Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:50]=[CH:49][C:35]5[N:36]=[C:37]([S:39][CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)[NH:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:50]=[CH:49][C:35]5[N:36]=[C:37]([S:39]([CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[O:60])[NH:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(SCc5cncn5CCC)[nH]c4c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(S(=O)Cc5cncn5CCC)[nH]c4c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]benzimidazol-5-yl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.64 g) was dissolved in methylene chloride (19.2 ml), and a solution of metachloroperbenzoic acid (0.27 g) in methylene chloride (12.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-[[(1-propylimidazol-5-yl)methyl]sulfinyl]benzimidazol-5-yl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 313) (0.21 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][O:5]1
Reactant: O=Cc1ccccc1F
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC1COC(c2ccccc2F)OC1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 2-fluorobenzaldehyde (24.8 g, 0.2, mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2 ml) was heated at 80°-100° C for 12 hours. The mixture cooled to room temperature and 100 ml of ether was added. The solution was washed with 2% potassium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The oil which remained (28.7 g) was distilled under 1 × 10-5 mm to give a product (18 g) which distilled at a pot temperature of 140°-145° C. This product was identified by infrared and elemental analysis as 5-hydroxy-2-(2-fluorophenyl)-1,3-dioxane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:9][CH2:8][CH2:7][C:6]4[S:5][CH:4]=[N:3][C:2]=4[CH3:1])=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1ncsc1CCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncsc1CCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
To a solution of 4-methyl-5-thiazole-ethanol (0.375 g, 2.62 mmol) in THF (1 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (11.0M in hexanes)(1.74 ml, 1.74 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.300 g, 0.872 mmol). The reaction mixture is stirred at room temperature for 18 hours, then quenched by the addition of water (5 ml). The mixture is partitioned between water and EtOAc (40 ml each). Five ml of 1 N HCl is added, and the layers are shaken and separated. The aqueous layer is extracted with EtOAc (50 ml) and the combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (1:2 hexane:EtOAc) to give the title compound as a pale yellow solid (0.094 g, 25%). Mass (m/z): 423.1 (M++1), 421.1 (M+−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Step H (1): To a solution of 2-(5-bromo-1H-indol-3-yl)acetic acid (1.0 g 3.94 mmol) in MeOH (5 mL) and Et2O (15 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 10 mL). The reaction was stirred at rt for 2 h. The solvents were removed and the residue was purified by flash chromatography to yield 900 mg of methyl 2-(5-bromo-1H-indol-3-yl)acetate (yield 85%). 1H NMR (500 MHz, CDCl3) δ ppm 3.71 (s, 3 H) 3.72 (s, 2 H) 7.16 (d, J=2.14 Hz, 1 H) 7.21 (d, J=8.55 Hz, 1 H) 7.27 (dd, J=8.55, 1.83 Hz, 1 H) 7.72 (d, J=1.53 Hz, 1 H) 8.12 (s, 1 H)
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:18])[CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCCl>[OH:18][C:4]1[CH2:5][CH:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: O=C1C=C(O)CC(c2cccc3ccccc23)C1
Solvent: ClCCCl
Product: CCC(=O)C1=C(O)CC(c2cccc3ccccc23)CC1=O

Procedure:
Stannic chloride (12.0 g) was added dropwise to a mixture of 3-hydroxy-5-(naphth-1-yl)-cyclohex-2-en-1-one (10 g) and propionyl chloride (4.25 g) in 1,2-dichloroethane (50 ml). the mixture was stirred and heated at reflux under nitrogen for 6 hr. After cooling, the mixture was poured onto ice. The dichloromethane extract was evaporated and the residue was heated at reflux with a 2M sodium hydroxide solution (20 ml) for 2 hr. After cooling, the solution was poured into an ice/hydrochloric acid mixture. The dried (Na2SO4) dichloromethane extract was concentrated and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 3-hydroxy-5-(naphth-1-yl)-2-propionylcyclohex-2-en-1-one as a white solid.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]([NH:18][C:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[NH:28])[CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(=O)NCCCCc2ccccc2)c1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1cccc(C(=O)NCCCCc2ccccc2)c1)N1CCCC1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.0 g, 0.006 moles, in 35 ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.5 ml; 0.008 moles, and the reaction was heated to reflux for 4 hours. The reaction cooled to room temperature and the solvent was decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 80° C. for 24 hours to give N-[3-(((4-phenylbutyl)amino)carbonyl)phenyl]-1-pyrrolidinecarboximidamide hydrochloride, 2.3 g, m.p. 197-198° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH3:28].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH2:23][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 233 μL (2.16 mmol) of 4-bromobutane in 30 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as a colorless oil: yield 533 mg (69%); silica gel TLC Rf 0.50 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ 0.90 (t, 3H, J=7.2 Hz), 1.34 (m, 2H), 1.77 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 4.91 (s, 62), 5.88 (s, 2H) and 7.40-7.44 m, 5H); 13C NMR (CDCl3) δ 13.95, 14.34, 19.29, 22.47, 27.41, 31.59, 31.73, 75.72, 107.94, 107.94, 128.01, 128.01, 128.22, 128.72, 129.30, 136.22, 147.38, 147.38, 152.60, 161.62, 161.62 and 165.08; mass spectrum (APCI), m/z 364.2394 (M+H)+ (C23H30N3O requires 364.2389).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](C(OC(C)(C)C)=O)[N:8]=[C:7]2[I:20].FC(F)(F)C(O)=O>ClCCl>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:20]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a stirred solution of tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (410 mg, 1 mmol) in dichloromethane (10 mL) was added drop-wise trifluoroacetic acid (5 mL) at room temperature and the reaction mixture was stirred for 1 hour. The mixture was washed with NaHCO3 aqueous, and then organic was dried over Na2SO4. After filtration and concentration, 5-(difluoromethoxy)-3-iodo-1H-indazole (300 mg, 97%) was obtained as a white solid, used in the next step without further purification. MS: (M+H)+=311.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35]I>>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:14])([F:1])[F:15])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc(SC(F)(F)F)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccc(SC(F)(F)F)cc1
Yield: 47.2 %

Procedure:
Step AAM (1): 2-(4-(Trifluoromethylthio)phenyl)acetic acid (4.7 g, 19.9 mmol) was deprotonated with NaHMDS 2.0 M in THF (19.9 mL, 39.8 mmol) and reacted with 1-chloro-4-iodobutane (2.44 mL, 19.9 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(trifluoromethylthio)-phenyl)hexanoic acid (3.07 g, 9.40 mmol, 47% yield) as a pale-yellow oil. LC-MS (M−H)− 325.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.32-1.51 (m, 2 H) 1.69-1.87 (m, 3 H) 2.01-2.17 (m, 1 H) 3.49 (t, J=6.56 Hz, 2 H) 3.59 (t, J=7.63 Hz, 1 H) 7.36 (d, J=8.24 Hz, 2 H) 7.61 (d, J=8.24 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]2[NH:15][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[N:16][C:4]=2[C:3]=1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cc(Oc2cccnc2)c(Cl)c(Oc2cccnc2)c1N
Product: Clc1c(Oc2cccnc2)cc2[nH]c(-c3ccccn3)nc2c1Oc1cccnc1

Procedure:
In the same manner as in Example 68 but using 4-chloro-3,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine and picolinic acid, the entitled compound was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:30][C:31]4[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:32]=4)=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a mixture of 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (2.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.81 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.19 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (1.43 g, yield 56%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-148° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([O:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([O:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSc1ncc(OCc2cccnc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(OCc3cccnc3)c(=O)[nH]2)cs1

Procedure:
A reaction mixture was prepared from 1.26 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.36 g. of 2-methylthio-5-(3-pyridyl)methoxy-4-pyrimidone in 20 ml. of pyridine. The reaction mixture was heated to reflux temperature for about 2 days. The pyridine was then removed by evaporation in vacuo and the resulting residue subjected to high pressure liquid chromatography over silica. Fractions shown by tlc to contain the desired compound were combined and the combined fractions rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone free base thus obtained was converted to the trihydrochloride salt by standard procedures. Recrystallization of the crude trihydrochloride salt from ethanol yielded 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone trihydrochloride melting at 183°-185° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([F:39])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
n-Butyl lithium (2.5M/Hexanes, 3.83 ml; 9.575 mmol) added dropwise to solution of diisopropylamine (1.36 ml; 9.62 mmol) at −78° C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to −78° C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2 g, 8.72 mmol) in THF (10 ml) was added dropwise, warmed to −40° C. for 1 hour, then cooled to −70° C.A solution of N-fluorobenzene-sulfonimide (3.02 g, 9.57 mmol) in THF (15 ml) was added dropwise, stirred at −78° C. for 1 hour, then stirred at room temperature overnight. Precipitated solid was filtered, washed with EtOAc (2×150 ml). Organic layer was washed with 1N HCl (30 ml), brine (100 ml), dried (MgSO4), filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding product as colorless oil (1.38 g: 64% yield). MS (ESMS, MH 249).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C\CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(/C=C\CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(1.00 g, 19.2mmol) was slowly added to a stirring solution of cis - 2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (2.00 g, 6.4 mmol) in EtOH (100 mL) and the solution was heated to reflux for 5 h. The resulting mixture was made acidic (pH<2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc (2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O (3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 800mg, 70%: 1H NMR (300 MHz, CDCL3) δ 1.26 (s, 2H, br), 3.421 (m, 2H), 3.78 (s, 3H), 5.81 (m, 1H), 6.40 (d, J=11.0 Hz, 1H), 6.62 (m, 2H), 6.90 (m, 1H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>C1(C)C(C)=CC=CC=1>[C:26]([O:22][CH:4]1[C@:3]2([CH2:1][CH3:2])[C@H:7]([C@@H:8]3[CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:12]=4[C@H:9]3[CH2:10][CH2:11]2)[CH2:6][CH2:5]1)(=[CH2:25])[CH3:27]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=C(C)OC1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC

Procedure:
Reflux a suspension of 5.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-triene-17β-ol, 100 mg. of xylene, and 3.9 g. of sodium hydride (50% in mineral oil) for 1.5 hours. Add 14.5 ml. of allyl bromide and reflux for 22 hours. Make the reaction mixture acidic with dilute hydrochloric acid and extract the organic layer with sodium bicarbonate solution. Chromatograph the residue on alumina (Grade I neutral) in hexane and eluate the product with ether to obtain dl-17β-allyloxy-13-ethyl-3-methoxygona-1,3,5(10)-triene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[C:9]([C:8]([C:4]1[CH:3]=[C:2]([B:19]([OH:25])[OH:20])[CH:7]=[CH:6][CH:5]=1)([CH3:13])[CH3:12])([OH:11])=[O:10]
Reactant: CC(C)(C(=O)O)c1cccc(Br)c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-bromo-phenyl)-2-methyl-propionic acid (2.18 mmol) in anhydrous ether (20 mL) is added tert-butyl lithium (1.7 M in pentane, 5.4 mL, 9.16 mmol) dropwise at −78° C. and this mixture is stirred for 30 minutes treated with tributyl borate (2.34 mL, 8.72 mmol). The reaction mixture is allowed to warm up to room temperature, stirred for 15 hours, diluted with ether, and quenched with 1 M H3PO4. After stirring for 30 minutes the ether layer is separated and extracted three times with 2 N NaOH (20 mL). The combined NaOH extracts are acidified with 6 N HCl to pH=1 and extracted three times with ether (50 mL). The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to afford 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid, which is used without further purification. MS: 209 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(#N)C>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccc(C=CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 33 %

Procedure:
Prepared from 4-methyl-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in acetonitrile in the presence of 1 equivalent of potassium carbonate for 40 minutes at 80° C. Yield: 33% of theory, Melting point: 126°-30° C. (ether).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C

Procedure:
To a suspension of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (0.100 g, 0.39 mmol) and cesium carbonate (0.376 g, 1.16 mmol) in MeCN was added benzyl bromide (0.06 mL, 0.46 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical tlc. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.