procedure:
The 3-{5-chloro-1-[5-(4-trifluoromethyl-phenyl)-pyridine-3-sulfonyl]-1H-indol-3-yl}-propionic acid methyl ester 13 (20 mg, 0.00038 mol) was dissolved in 4 mL mixture of tetrahydrofuran:1N LiOH (4:1) and stirred vigorously overnight. TLC (20% ethyl acetate hexane) indicated absence of starting material and a new spot. The reaction was acidified by adding 1N HCl (pH 0-1 by pH paper) and extracted with 12 mL of ethyl acetate, which was dried over MgSO4. A silica plate was carried out using 2% methanol/chloroform to isolate the desired compound. 1H NMR consistent with structure. MS(ESI) [M−H+]−=507.02 (calculated 508.90).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Br)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Brc1ccc2oc(Cc3ccccc3)cc2c1

Procedure:
A mixture of 42.2 g. (0.14 mol.) of 2-benzoyl-5-bromobenzofuran and 35 ml. of 98% hydrazine in 70 ml. of diethylene glycol is warmed for a few minutes on a steam bath. Then 23.3 g. of potassium hydroxide is added and the reaction mixture is refluxed for 2 hours. After cooling, water is added to the mixture and the resulting aqueous solution is extracted with benzene. The extract is washed with water, 10% aqueous hydrochloric acid and water, dried (MgSO4) and concentrated to yield 2-benzyl-5-bromobenzofuran.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=O)[C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[N:19][OH:20])[C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde (step B, 0.415 g, 1.721 mmol), hydroxylamine hydrochloride (0.179 g, 2.58 mmol), and sodium acetate (0.212 g, 2.58 mmol) in methanol (5 mL) was heated at reflux for 45 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water (10 mL), and the solid was collected by vacuum filtration, washed with water (2×5 mL), and dried overnight under reduced pressure to give 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde oxime (0.360 g, 1.41 mmol, 82% yield). The compound had an HPLC ret. time=2.43 min. (condition A); LC/MS M+1=256.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(O)(=O)C.O.[NH2:29][NH2:30].O>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:29][NH:30][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 15 grams 3,3-dibenzoyl-propionic acid ethyl ester and 3 grams glacial acetic acid in 90 milliliters ethanol was added at room temperature drop by drop a solution of 3.0 grams hydrazine hydrate in 10 milliliters ethanol followed by stirring at room temperature for 3 hours. The reaction mixture was then clarified by treatment with activiated carbon, and 150 milliliters water were added to the clear solution followed by cooling in an ice bath. The precipitate formed thereby was filtered off by suction, dried and taken up in 400 milliliters benzene. The benzene solution was extracted first with a saturated aqueous solution of sodium bicarbonate and thereafter with water. The benzene solution was dried and benzene distilled off. By the addition of about three times this volume of cyclohexane, a precipitate representing the ester reaction product was formed which was separated by filtration. 13.1 grams 3,5-diphenyl-1H-pyrazol-4-acetic acid-ethyl ester melting at 117°-118° C. were obtained, representing a yield of 86%.