Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:5]2[N:6]=[C:2]([S:1][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)[NH:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Fc1cc2nc(S)[nH]c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(F)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
A solution of 2-mercapto-5-chloro-6-fluoro-benzimidazole (1.2 g, 5.92 mmol) in tetrahydrofuran (10 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.379 g, 9.47 mmol) and tetrahydrofuran (5 ml). The mixture is stirred at room temperature for 2 hours. A solution of 5-nitro-2-furaldehyde (0.836 g, 5.92 mmol) in tetrahydrofuran (15 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of dichloromethane and methanol (98/2, v/v) to yield 370 mg of 5-(6-chloro-5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as an orange powder. Yield=21%. Analytical LC/MS (method B): retention time=3.58 min., m/z=296.98 (1 Cl, positive ion mode).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:32])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:32])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 100 %

Procedure:
Cholic acid (1a) (2.0 g, 4.9 mmol) in THF (40 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald: diazald is N-methyl-N-nitroso-p-toluenesulphonamide) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (2.1 g, 100%). Recrystallisation from methanol afforded pure methyl cholate1 (1.3 g, 63%): m.p. 158°-159° C. (crystals began to melt 86°-88° C. and then resolidified--this was probably due to the retention of methanol in the crystals, see NMR data) [Lit1 156°-158° C.]; 1H NMR (60 MHz; CDCl3) δ0.66 (3H, s, 18-CH3), 0.87 (3H, s, 19-CH3), 3.0-3.6 (1H, m. 3β-H), 3.2-3.5 (3H, m [exchanges on adding D2O], 3α, 7α and 12α OH's), 3.48 (s, MeOH of crystallisation [ca. 1 mol equiv.]), 3.65 (3H, s, 24-OMe), 3.7-3.9 (1H, m, 7β-H), 3.8-4.0 (1H, m, 12β-H); IR (nujol mull) 3392, 3300 (OH's), 1734 (C=O) cm-1.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:27][CH2:26][C:25](=[CH:28][O:29]C)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:31])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].CC(C)=O.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:31])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3CCC(C4CCC(=COC)CC4)CC3)c(F)c2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC(C=O)CC4)CC3)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
The compound (27) (7.64 g) and acetone (25 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 6N-Hydrochloric acid (8 ml) was added dropwise thereto in the temperature range of 40° C. to 50° C., and the mixture was stirred for 3 hours, and cooled slowly to room temperature. Water (100 ml) and toluene (100 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume), and dried, giving 2.29 g of 4′-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)bi(cyclohexane)-4-carbaldehyde (28). The yield based on the compound (27) was 31.0%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[C:11](Cl)([Cl:13])=[O:12]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:11]([Cl:13])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: Cc1ccccc1C
Product: CC1(C)CCCC(C)(C)N1C(=O)Cl

Procedure:
A solution of 29.7 g (0.21 mol) of redistilled 2,2,6,6-tetramethylpiperidine in 50 ml of xylene is added dropwise in the course of 1.5 hours, at -40°, to 40.2 g of a 25.7% solution of phosgene in xylene (0.105 mol), with stirring and under an inert gas atmosphere. After adding the amine, the mixture is stirred for a further 4 hours at -10° and for 18 hours at -5° to 0°. The 2,2,6,6-tetramethylpiperidinocarboxylic acid chloride which is thus obtained is not isolated but is now treated with a solution of 19.73 g (0.05 mol) of N,N'-bis-(2,2,6,6-tetramethyl-piperid-4-yl)-hexamethylenediamine and 20.4 ml (0.12 mol) of diisopropyl-ethylamine in 50 ml of xylene, this solution being added in the course of 2 hours, at -10°. After stirring for a further 18 hours at room temperature and for 6 hours at 50° C., the reaction mixture is cooled to room temperature, diluted with 300 ml of hexane and extracted four times with 150 ml of water, the organic phase is dried over sodium sulfate and the solvents are distilled off completely under a waterpump vacuum. The residue, which solidifies as crystals after a short time, is recrystallised from acetonitrile, and by this means pure N,N'-bis(2,2,6,6-tetramethylpiperid-4-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperidinocarbonyl)-hexamethylenediamine is obtained as a colourless compound with a melting point of 137°-139°. ##STR40##
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][CH2:4][C@@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[F:38][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH3:6]
Reactant: C[C@@H](COC(F)F)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COC(F)F)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide (10 mg, 0.018 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (30 ul, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane) to afford 2 mg (32%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=419; 1H NMR (300 MHz, DMSO-d6) δ: 12.86 (br. s., 1H), 9.11 (s, 1H), 8.47 (s, 1H), 8.49 (dd, J=9.1, 5.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.70 (dd, J=9.8, 2.3 Hz, 1H), 7.15 (td, J=9.2, 2.1 Hz, 1H), 6.70 (t, J=75.2 Hz, 1H), 4.36-4.54 (m, 1H), 4.16 (s, 3H), 4.00 (d, J=4.5 Hz, 2H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([C:14]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CN)C2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixed anhydride is prepared by reacting 2.0 g of Boc-D-methionine with 0.90 ml of N-methylmorpholine and 1.06 ml isobutylchloroformate in 15 ml of tetrahydrofuran at -20° C. A solution of 2.84 g of methyl glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride in 15 ml tetrahydrofuran is neutralized with 0.78 ml N-methyl morpholine and added to the mixed anhydride reaction above. The reaction mixture is stirred for 2 hours at room temperature and allowed to stand overnight. The reaction mixture is diluted with 200 ml of ethyl acetate. The ethyl acetate layer is collected and washed with water, followed by washes with 0.2 M potassium bisulfate, water, and 1 M potassium bicarbonate and dried over magnesium sulfate. The solution is filtered and the solvent removed under reduced pressure. Purification of the residue by low pressure chromatography on silica gel affords methyl Boc-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR17##
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate (0.23 g, 0.70 mmol) in a mixture of tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide (0.15 g, 3.51 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and acidified to pH=6 with acetic acid. The white solid precipitated was collected by filtration, washed with water and dried in air to afford the title compound as a white solid (0.20 g, 95%): MS (ES+) m/z 301.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (182 mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (184 mg) is dissolved in ethanol (5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (305 μl), and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (184 mg). MS (m/z): 598 [M+H]+
Reaction SMILES: F[C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15].CC(C)([O-])C.[K+]>O.Cl>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: O=C(O)c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COCCOc1cccnc1C(=O)O
Reaction time: 18 h
Yield: 26 %

Procedure:
3-Fluoropyridine-2-carboxylic acid (150 mg, 1.06 mol), 2-methoxyethanol (1.5 mL) and potassium tert-butoxide (356 mg, 3.18 mmol) were charged to a sealed tube under nitrogen then stirred at 100 C for 18 h. The mixture was then diluted with water (3 mL), 1M HCl was added to bring the solution to pH 5 and the mixture was extracted with DCM (2×5 mL). 1M HCl was added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (2×5 mL). The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a brown gum (54 mg, 26%). Method C HPLC-MS: MH+ requires m/z=198. Found: m/z=198, Rt=0.29 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.Cl.N([O-])=O.[Na+].[Na+].[I-:23]>O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([I:23])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2c(F)cccc2F)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(F)c1Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
Into a 250-mL 4-necked round-bottom flask, was placed 4-(2,6-difluorophenoxy)-aniline (8.84 g, 39.96 mmol, 1.00 equiv), hydrogen chloride (37%) (10.14 g, 277.81 mmol, 6.95 equiv) and water (20 mL). NaNO2 (3.04 g, 44.06 mmol, 1.10 equiv) in water (10 mL) was added dropwise with stirring at 0° C. over 5 min., and the reaction mixture was stirred for 30 mins at 0° C. The reaction mixture was added into a solution of NaI (18 g, 120.00 mmol, 3.00 equiv) in water (20 mL) at 25° C. in batches over 5 min. The resulting solution was stirred for 2 h at 25° C. and then extracted with of ethyl acetate and the organic layers were combined. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 10.2 g (77%) of 1,3-difluoro-2-(4-iodophenoxy)benzene as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:5][CH:4]=1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=Cc4ccncc4)c4ccccc4)cc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C)c3ccc(C(Cc4ccncc4)c4ccccc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A solution of cis- and trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole (70 mg, Example 22) in a mixture of tetrahydrofuran and methanol (20 ml; 1:1, v/v) was heated at 45-50° C. under an atmosphere of hydrogen in the presence of 6% palladium on activated charcoal then stirred overnight at room temperature. The mixture was filtered through celite then evaporated. The residue was subjected to high pressure liquid chromatography using a hypersilC18 BDS column (250×20 ml, 8 micron) and eluting with methanol containing 0.1% ammonium hydroxide to yield the title compound (13 mg) as an oil. NMR (CDCl3): δ 2.30(s, 3H); 3.30-3.40(m, 2H); 3.70(s, 3H); 4.30-4.40(m, 1H); 5.10(s, 2H); 6.80-7.50 (m, 13H); 8.30-8.35(m, 2H); 8.50(bs, 2H).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:27])[CH:8]([O:24][CH2:25][CH3:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)C>O.O1CCOCC1>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([O:24][CH2:25][CH3:26])[C:7]([OH:27])=[O:6])=[CH:15][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Yield: 99.2 %

Procedure:
Lithium hydroxide hydrate (7.4 g; 177 mmole) dissolved in water (150 ml) was added to a solution of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester (23.25 g; 70.8 mmole) in dioxan (150 ml). After stirring at room temperature over night dioxan was evaporated in vacuo, water was added and the mixture was washed with diethyl ether. The water phase was acidified with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and the solvent was evaporated in vacuo to give 21.1 g (yield 99.2%) of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C[O-].[Na+]>CN(C=O)C>[NH2:10][C:9]1[C:3]2=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=[C:2]2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1c(Cl)ccc[n+]1[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc[n+]([O-])c2c1N
Yield: 60 %

Procedure:
To a solution of 3-chloro-2-cyanopyridine (40g, 0.29 mol) in 500 mL acetic acid added hydrogen peroxide (30%, 52 g, 0.45 mol) dropwise. After stirring at 90° C. for 18 h, the reaction is cooled to 25° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H2O is added dropwise. The reaction is concentrated to remove the bulk of the acetic acid and the residue is partitioned between 1M NaOH and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc to provide 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The N-oxide from above (12.2 g, 79 mmol) was taken up in DMF (160 mL) at 0° C. Methyl thioglycolate (7.1 mL, 79 mmol) was added followed by sodium methoxide (8.5 g, 160 mmol) in portions. The RXN was stirred for 1 h. The RXN was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc. 10.6 g (60%) of 3-amino-2-carbomethoxythieno[3,2-b]pyridine-4-oxide was obtained. The pyridine-N-oxide (10.6 g, 47 mmol) is mixed with phosphorous oxychloride (100 mL). The RXN is heated to 80° C. for 30 min. The RXN is concentrated and partitioned between CH2Cl2 and NaHCO3 sln. The CH2Cl2 layer is dried (MgSO4), filtered, cone, and chromatographed (5:1 hex:EtOAc). 8.3g (73%) of the 5-chloro and 2.0 g (18%) of the 7-chloro product were obtained: 1H NMR (300 MHz, CDCl3 (5-chloro)) δ3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M+H)+. 1H NMR (300 MHz, CDCl3 (7-chloro)) δ3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCI/NH3) m/e 243 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:11]1([C:16](=O)[CH2:17][C:18](OCC)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:16]2[CH:17]=[C:18]([OH:19])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)C1CCCC1
Product: N#Cc1ccnc(-n2nc(C3CCCC3)cc2O)c1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-cyclopentyl-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12](Cl)[N:7]2[N:6]=1)=[N+:2]=[N-:3].NC(N)=[S:18]>C(O)C>[N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:18])[N:7]2[N:6]=1)=[N+:2]=[N-:3]
Reactant: Cc1cc(Cl)n2nc(CN=[N+]=[N-])nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(S)n2nc(CN=[N+]=[N-])nc2n1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
2-Azidomethyl-7-chloro-5-methyl[1.2.4]triazolo-[1,5-a]pyrimidine (2.98 g) are suspended in 70 ml of ethanol, treated with 1.1 g of thiourea and heated at reflux for 45 minutes. The reaction mixture is stirred in an ice bath for 30 minutes. The resulting precipitate is filtered off under suction and dried in a vacuum at 40° C. There are obtained 2.76 g of 2-azidomethyl-5methyl[1.2.4]triazolo[1,5-a]pyrimidine-7-thiol as yellow crystals of melting point 214°-215° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][C:14]#[CH:15])[C:9]1=[O:16].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[C:9]1=[O:16]
Reactant: C#CC[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Yield: 86.7 %

Procedure:
To a solution of (3R,45)-1-(2-tetrahydropyranyloxy)-3-(2-propyne-1-yl)-4-methylazetidin-2-one (1.32 g, 5.83 mmol) in 20 mL of toluene is added tributyltin hydride (1.70 g, 5.83 mmol) and AIBN (30 mg). The resulting solution is heated at reflux for 4 h then concentrated ir vacuo. The reaction mixture is purified by silica gel chromatography (elution with 8:1 hexanes-EtOAc) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one as an oil (2.6 g, 87% yield).