Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1>[CH3:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C:46](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:47]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
10.0 g (16 mmol) of crude ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (HPLC purity, method 3: 82.1%) as obtained in Example 2, step (g), was suspended in a mixture of 7.07 g (51 mmol) of potassium carbonate, 42.7 mL of water and 427 mL of tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes. After cooling to 15° C., 2.81 g (17 mmol) of hexyl chloroformate were added while keeping the reaction temperature between 15 to 20° C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and the solid was discarded. The organic phase was extracted from the mother liquors, and the solvent was removed by vacuum distillation. The residue was dissolved in 200 mL of dichloromethane, and residual aqueous phase was extracted. The organic phase was dried with anhydrous sodium sulfate. The solvent was removed under vacuum to yield 11.0 g of crude dabigatran etexilate as a red slurry. Purity (HPLC, method 1): 87.3%. Content of compound (A2) (HPLC, method 1): 9.8%.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9].CCCCCC.C[CH2:30][O:31]C(C)=O>CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:6]([C:10]1[C:15]([CH2:30][OH:31])=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: CCCCc1cc(Cl)nnc1-c1ccccc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CO
Temperature: 75 °C

Procedure:
Concentrated H2SO4 (0.17 ml, 3.2 mmol), (NH4)2S2O8 (0.575 g, 2.52 mmol) and AgNO3 (4 mg) are added to a solution of 4-butyl-6-chloro-3-phenyl-pyridazine (0.526 g, 2.1 mmol) in MeOH (12 mL) and water (6 mL). The mixture is heated at 75° C. for 3 h and the solvent is then evaporated in vacuo. The residue is partitioned between saturated aqueous NaHCO3 solution (30 mL) and EtOAc (30 mL) and the organic layer is washed with water (25 mL), brine (25 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatography (silica gel, 2:1 hexane, EtOAc) provides the product as a light yellow solid. LC-MS (M+1) 277. 1H NMR (δ, CDCl3) 7.42-7.50 (m, 5H), 4.87 (s, 2H), 2.75 (t, J=8.1 Hz, 2H), 2.40 (s, 1H), 1.34-1.43 (m, 2H), 1.17-1.25 (m, 2H), 0.74 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[C:22](=[O:33])[N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:21]2[C:22](=[O:33])[N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][N:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccccn2)C1
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1ccnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of 1-tert-butyloxycarbonyl-trans-3-amino-4-(2-pyridyl)pyrrolidine from step 7 above (2.5 g, 9.5 mmol), 3-bromo-1-ethoxycarbonylmethylpyrazinone (2.5 g, 9.5 mmol), and DIEA (1.9 mL, 11 mmol) in toluene (30 mL) was heated to reflux for 24 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 60-85% EtOAc:hexanes to give the title compound as an amorphous solid (3.4 g; TLC Rf=0.5, 4:1 EtOAc:hexanes; HPLC RT=5.92 min, method A).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16]([CH2:18][C:19](O)=[O:20])#[N:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:19](=[O:20])[CH2:18][C:16]#[N:17])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: N#CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#CCC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorobenzyl)piperazin-2-one (1.99 g, 9.6 mmol), cyanoacetic acid (0.82 g, 9.6 mmol), EDC (2.02 g, 10.5 mmol), and HOBt (0.15 g, 0.96 mmol) in anhydrous DMF (40 mL), N,N-diisopropylethylamine was added until the solution is about pH 6. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between chloroform and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. The residue was subjected to column chromatography on silica gel eluting with a mixture of 9:1:0.1 mixture of chloroform, methanol, and aq ammonium hydroxide. Collection and concentration of appropriate fractions provided the title product. Residual protic solvent was removed by co-evaporation with benzene (3×). ES MS M-OCH3=276
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH:7]=[C:8]([C:19]([CH3:21])=O)[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])([O-:3])=[O:2].C(O)(=O)C.[C:29]([CH2:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34])(=[NH:31])[NH2:30].C[O-].[Na+]>C(O)(C)C>[NH2:30][C:29]1[NH:31][C:19]([CH3:21])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])[CH:7]([C:6]2[CH:22]=[CH:23][CH:24]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:32]=1[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCO[N+](=O)[O-]
Reactant: N=C(N)CC(=O)OCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)OCCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCO[N+](=O)[O-])=C(N)N1
Yield: 65.9 %

Procedure:
500 ml of an isopropanol solution containing 18.8 g (55.7 mmoles) of 3-nitrooxypropyl 2-(3-nitrobenzylidene)acetoacetate, 14.76 g (55.7 mmoles) of 3-nitrooxypropyl amidinoacetate acetate and 3.00 g (55.7 mmoles) of sodium methoxide were heated under reflux for 90 minutes. The solution was then cooled and insolubles were filtered off. The isopropanol was then evaporated off under reduced pressure. The resulting residue was dissolved in methylene chloride, and the solution was washed with water and dried over anhydrous sodium sulfate. The methylene chloride was evaporated off under reduced pressure, to give a residue, which was purified by silica gel column chromatography, eluted with a 3:1 by volume mixture of toluene and ethyl acetate, and the product was recrystallized from toluene, to afford 19.3 g (yield 65.9%) of the title compound as yellow powdery crystals, melting at 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Fe]
Agent: [Ru+2]
Agent: CC[O-]
Solvent: CCO
Product: CC(O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Fe, R=n-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in ethanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 80° C. After the mixture was cooled to room temperature, p-chloroacetophenone (0.4 mmol), ethanol (2 mL) and a solution of sodium ethoxide in ethanol (0.2 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (5 atm) at 0° C. The solvent was removed under reduced pressure, the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-chlorophenyl)ethanol was obtained and the ee value (ee=97%) was measured by GC analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Oc1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CCc2cc(O)ccc2C1
Reaction time: 8 h

Procedure:
1.2 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are suspended in 50 ml of methylene chloride, 1.2 ml of triethylamine are added, and a solution of 1.4 g of 4-chlorobenzoyl chloride in 10 ml of methylene chloride is added dropwise with stirring and cooling. After standing overnight, the mixture is extracted by shaking with 2N hydrochloric acid and water, and the organic phase is dried and evaporated in a rotary evaporator. A colorless oil remains, and this crystallizes on trituration with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Br:42])[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCCCO.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.CN(C=O)C>[Br:42][C:39]1[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]4[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=4[C:30]4[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:48][CH2:49]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCCCO
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (150 mg, 0.184 mmol, 1 equiv), SPhos (15 mg, 0.037 mmol, 0.2 equiv), Pd(OAc)2 (8 mg, 0.037 mmol, 0.2 equiv), n-BuOH (0.055 mL, 0.74 mmol, 4 equiv), and Cs2CO3 (90 mg, 0.276 mmol, 1.5 equiv) in 10:1 DMF:water (3.6 mL) was heated to 80° C. for 2 h. More Pd(OAc)2 (41 mg) was added and the reaction was stirred for 3 h. The reaction was then removed from heat and stirred at ambient temperature for 4 d. More Pd(OAc)2 (10 mg) was heated to 85° C. for 5 h. The reaction was then removed from heat. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (63 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=8.0 Hz, 1H), 8.11 (d, J=6.8 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.11 (dd, J=9.0, 3.0 Hz, 1H), 7.03-6.90 (m, 2H), 6.15 (br. s., 1H), 4.47 (d, J=6.3 Hz, 1H), 3.95 (t, J=11.2 Hz, 1H), 3.80-3.66 (m, 5H), 3.57-3.42 (m, 2H), 3.09 (d, J=11.3 Hz, 1H), 2.71 (d, J=11.8 Hz, 1H), 2.57 (s, 3H), 2.01-1.66 (m, 10H), 1.28 (s, 3H), 1.24 (s, 9H), 1.11 (d, J=6.0 Hz, 3H). LCMS (ESI, M+1): 736.20.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:26][CH2:25][C:20]3(OCC[O:21]3)[CH2:19][CH2:18]2)[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:27]=[C:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][N:14]1[CH:17]1[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(N[C@H]1CCN(C2CCC3(CC2)OCCO3)C1=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)=O
Product: O=C1CCC(N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Yield: 100.8 %

Procedure:
8-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-1,4-dioxaspiro[4.5]decane (2.70 g, 7.21 mmol, 1 eq.) and p-toluene sulfonic acid (0.14 g, 0.721 mmol, 0.1 eq.) were dissolved in acetone (20 mL) at room temperature. Refluxed for 4 hours. Reaction was not complete by TLC. Added 1 N HCl (10 mL). Refluxed for 10 minutes. Stripped off the acetone. Added saturated sodium bicarbonate (25 mL). Extracted 3 times with methylene chloride (25 mL). The organic layers were combined, dried over sodium sulfate and stripped to give benzyl (3S)-2-oxo-1-(4-oxocyclohexyl)-pyrrolidin-3-ylcarbamate (2.40 g) as an amber glass. Yield=95%. LCMS detects (M+)+=375.14.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[CH:14][N:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38]C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38][C:6](=[O:7])[N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[CH:14][N:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2-n2ccnc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F

Procedure:
4H,6H-3,5,10b-Triaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester was deprotected using trifluoroacetic acid and the resulting salt was coupled with (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid using HOBT, EDC and DIPEA to afford [3-oxo-3-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester as a viscous oil.
Reaction SMILES: C(N(CC)CC)C.CN1CCN(C)C1=O.Br.[NH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1.Cl[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>O1CCCC1>[CH:36]([S:37]([NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:25][CH:26]=1)(=[O:39])=[O:38])=[CH2:35]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: C=CS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.3 %

Procedure:
3.54 g of triethylamine was added to a 1,3-dimethyl-2-imidazolidinone suspension (35 ml) containing 3.10 g of 6-[4-(3-aminopropyl)phenyl]pyridazin-3(2H)-one hydrobromide. Then, a tetrahydrofuran solution (15 ml) containing 1.95 g of chloroethylsulfonyl chloride was added to the mixture, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water and extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (10:1)) to obtain 1.19 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-pyridazin-3(2H)-one.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8](=O)[C:4]=2[CH:5]=[N:6][CH:7]=1.[NH3:12].CO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:12])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C1CCc2c(Br)cncc21
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: NC1CCc2c(Br)cncc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
4-Bromo-5H-cyclopenta[c]pyridin-7(6H)-one (1.01 g, 4.76 mmol), titanium (IV) isopropoxide (2.79 mL, 9.53 mmol) and ammonia, 2M in MeOH (11.9 mL, 23.8 mmol) were stirred at RT for 5 h. The reaction mixture was cooled to 0° C. and NaBH4 (270 mg, 7.14 mmol) was added in three portions over 20 min; the resulting mixture was stirred at RT for an additional 1.5 h. The reaction was quenched by pouring it into ammonium hydroxide (25%) (24.8 mL, pH 9-10), the precipitate was filtered and washed with AcOEt (3×, each time suspended in AcOEt and stirred for 5 min). The organic layer was separated and the remaining aqueous layer was extracted with EtOAc. The combined organic extracts were extracted with aq. 1 M HCl. The acidic aqueous extracts were washed with EtOAc (1×), then treated with aq. sodium hydroxide (2 M) to give a pH of 10-12, and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (530 mg, 52% yield in 70% purity, determined by 1H-NMR) as dark green amorphous solid. MS: 213.0 (M+H+, 1Br).
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH:13]([OH:22])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[Na+]>CN(C)C=O.CN(C1C=CC=CN=1)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH:13]([O:22][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(CCc1cccnc1)COc1ccc(Br)cc1
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(Br)cc1
Reaction time: 26 h

Procedure:
Imidazole (0.73 g) and dimethylaminopyridine (10 mg) was added to a solution of (±)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (2.20 g) in dimethylformamide (15 ml). When the mixture was homogeneous solid tert-butyldimethylsilyl chloride was added and the solution stirred for 26 hours. A saturated aqueous solution of sodium chloride (200 ml) was added and the mixture extracted with ether (3×100 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as an oil (2.75 g).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.CO.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.210 g, 0.40 mmol) was suspended in 10:1 methanol/H2O and pTsOH.H2O (0.008 g, 0.04 mmol) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was diluted with EtOAc. The organic solution was washed with sodium bicarbonate (2×), brine (1×) and dried over Na2SO4. After filtration, the filtrate was concentrated, and recrystallized from EtOAc and heptane. This solid was washed with heptane-CH2Cl2 (1:1 and dried in vacuo at 60 C to give N-((R)-2,3-Dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as a white solid, (0.136 g, 70%). Product shrinks at 90.8 C, melts at 115-117 C. Analysis shows C, 40.92; H, 3.16; N, 5.41; F, 11.30; I, 23.92 (6.75% EtOAc, 0.96% heptane).
Reaction SMILES: [CH3:1]Br.[CH:3]1([P:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([SH:11])=[S:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH:3]1([P:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([S:11][CH3:1])=[S:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: CBr
Product: CSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
Methyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain methyl dicyclohexylphosphinodithioate, m.p. 75°-75.5° C, which on testing lasted 1500 hours* longer than the control. The average total number of hours required to each failure was 3.4 times that of the control.
Reaction SMILES: CO.Cl.[CH3:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19]C1CCCCO1)[C:8]([NH:10][CH3:11])=[O:9]>[Cl-].[Na+].O>[OH:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7](=[N:6][O:5][CH3:4])[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)C(=NOC)c1ccccc1COC1CCCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methanol (2 ml) and a 36% aqueous hydrochloric acid solution (0.01 g, 0.0001 mol) were added to an E/Z mixture of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.31 g, 0.001 mol), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, half-saturated brine (80 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.21 g, Yield: 94.6%, E/Z=97/3) as colorless crystals.