Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3cnn4CCCC(=O)O)no2)cc1Cl
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of ethyl 4-[4-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoate (D60) (1.5 g, 3.20 mmol) in hot ethanol (15 ml) was treated with sodium hydroxide (7.5 ml, 15.00 mmol) and stood for 1 hr. The solvents were evaporated and the residue partitioned between ethyl acetate/water. Acetic acid was added to adjust the pH to 5 and the layers separated. The organic layer was dried over magnesium sulphate and evaporated. The crude material was triturated with ether to give the title compound (1.1 g) as a white solid. 5H (d6-DMSO, 400 MHz): 1.37 (6H, d), 2.08 (2H, m), 2.23 (2H, t), 4.54 (2H, t), 4.90 (1H, m), 7.47 (1H, d), 7.62 (1H, dd), 7.97 (1H, d), 8.01 (1H, d), 8.17 (1H, dd), 8.26 (1H, d), 8.56 (1H, s), MS (ES): C22H2135ClN4O4 requires 440; found (MH+) 441.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH:13]([F:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[F:16][CH:13]1[C:12]2[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:3]=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: COC(=O)c1nc2c(s1)C(F)COc1ccc(Br)cc1-2
Product: COC(=O)c1nc2c(s1)C(F)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate was reacted similarly to as described in General Procedure P with non-critical modifications to afford 142 mg (94%) of methyl 9-bromo-4-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Methyl 9-bromo-4-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-fluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepin o[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 29 mg and 30 mg (37% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-fluorine substitution position for each isomer was not determined.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27](=[O:36])[CH2:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15].C(OC(C)=C)(=O)C>C(Cl)Cl>[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27]([O:36][C:1](=[O:3])[CH3:2])=[CH:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)c2ccc(OC(C)=O)cc21
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(OC(C)=O)=CC[C@@H]23)c2ccc(OC(C)=O)cc21

Procedure:
10.0 g. of 3-hydroxy-6β-ethoxycarbonylmethyl-1,3,5(10)-estratrien-17-one -- produced in accordance with A2 -- is acetylated with 20 ml. of acetic anhydride in 20 ml. of pyridine for 20 hours at room temperature. After precipitation into ice water, filtration, and taking up the precipitate in methylene chloride, the reaction product is dried and evaporated, thus obtaining 11.8 g. of 3-acetoxy-6β-ethoxycarbonylmethyl-1,3,5(10) estratrien-17-one, which is heated to the boiling point with 140 ml. of isopropenyl acetate in the presence of 1.4 g. of p-toluenesulfonic acid and then subjected to a slow distillation. The cooled reaction product is diluted with methylene chloride and washed with sodium bicarbonate solution and water, dried, and evaporated, thus resulting in 13.3 g. of a crude product. After chromatography on silica gel, pure 3,17-diacetoxy-6β-ethoxycarbonylmethyl-1,3,5(10),16-estratetraene is obtained as an almost colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[Na+].[I-:18]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][I:18]
Reactant: [I-]
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][C:34]=1[O:42][C:43]([F:44])([F:45])[F:46])(=[O:40])=[O:39])[C:6](=[O:11])[C:5]2([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(NCCC(=O)OC(C)(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NCCC(=O)OC(C)(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 88.2 %

Procedure:
With 1.50 g of tert-butyl N-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-β-alaninate, which is the compound described in Preparation 1.29A of the brochure Publication No. WO03/008407, and 1.15 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.13 g of the title compound (light yellow solid) was obtained by a similar method to Example 2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:28])=[CH:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[BH4-].[Na+]>CO.Cl.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:28])=[CH:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][CH:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCC(=O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Yield: 100.2 %

Procedure:
A solution of 10.00 g 4-oxo-undecanoic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester was dissolved in 60 ml methanol and a trace of bromocresol green was added. When 1.63 g sodium borohydride was added, the color changed immediately from yellow to deep blue. Several drops of 2N HCl/methanol solution turned the color of the reaction back to yellow. The reaction was stirred for 2½ hours, with occasional addition of acid to maintain the yellow color. The reaction mixture was evaporated to dryness and water was added to the residue. This solution was extracted with ether and washed with water. The solution was dried, filtered and evaporated to dryness to yield 10.07 g of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[N:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[N:29]=2)=[CH:21][CH:20]=1.[ClH:35]>O1CCOCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[O:7][N:6]=4)[CH:9]=3)[N:29]=2)=[CH:23][CH:24]=1.[ClH:35].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[O:7][N:6]=4)[CH:9]=3)[N:29]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(Cl)cc2)n1
Reactant: O=Cc1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(CNCc1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde and 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine as described in example 7 step 3. The free amine was then treated with HCl in dioxane (2 M) at 0° C. and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The crude was purified by washing with dry hexane to get 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine hydrochloride (20 mg, yield 6%). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br s, 2H), 8.26 (s, 1H), 8.11-8.08 (m, 2H), 7.85-7.80 (m, 3H), 7.69-7.65 (t, J=7.6 Hz, 1H), 7.55-7.52 (d, J=8.5 Hz, 2H), 4.28 (br s, 2H), 3.12 (m, 2H), 1.33 (s, 6H). MS (ESI) m/z: Calculated for C23H20ClF3N4O2: 476.12. found: 477.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10](=[O:13])[CH2:11][CH3:12])[C:3]=1[C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([OH:18])=[O:17].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[C:26]([CH:47]=1)[CH2:27][NH:28][C:29]([C@H:31]1[N:35]([C:36](=[O:46])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)O)[N:34]=[CH:33][CH2:32]1)=[O:30].C(Cl)CCl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10](=[O:13])[CH2:11][CH3:12])[C:3]=1[C:14]([CH3:19])([CH3:20])[CH2:15][C:16]([O:18][C@H:37]([C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[C:36]([N:35]1[C@H:31]([C:29](=[O:30])[NH:28][CH2:27][C:26]2[CH:47]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=2[N:48]2[CH:52]=[N:51][N:50]=[N:49]2)[CH2:32][CH:33]=[N:34]1)=[O:46])=[O:17]
Reactant: CCC(=O)Oc1cc(C)cc(C)c1C(C)(C)CC(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(=O)Oc1cc(C)cc(C)c1C(C)(C)CC(=O)O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
To a solution of 3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoic acid (160 mg, 0.57 mmol) and (S)—N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((R)-2-(4-fluorophenyl)-2-hydroxyacetyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (263 mg, 0.57 mmol) in DCM (3 mL) and DMF (3 mL) was added EDC (165 mg, 0.86 mmol) and DMAP (7 mg, 0.06 mmol). The clear colorless solution was stirred at rt for 48 h. The mixture was diluted with DCM and washed with water, 1M HCl and sat NaHCO3. The organic phase was dried, filtered, evaporated and purified by flash chromatography (DCM/EtOAc gradient from 4:1 to 2:1) to give (R)-2-((S)-5-(5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl 3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate (380 mg, 92%) as a semisolid.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:22]1([C@H:28]([CH2:30][OH:31])[NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:31][CH2:30][C@H:28]([NH:29][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCCC(=O)O
Reactant: N[C@@H](CO)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](CO)c1ccccc1
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of 4-pentenoic acid (2.55 mL, 25.0 mmol) in DMF (312 mL) cooled in an ice/water bath was added HOBt (3.37 g, 25.0 mmol) and EDC (4.79 g, 25.0 mmol) and the resulting solution was stirred for 30 min (R)-(−)-2-phenylglycinol (3.43 g, 25.0 mmol), iPr2NEt (17.8 mL, 100 mmol), and DMAP (0.305 g, 2.50 mmol) were subsequently added and the reaction mixture was stirred 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous layer was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 3.5 g of product as a colorless oil in 64% yield. LRMS (M+H)+: 220.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[C:20]([C:21]([F:24])([F:22])[F:23])[C:13]=12
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1

Procedure:
10 mg of 10% palladium-on-carbon are added to a solution of 129 mg (0.38 mmol) of N-(2-fluoro-4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 5 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through kieselguhr and the kieselguhr is washed with ethanol. The filtrate is concentrated. The product is purified by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)=[CH:26][N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)nc1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(COc2ccc(COc3ccc(CCCn4ccnc4)cc3)cn2)cc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-benzyloxy-5-chloromethylpyridine to give 2-benzyloxy-5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]pyridine. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([CH:16]=[CH:17][N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[N:12]([CH:16]=[CH:17][N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccn3ccnc23)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccn3ccnc23)cc1

Procedure:
Add 45 g of iron powder to a solution of 15 g (62.7 mmol) of the product from Example 19 in 400 ml of 75% acetic acid. Heat to 60°-70° C. for 2 hr. Filter the reaction mixture over celite and concentrate the filtrate to approximately 50 ml under vacuum. Neutralize the residue with saturated sodium carbonate solution and extract with three 200 ml portions of methylene chloride. Dry the combined extracts over sodium sulfate, treat with charcoal and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCN(C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-methylpiperidin-4-amine via General Procedure E to give 4.6 mg of 284 following reverse phase purification. MS (Q1) 476.3 (M)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38].IC1C=CC(NC(C2C=CC(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=NC=2)=O)=CC=1C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCS(N)(=O)=O
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)cc2)c1
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)ccc1I
Product: CCS(=O)(=O)NC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)CC2)CC1

Procedure:
N-(3-tert-Butyl-phenyl)-4-[4-(4-ethanesulfonylaminocarbonyl-cyclohexanecarbonyl)-piperazin-1-yl]-benzamide was prepared from 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid and ethyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide above. The product was isolated after silica gel purification with 0-3% MeOH in CH2Cl2 gradient. HRMS m/z calcd for C31H42N4O5S [M+H]+: 583.2949. Found: 583.2945.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])[CH3:21].C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>ClCCl.C(OCC)(=O)C.O>[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH:25][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
N-Benzyloxycarbonyl-L-valine (1.25 g) and L-valine ethyl ester hydrochloride (1.08 g) are dissolved in dichloromethane (15 ml) and thereto are added triethylamine (1.54 ml) and further 1-methanesulfonyloxy-1,2,3-benzotriazole (1.07 g) under ice-cooling. After allowing to stand at room temperature for 72 hours, to the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried and then the solvent is distilled off to give N-(N-benzyloxycarbonyl-L-valyl)-L-valine ethyl ester (1.70 g). The product is washed with petroleum ether to give powdery product (1.50 g), melting point: 93°-93.5° C.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].C(=O)([O-])O.[Na+].[C:16](#[N:18])[CH3:17]>>[CH3:17][C:16]1[O:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[C@H:4]([CH2:1][CH2:2][CH3:3])[N:18]=1
Reactant: CCC[C@H]1O[C@@H]1C(=O)OC
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OC
Temperature: 5 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
Acetonitrile (15 ml) was added to methyl (2S,3R)-3-propyl-2-oxiranecarboxylate (1.42 g, 9.8 mmol). The mixture was cooled to 5° C., and boron trifluoride diethyl ether complex (1.24 g, 11 mmol) was gradually added dropwise. The mixture was stirred at room temperature for 6 hours, and saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added. The mixture was concentrated, and was extracted with ethyl acetate (30 ml). The organic layer was washed with water (10 ml×2), and the solvent was evaporated away under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.23 g, yield: 76%).
Reaction SMILES: N[C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12].N([O-])=O.[Na+].[OH-].[Na+].[H+].[B-](F)(F)(F)[F:30]>>[F:30][C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(F)nc21
Temperature: -20 °C
Yield: 23 %

Procedure:
3 g of 2-amino-2'-O-methyladenosine, the Compound 30 in Example 15, was dissolved in 35 ml of 42% fluoboric acid. 1.3 g/10 ml aqueous solution of sodium nitrite was added to the solution with stirring at -5° C. to -10° C. and stirred for one hour. The reaction mixture was cooled to -20° C. and neutralized by 50% sodium hydroxide aqueous solution. The solution was desalted by hydrophobic column chromatography and crystallized from methanol to give 697 mg of 2-fluoro-2'-O-methyladenosine (Compound 29).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:53]([O:52][C:50]([N:60]1[CH2:65][CH2:64][N:63]([C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)=[O:14])[CH2:62][CH2:61]1)=[O:51])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Yield: 71.4 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.25 g, 1.1 mmol), HATU (0.46 g, 1.2 mmol), DIPEA (0.57 mL, 3.3 mmol), 1-Cbz-piperazine (0.21 mL, 1.1 mmol) and DMF (5 mL) to furnish the intermediate compound benzyl-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate as a white solid (339 mg, 72%), umax (CHCl3)/cm−1 3014, 2863, 1688, 1644, 1427, 1367, 1205, 1168.