Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH2:13][CH2:14][OH:15])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[OH:15][CH2:14][CH2:13][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][O:24]1
Reactant: C=Cc1ccc2c(c1CCO)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethenyl-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 5.9 mmol) was added to a flask containing a stir bar. To the flask was then added dichloromethane (20 mL). The flask was placed in a cool bath of 0° C.; to the flask was poured mCPBA (1.5 g, 8.8 mmol) and the resulting mixture was stirred at room temperature for overnight; LC as well as TLC (hexanes/EtOAc=1/1) indicated that reaction had gone to completion. The solution was treated with dichloromethane and washed with NaHCO3, Na2S2O3, and water, the organic layer was then dried over Na2SO4, filtered and concentrated to dryness, it was then treated with AcOH (20 mL) and stirred overnight; LC indicated formation of cyclized product. The solvent was removed and the resulting residue was absorbed onto silica gel and the title compound was isolated with the solvent system of hexanes/EtOAc (1/1).
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[C:5]3[CH2:6][CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: N#CN
Reactant: Nc1ccc2c(c1[N+](=O)[O-])CCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A mixture of 4-nitro-5-indanamine (3) (0.67 g, 3.8 mmol) and cyanamide (0.63 g, 15.0 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (5 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (3×5 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 4 (279 mg, 37%) as a yellow powder: mp (MeOH/DCM) 270-274° C.; 1H NMR [(CD3)2SO] δ 7.56 (d, J=8.4 Hz, 1H, H-6), 7.31 (d, J=8.4 Hz, 1H, H-5), 6.79 (br s, 2H, NH2), 3.55 (br t, J=7.5 Hz, 2H, H-9), 2.95 (br t, J=7.7 Hz, 2H, H-7), 2.09-2.20 (m, 2H, H-8); 13C NMR [(CD3)2SO] δ 159.4, 148.7, 140.9, 136.0, 131.6, 128.1, 123.9, 34.6, 32.1, 24.1. Anal. calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.5; H, 5.0; N, 27.7%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=1[NH2:11]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(O)c1N
Yield: 83 %

Procedure:
To a solution of 1.0 g (6.53 mmol) of 3-hydroxyanthranilic acid in 15 mL of methanol was added 5.0 mL of BF3 -methanol complex and the resulting solution was heated to reflux for 24 h. After cooling to room temperatue the reaction mixture was poured into saturated sodium carbonate solution and then extracted with ether. The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.90 g (83%) of the desired product as a brown solid. Electrospray Mass Spec: 167.8 (M+H)+
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:6])[CH2:2][CH3:3].[Mg]>CO.C(OCC)(=O)C>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[N:8]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6])[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)c1cc2cc(OC)ccc2n1Cc1ccccc1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(CCC)C(=O)C1Cc2cc(OC)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of 2-(di-n-propylaminocarbonyl)-5-methoxy-1-benzylindole (654 mg, 1.79 mmol) in 18 mL of methanol was added magnesium turnings (0.87 g, 36 mmol) at 0° C. After the reaction mixture was stirred for 12 h with slowly warming up to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with 1 M HCl, saturated NaHCO3 aqueous solution and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (405 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9].[CH3:17]O>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(CC(=O)O)cc(O)c1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(O)c([N+](=O)[O-])c(OC)c1

Procedure:
A solution of 3-hydroxy-5-methoxy-4-nitrophenylacetic acid (0.76 g, Reference Example 12) in methanol (100 mL) and concentrated hydrochloric acid (5 drops) was heated at reflux through 3A molecular sieve for 4 hours, then evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with dichloromethane, then with a mixture of methanol and dichloromethane (1:49, v/v) to give the title compound (0.34 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:16](=[O:17])[N:15]3[C:10]([C:11](=[O:18])[O:12][CH2:13][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=1.[NH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22]>C(#N)C>[OH:12][CH2:13][CH2:14][N:15]1[C:16](=[O:17])[C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=[C:10]1[C:11]([NH:19][C@@H:20]([CH3:23])[CH2:21][OH:22])=[O:18]
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Reactant: C[C@H](N)CO
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)CO)n(CCO)c2=O)cn1
Temperature: 85 °C

Procedure:
A mixture of 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (1.440 g, 5.872 mmol) and (2S)-2-aminopropan-1-ol (1.714 g, 22.82 mmol) in acetonitrile (3 mL) was heated to 85° C. for 20 minutes. The reaction mixture was then allowed to cool to room temperature and diluted with additional acetonitrile (10 mL). Filtration and rinsing with acetonitrile (10 mL) afforded the product as a white solid. Yield: 1.62 g, 5.06 mmol, 86%. 1H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J=6.8 Hz, 3H), 2.14 (d, J=0.9 Hz, 3H), 3.33-3.46 (m, 2H), 3.59-3.66 (m, 2H), 3.89-4.01 (m, 1H), 4.18-4.29 (m, 2H), 4.80 (t, J=5.8 Hz, 1H), 4.94 (t, J=5.4 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 7.32-7.34 (m, 1H), 7.69 (d, J=7.5 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 8.67 (br d, J=8.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[CH:4]=1.[F:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:26]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:26]=1[CH2:27][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12](=[O:22])(=[O:23])[N:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:16]1=[O:17]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: COc1cc(OC)nc(N2C(=O)Nc3ccccc3S2(=O)=O)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(N2C(=O)N(Cc3c(F)cc(OC)cc3F)c3ccccc3S2(=O)=O)c1
Yield: 3.3 %

Procedure:
The title compound was prepared from 2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA33) (101 mg, 0.3 mmol), 2,6-difluoro-4-methoxybenzyl bromide (85 mg, 0.36 mmol) and K2CO3 (124 mg, 0.9 mmol) in DMF (1.5 mL) using the methods of (115). After trituration with Et2O further purification by preparative HPLC (method C) yielded the title compound (7 mg, 0.01 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[BH4-].[Na+]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: Brc1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: Brc1cccc2c1CCNC2

Procedure:
In close analogy to the procedure described above, 5-Bromo-isoquinoline is reacted with sodium borohydride to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C@H:4]([N+:17]([O-])=O)[CH2:3]1.C(O)(=O)C>CO.[Zn]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:15])[F:16])[C@H:4]([NH2:17])[CH2:3]1
Reactant: CN1C[C@@H]([N+](=O)[O-])[C@H](c2ccccc2C(F)(F)F)C1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C[C@@H](N)[C@H](c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Racemic (3R,4S) and (3S,4R)-1-Methyl-3-nitro-4-(2-(trifluoromethyl)phenyl)-pyrrolidine (296.8 mg, 1.082 mmol) was dissolved in MeOH (5 mL) and Acetic Acid (5 mL) then zinc (354 mg, 5.41 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The suspension was filtered over celite and washed with methanol. The filtrate was concentrated in vacuo and the residue was suspended in ethyl acetate, cooled in an ice bath, and basified with conc. NH4OH. The organic phase was separated and washed with brine. The organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo to give racemic (3R,4S) and (3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-amine (230.9 mg, 0.945 mmol, 87%), which was carried onto the next step without further purification. MS ESI calc'd. For C12H15F3N2 [M+1]+ 245, found 245.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:20])[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Temperature: 25 °C

Procedure:
A solution of 2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole (0.800 g, 2.94 mmol) and sodium acetate (0.482 g, 5.88 mmol) in acetic acid (10 ml) is refluxed for 55 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (4 ml) and 5M potassium hydroxide (KOH) (15 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 0.582 g (78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2cnccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-pyrazinylbenzaldehyde (prepared as described in Reference Example 17) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([O:33][CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OC4CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 197. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.25 (dd, J=8.7, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 6.99 (d, J=10.2 Hz, 2H), 4.82 (dd, J=10.4, 3.7 Hz, 1H), 4.77-4.66 (m, 1H), 4.21 (ddd, J=49.1, 7.8, 2.9 Hz, 1H), 4.10-3.90 (m, 2H), 3.90-3.80 (m, 2H), 3.75 (s, 3H), 3.51 (ddd, J=12.0, 9.4, 2.8 Hz, 2H), 3.14-3.01 (m, 1H), 2.10-1.97 (m, 3H), 1.85-1.55 (m, 5H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C:22](=[O:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[O:33]1[C@H:16]2[CH2:15][C@H:14]3[C@:19]([CH3:20])([CH2:18][C@@H:17]12)[C@@H:21]1[C@H:11]([C@H:8]2[C@@:6]([CH2:23][C:22]1=[O:24])([CH3:7])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)[CH2:12][CH2:13]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
17β-Methoxycarbonyl-5α-androst-2-en-11-one (6.63 g.) and m-chloroperbenzoic acid (4.84 g.) were stirred with chloroform (115 ml.) for 16 hours. The solution was diluted with chloroform, washed with 2% aqueous potassium hydrogen carbonate, dried (MgSO4) and evaporated to a gum. Crystallisation from ethyl acetate/light petroleum afforded pure title compound. (1.64 g.) as colourless rods; m.p. 140°-145°; [α]D + 74.2°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:26].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:26])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: N
Reactant: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)NC1=S
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)N=C1N
Temperature: 100 °C
Yield: 30 %

Procedure:
6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (Example 49 Step 2), directly from the previous step was dissolved in dry DMF (4 mL) in a microwave vial. Ammonia, 7M in MeOH (18 mL, 126 mmol) was added. The vial was sealed and the reaction was heated at 100° C. for 60 min in a microwave reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 18 mL, 126 mmol) and heated at 120° C. for 30 min in a microwave reactor. This cycle was repeated three more times. After evaporation of the solvent, the remaining product was subjected to flash chromatography (0-7% of MeOH(NH3) in DCM) to give the title compound as a mixture of isomers (1.29 g, 30% yield over two steps): MS (ES+) m/z 406 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCBr
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(/C=C/c2nc3sccn3c2C(=O)OCC)cccc1OC(F)F
Yield: 100.2 %

Procedure:
Alkylation of Intermediate 6 (400 mg, 1.052 mmol) with 1-bromopentane (157 mg, 1.262 mmol) in presence of potassium carbonate (160 mg, 1.157 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A gave 475 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J=7.2 Hz, 3H), 1.30-1.40 (m, 5H), 1.44-1.52 (m, 2H), 1.72-1.78 (m, 2H), 3.93 (t, J=6.6 Hz, 2H), 4.40 (q, J=6.9 Hz, 2H), 7.19 (t, J=73.8 Hz, 1H), 7.21-7.30 (m, 2H), 7.43-7.49 (m, 1H), 7.53-7.58 (m, 1H), 7.77 (d, J=16.2 Hz, 1H), 7.86 (d, J=16.2 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 451.19 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CO.O.[Zn]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][C:22]5=[O:27])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:31]=1
Reactant: O=C1COCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5=O)cn4)sc23)c(F)c1
Yield: 51.4 %

Procedure:
To a suspension of 121 (135 mg, 0.281) in MeOH (10 mL) was added Zinc powder (184 mg, 2.81 mmol) and NH4Cl (60.1 mg, 1.124 mmol) in water (1 mL) and the reaction mixture was stirred at reflux for 5 hours then stirred at RT for 2 days. The mixture was filtered, concentrated, dissolved in DCM and MeOH and the resultant solution was then washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid 122 (65 mg, 51% yield) was used directly in the next step with no additional purification. MS (m/z)=451.49 (M+H)
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[I-:18].[Na+]>C(#N)C>[I:18][CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(CCC(=O)OCc1ccccc1)OCCl
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCC(=O)OCc1ccccc1)OCI

Procedure:
3-Benzyloxycarbonylpropionic acid chloromethyl ester (2 g, 1.38 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.6 g, 10.9 mmole) was added to the solution After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave internediate 3-benzyloxycarbonylpropionic acid iodomethyl ester in quantitative yield. This intermediate is bonded to an accessible function of a drag, such as a ring hydroxy or carboxy function using conventional alkylation/acylation conditions as described generally herein. Following deprotection of the terminal carboxy, a di/trifunctional linker bearing R2, such as 1,3-bis-O-(L-valyl)glycerol or iodomethyloxy-L-valyl is acylated/alkylated thereon or R2 amide bonded thereon by conventional techniques as described herein, such as with DCC coupling agent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:22])=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[Cl:22]
Reactant: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Temperature: 110 °C
Yield: 83.8 %

Procedure:
6-Bromo-2-(3-fluorophenyl)-quinolin-4-ol (5.2 g, 16.3 mmoles) was placed in a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water was cautiously added dropwise until all of the POCl3 was consumed. Material crystallised from the water and solids were collected by filtration. The solids were washed with water, placed in a 250 mL Erlenmeyer and triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the product was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15]1[CH:20]=[C:19]2[CH:21]=[CH:22][C:23]3[C:28](=O)[O:27][C:25](=[O:26])[C:24]=3[C:18]2=[CH:17][CH:16]=1>>[O:26]=[C:25]1[C:24]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:20][C:19]=3[CH:21]=[CH:22][C:23]=2[C:28](=[O:27])[N:1]1[CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2ccc3ccccc3c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(1,3-dioxo-1,3-dihydro-benzo[e]isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.55 g, 73%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.97 mmol) and 1,2-naphthalic anhydride (0.51 g, 2.56 mmol), and the obtained product was identified with the following NMR data.