Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]1([CH2:13][CH2:14][CH2:15][Br:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH:1]1([C:10]2[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][CH2:15][Br:16])=[CH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCc1ccccc1
Reactant: C1=CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: BrCCCc1ccc(C2CCCCC2)cc1
Reaction time: 14 h

Procedure:
17 parts by weight of cyclohexene are added dropwise at +10° C. to a mixture of 40 parts by weight of 3-phenylpropyl bromide and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 and the solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 35 parts by weight of 3-(4-cyclohexylphenyl)-propyl bromide are obtained.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([NH2:23])=[CH:21][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:19]2)[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.N#N.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:23][C:22]1[N:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[N:19]=[C:20]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:21]=1
Reactant: C[C@@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Pd]
Agent: N#N
Agent: O=C[O-]
Solvent: CCO
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A solution of Intermediate 152a (0.39 g, 1.0 mmol) in ethanol (IMS grade, 10 mL) was purged with N2 then 10% Pd/C (0.11 g, 0.1 mmol Pd) was added. The mixture was purged with H2 then stirred under an atmosphere of H2 (balloon) at ambient temperature for 2 h, then at 50° C. for 1.5 h and 45° C. for 30 mins. Another portion of Pd/C (0.11 g, 0.1 mmol Pd) was added and the mixture was stirred at 45° C. for 16 h. The cooled reaction mixture was purged with N2 and treated with water (2 mL) then ammonium formate (0.65 g, 10.3 mmol) and heated to reflux for 5. Another portion of ammonium formate (0.65 g, 10.3 mmol) and Pd/C (0.11 g, 0.1 mmol) were added and the mixture was stirred at reflux for 16 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-75% EtOAc in cyclohexane to give the title compound (0.25 g, 83%) as a pink gum. LCMS (Method 3): Rt 2.44 min, m/z 290.3 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.B(OC)(OC)[O:18]C.C(OO)(=O)C.S(=O)(O)[O-].[Na+]>O1CCCC1>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([OH:18])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of Example 68A (7.9 g, 36.6 mmol) in tetrahydrofuran (100 mL) cooled to −78° C. under nitrogen was added butyllithium (1.6M in hexanes, 37 ml, 59.2 mmol) drop wise over 10 minutes. The reaction was stirred for 20 minutes and trimethyl borate (6.7 mL, 59.2 mmol) was added drop wise over 5 minutes. The resulting mixture was stirred for 2 hours at −78+ C. and peracetic acid (32% in acetic acid, 13 mL, 59.2 mmol) was added. After 10 minutes at −78° C. the reaction was warmed to 0° C. and stirred for 1 hour. The reaction was cooled to −10° C. and treated with 10% aqueous sodium bisulfite (30 mL). The mixture was concentrated to ⅓ volume and extracted with ether (300 mL). The organic phase was washed with water (300 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide 5.2 g of the title compound (92%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.25 Hz, 6H) 4.95-5.17 (m, 1H) 6.57 (d, J=8.82 Hz, 1H) 7.14 (dd, J=8.82, 2.94 Hz, 1H) 7.65 (d, J=2.94 Hz, 1H) 9.21 (s, 1H); MS (DCI) m/z 154.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C.O>[CH:20]1([CH2:23][N:5]2[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(CC2CC2)c(C(N)=O)c1[N+](=O)[O-]

Procedure:
A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO98/49166) (40.0 g, 217 mmol) in dry DMF (300 ml) was treated with cesium carbonate (77.8 g, 239 mmol). To this, in a single portion, was added cyclopropylmethyl bromide (22.9 ml, 239 mmol) and the resultant suspension stirred at RT for 6 h. After condensation in vacuo, the residue was partioned between ethyl acetate (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partioned between water (200 ml) and methylene chloride (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried over MgSO4, and condensed to a solid (40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, methylene chloride:methanol 98:2) crystallising from a mixture of methylene chloride (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (12 g, 50 mmol). Crystallisation of the mother liquors from acetonitrile gave the more polar component (Rf=0.19, methylene chloride:methanol 98:2) (10 g, 42 mmol) which was confirmed as the 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe experiements. The mother liquors contained further material as a mixture of regioisomers (20 g, 84 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:35])=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Cc1cc(F)ccc1O
Product: Cc1cc(F)ccc1Oc1ncc(Cl)cc1C(=O)N[C@@H](C)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-fluoro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.6 Hz), 8.22 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=2.6 Hz), 7.96 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.13–6.93 (3H, m), 5.39 (1H, dq, J=7.6, 6.9 Hz), 2.12 (3H, s), 1.60 (3H, d, J=6.9 Hz), 1.58 (9H, s); MS (ESI) m/z 485 (M+H)+, 483 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=4[F:44])=[O:32])=[C:26]([Cl:45])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:35]=4[F:44])=[O:32])=[C:26]([Cl:45])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(Cl)c3)c3c(N)ncnn23)CC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(Cl)c3)c12
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
A suspension of Example 266 (1.64 g, 2.53 mmol) in 50 mL 1,2-dichloroethane was treated with 10 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (15 mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (1.2 g, 87%) as a tan solid. 1H-NMR (DMSO-d6) δ 8.64 (dd, 1H), 8.23 (d, 1H), 7.88 (s, 1H), 7.46-7.54 (m, 2H), 7.34-7.43 (m, 2H), 6.55 (s, 1H), 3.17 (tt, 2H), 2.96-3.05 (m, 2H), 2.60 (dd, 2H), 1.60-1.85-1.95 (m, 2H), 1.56 (ddd, 2H); MS [M+H]+=548.3; LCMS RT=2.94 min.
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:20](=[O:22])[C@@H:18]([CH3:19])[NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[CH2:10][S:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCOC(=O)CN
Reactant: C[C@@H](NC(=O)CNC(=O)CSC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@@H](C)NC(=O)CNC(=O)CSC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
Benzoylmercaptoacetylglycyl-D-alanine in an amount of 150 mg is dissolved in 40 ml of tetrahydrofuran and the solution is cooled in an ice bath at 0° C. A solution of 50 mg of glycine-ethyl ester and 100 mg of dicyclohexylcarbodiimide in 15 ml of tetrahydrofuran is slowly added while stirring magnetically. The mixture is stirred at 0° C. for 2 hours and then at room temperature for 15 hours. The resulting precipitate is then filtered off and the filtrate is evaporated to dryness under reduced pressure. The solid residue is shaken with a mixture of 50 ml of water and 50 ml of methylene chloride. The organic layer is separated, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The solid residue is shaken five times with 15 ml of acetone which is each time filtered off. The collected filtrates are concentrated in vacuo to 15 ml and diethylether is added dropwise thereto while stirring until complete formation of precipitate. The precipitate is filtered off, washed with diethyl ether and dried over phosphorous pentoxide in vacuo. In this manner, 155 mg (55.1% yield) of benzoylmercaptoacetylglycyl-D-alanylglycine ethyl ester are obtained. The identity of this compound is confirmed by mass spectrometry, proton-NMR analysis and elementary analysis: mp 137° C.; [α]D20 +20.5 (C=1 in methanol); mass spectrum m/e- 410; nmr (DMSO-d6): δ1.22 (3H, d, CH3), 3.77 (2H, d, γ--CH2 --N), 3.81 (2 H, d, α--CH2 --N), 3.87 (2H, s, CH2 --S), 4.33 (1H, q, β--CH), 8.08 (1H, d, β--NH), 8.28 (1H, t, α--NH), 8.42 (1H, t, γ--NH), 7.5-8.04 (5H, complex, aromatic), 4.08 (2H, q, OCH2), 1.18 (3H, t, ester-CH3).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:2]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].C1C[O:25]CC1>O.C(Cl)Cl>[OH:25][CH:2]([CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: C1CCOC1
Reactant: N#CCCCCCCCC1OC1CCCCCCCC#N
Solvent: ClCCl
Solvent: O
Product: N#CCCCCCCCC(O)C(O)CCCCCCCC#N
Reaction time: 24 h

Procedure:
To a solution of 0.10 g like-8,8′-(oxirane-2,3-diyl)dioctanenitrile in 5.0 g THF was added 0.50 mL of a solution of 0.0988 g 70% HClO4 in 1.9104 g water. After standing for 24 h at room temperature, the mixture was diluted with 250 mL CH2Cl2, which resulted in the separation of aqueous droplets. The mixture was dried over Na2CO3 and evaporated to afford 0.10 g of product as a white powder.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:9]=2)[N:4]=1.C([O-])(O)=[O:28].[Na+]>>[CH3:13][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:9]=2)[NH:4][C:3](=[O:28])[CH:12]=1
Reactant: O=C([O-])O
Reactant: Cc1ccncc1N1CCN(c2ccc3nc(Cl)cc(C)c3c2)C1=O
Agent: Cl
Agent: [Na+]
Product: Cc1ccncc1N1CCN(c2ccc3[nH]c(=O)cc(C)c3c2)C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 80.85 %

Procedure:
1N HCl (5 mL) was added to 1-(2-chloro-4-methyl-quinolin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (21A: 50 mg, 0.1418 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mass was cooled to 0° C., aqueous NaHCO3 was added till a pH of about 8 was attained. The reaction mixture was extracted with chloroform. The organic layer was dried over Na2SO4 and concentrated to afford 38 mg of the product (80.85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH2:18][N:19]=[C:20]=[O:21])=[CH:16][CH:15]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:24])=[CH:23][CH:22]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2cnccc2c1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1ccc2cnccc2c1

Procedure:
Prepared from 6-aminoisoquinoline (Description 51) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:14]3[C:15]([OH:18])=[N:16][O:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:14]3[C:15]([O:18][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[N:16][O:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(COc2cccc3onc(O)c23)cc1
Reactant: COC(=O)C1(CN2CCC(CO)CC2)CCCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCc5ccc(OC)cc5)c34)CC2)CCCC1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
To a solution of 4-[(4-methoxybenzyl)oxy]-1,2-benzisoxazol-3-ol (100 mg, 0.369 mmol, EXAMPLE 9, step 2) and methyl 1-{[4-(hydroxymethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate (141 mg, 0.553 mmol, EXAMPLE 9, step 3) in toluene (2.5 mL) was added cyanomethylenetributylphosphorane (178 mg, 0.737 mmol) at room temperature. The reaction mixture was heated at 100° C. for 20 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 5:2 to 3:2) to give 116 mg (62%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C=O)C>[Br:15][C:12]1[S:11][C:10]([C:7]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=2)[C:4]#[N:5])=[N:14][CH:13]=1
Reactant: N#Cc1cc(-c2nccs2)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ncc(Br)s2)ccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 0.1 %

Procedure:
To 2-fluoro-5-(thiazol-2-yl)benzonitrile (21.8 g, 106.7 mmol) in anhydrous DMF (200 mL) was added recrystallized N-bromosuccinimide (22.7 g, 128 mmol). The reaction mixture was stirred at room temperature for 23 h under N2. The reaction mixture was basified with 1N NaOH and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield orange oil. The crude product was purified by silica gel flash chromatography (20% EA/Hexanes) to produce 21 mg (70%) of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 as half-white solid. LCMS-ESI (m/z) calculated for C10H4BrFN2S: 283.1; found 284.9 [M+H]+, tR=3.82 min. 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J=5.9, 2.3 Hz, 1H), 8.08 (ddd, J=8.8, 4.9, 2.3 Hz, 1H), 7.78 (d, J=4.8 Hz, 1H), 7.31 (t, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CC(=CC)C.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+].Cl>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]([C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:22])=[O:14])=[CH:11][CH:12]=1)([CH3:6])[CH3:5])=[O:15]
Reactant: COC(=O)C(C)(C)c1ccc(C=O)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
5.60 g (27 mmol) of 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl ester was dissolved in 112 mL of tert-butanol; 16.97 mL (11.20 g=136 mmol) of 2-methyl-2-butene was added, followed by a solution of 7.98 g (71 mmol) of sodium chlorite and 6.35 g (41 mmol) of sodium dihydrogen phosphate in 56 mL of water. After 20 hours, the reaction mixture was poured into crashed ice/EtOAc, the pH was adjusted to ˜3.0 with aq. HCl (1N) and it was extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by recrystallisation from EtOAc/heptane to give 3.00 g of the title compound as colorless solid. MS: 221.2 [(M−H)−].
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=O)[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].CCN(CC)CC>C(Cl)Cl>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([NH:37][CH2:35][CH3:36])=[O:20])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 0.037 g (0.08 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine and 0.06 mL (0.12 mmol) of ethylamine in 2 mL of CH2Cl2 at rt was added 0.031 g (0.12 mmol) of BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride, Aldrich) and 0.045 mL Et3N and the reaction mixture was stirred for 18 h. The reAction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.85-7.90 (m, 3H), 7.45-7.56 (m, 4H), 7.09-7.19 (m, 2H), 6.96-7.03 (m, 2H), 3.94-4.49 (m, 4H); Mass Spectrum (ESI) m/e=488 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH3:24]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH:22]([CH2:21][O:20][CH3:19])[CH2:23][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Reactant: CCC(N)COC
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 85.9 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1-methoxymethyl-propylamine (0.14 g, 1.32 mmol) were treated as in Part D of Example 9 to yield 0.21 g (88%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)+, 97].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:22]([NH2:24])=O>>[OH:8][C:7]1[C:6]2[C:5]3[CH2:12][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=[CH:22][N:24]=1
Reactant: NC=O
Reactant: CCOC(=O)CC1CCc2sc(N)c(C(=O)OCC)c2C1
Product: CCOC(=O)CC1CCc2sc3ncnc(O)c3c2C1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of ethyl 2-amino-5-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (20.68 g, 66.41 mmol, 1.00 equiv) in 100 mL of formamide was stirred overnight at 180° C. in an oil bath. After the starting material disappeared, the reaction was cooled to room temperature and quenched with water, extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) to afford ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (10.10 g, 52%) as yellow oil. LC-MS (ES, m/z): 293 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH:13](OCC)=[O:14]>>[CH:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:14]
Reactant: C=CCCCCCCCCCN
Reactant: CCOC=O
Product: C=CCCCCCCCCCNC=O
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of commercially available 1-aminoundec-10-ene (1 g) dissolved in ethyl formate (3.5 mL) was kept at 50° during 3 h. Evaporation of the solvent yielded 1.18 g of N-formyl-1-aminoundec-10-ene (yield: 99%).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1)[CH:11]=[CH2:12].[OH-:39].[Na+].OO>O1CCCC1.C(O)C>[OH:39][CH2:12][CH2:11][CH2:10][O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1
Reactant: [OH-]
Reactant: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]12CC[C@H](OCCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reaction time: 6 h

Procedure:
To a solution of 0.17 g of 9-borabicyclo[3.3.1]nonane in 35 ml of dry tetrahydrofuran, 0.50 g of 3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 10 ml of tetrahydrofuran were added under nitrogen atmosphere, at room temperature. The solution was stirred for 6 hrs then 0.75 ml of ethanol, 0.25 ml of sodium hydroxide 6N and 0.50 ml of hydrogen peroxide 30% were added. The mixture was stirred at 50° C. for an hr, quenched with a solution of 0.76 g of potassium carbonate in 20 ml of water and the organic solvent distilled under reduced pressure. The residue was extracted with methylene chloride, the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 70/30 as eluant to give 0.40 g of 3β-(3-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white amorphous solid.