Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:53][S:54]([N:57]1[CH2:61][CH2:60][CH:59](O)[CH2:58]1)(=[O:56])=[O:55]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[O:19][CH:59]1[CH2:60][CH2:61][N:57]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:58]1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(OC2CCN(S(C)(=O)=O)C2)c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (150 mg, 506 μmol) in 5 mL of THF under N2 was added triphenylphosphine (146 mg, 557 μmol). The solution was chilled to 0° C. in an ice bath and then diisopropyl azodicarboxylate (108 μL, 557 μmol) was added dropwise to the reaction. After stirring for 15 min 0° C., a solution of 1-(methylsulfonyl)pyrrolidin-3-ol (84 mg, 506 μmol) in THF was added to the reaction. The reaction was allowed to warm to room temperature and it was stirred for 10 h. The reaction was concentrated and diluted with EtOAc. The organic solution was extracted with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 10% to 80% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (1R)—N-(4-chloro-3-(1-(methylsulfonyl)pyrrolidin-3-yloxy)benzyl)-1-(3-chlorophenyl)ethanamine 99 (83 mg, 37% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.26 (d, 1H) 1.73 (d, J=6.85 Hz, 3H) 2.25-2.32 (m, 2H) 2.91 (s, 3H) 3.51-3.60 (m, 2H) 3.62-3.66 (m, 2H) 4.00 (d, 1H) 4.20 (d, 1H) 4.50 (m, 1H) 5.08-5.13 (m, 1H) 6.99-7.07 (m, 1H) 7.14-7.18 (m, 1H) 7.43-7.52 (m, 4H) 7.57 (m, 1H). Mass spectrum: calculated for C20H24Cl2N2O3S 443.4. found 444.4 (M++1).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]([F:30])([F:29])[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH:24]([O:27][NH2:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:28][O:27][CH:24]1[CH2:23][CH2:22][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:30])([F:9])[F:29])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH2:26][CH2:25]1)=[O:8])[CH3:7]
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chlorooxoacetate (0.145 ml, 1.30 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (390 mg, 1.15 mmol) and triethylamine (0.246 ml, 1.76 mmol) in CH2Cl2 (8 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3 solution (10 ml) and concentrated in vacuo to give crude product of N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C1COCC1>[ClH:12].[Cl:12][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cl
Product: Nc1ncccc1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of (2-aminopyridin-3-yl)methanol (1.0 g) in THF (dry) (10 mL) was added dropwise to a solution of thionyl chloride (0.736 mL) in THF (dry) (30 mL) at 0° C. The mixture was stirred at room temperature for 30 min and concentrated in vacuo to give 3-(chloromethyl)pyridin-2-amine hydrochloride as a yellow gum. NaH (60%, 147 mg) was added to a mixture of 4-(1-methylpropyl)phenol (503 mg) in DMF (dry) (7 mL) at 0° C. The mixture was stirred at the same temperature for 20 min, then was added with the prepared 3-(chloromethyl)pyridin-2-amine hydrochloride (300 mg) at the same temperature. The mixture was stirred at 0° C. for 20 min, room temperature for 1 hr and 60° C. for 1 hr. Silica-gel was added to the mixture and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (151 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])[C:9]2[CH:13]=[C:12]([C:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH:15]=3)[S:11][C:10]=2[C:21]([OH:23])=[O:22])[CH2:4][CH2:3]1.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:34]([O:41][N:42]=[C:17]1[CH2:18][CH2:19][C:14]([C:12]2[S:11][C:10]([C:21]([OH:23])=[O:22])=[C:9]([N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)[C:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[CH:13]=2)=[CH:15][CH2:16]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=O)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=NOCc4ccccc4)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxo-cyclohex-1-enyl)-thiophene-2-carboxylic acid (30 mg, 0.065 mmol) in a 2:1 H2O-ethanol mixture (3 mL) were added O-benzylhydroxylamine hydrochloride (21 mg, 0.13 mmol) and sodium acetate (18 mg, 0.13 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was extracted with CH2Cl2, organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with 2-15% MeOH in CH2Cl2 to give 20 mg (54%) of 5-{4-benzyloxyimino-cyclohex-1-enyl}-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO.C(OCC)C>[NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cnccc1C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1N

Procedure:
A suspension of 3-aminoisonicotinic acid (13.81 g, 100 mmol, prepared using the procedure described in Crum J. D.; Fuchsman, C. H. J. Heterocyclic Chem., 1966, 3, 252) in methanol (250 mL) was treated with thionyl chloride (14.7 mL, 200 mmol) and heated to reflux for 3 days. The yellow solution was concentrated to dryness to provide a yellow solid. This solid was suspended in 200 mL of ethyl ether and treated with 400 mL of saturated, aqueous NaHCO3 and the biphasic solution was stirred until all of the solids were dissolved. The layers were separated and the aqueous phase was extracted with 2 additional portions of ethyl ether. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the title compound as a light yellow solid. MS (DCI/NH3) m/z 153 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N(CC)CC)C.[OH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17]1.[Cl-].[NH4+]>ClCCl>[O:21]=[C:19]1[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17][C@H:16]([CH2:15][O:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:20]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
Ethyl chloroformate (5.7 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for 18 hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 4 mg (17%) of ethyl carbonate (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester as a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)C=CN=[CH:2]1.[N:32]1C=CC=[CH:34][CH:33]=1.N1C=CC=N1.N1C=CN=C1>C(N(CC)CC)C.C1COCC1.C1(C)C=CC=CC=1>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:2]=[CH:34][CH:33]=[N:32]1
Reactant: c1ccncc1
Reactant: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Agent: c1c[nH]cn1
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)c2c(-n3cccn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared according to the procedure outlined above for 2-(N-imidazolyl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 27, Table 1), above, except pyridine was used as the solvent in place of toluene, THF and triethylamine and pyrazole was used as the nucleophile in place of imidazole. 1H NMR (300 MHz, CDCl3) δ 7.82(d, 1H, J=2.55 Hz), 7.65(d, 1H, J=1.51 Hz), 7.18(d, 1H, J=8.57 Hz), 7.01(s, 2H, benzoyl Hs), 6.96(d, 1H, J=8.61 Hz), 6.30(t, 1H, J=1.88 Hz), 3.96(s, 3H, OMe), 3.86(s, 3H, OMe), 3.75(s, 6H, 2×OMe).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[ClH:22].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc(Cl)cc1)c1ccc2cc[nH]c2c1
Product: Cl
Yield: 92 %

Procedure:
[3-(1H-Indol-6-yl)-3-(4-chloro-phenyl)-propyl]-methyl-amine XLV was prepared as a hydrochloride (240 mg, 92% yield) from 3-(1H-indol-6-yl)-3-(4-chloro-phenyl)-N-methyl-propionamide, using the procedure described for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=299.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[N:35]=[CH:34][C:33]=1[NH2:45].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:43])([CH3:44])[C:39]([F:40])([F:41])[F:42])[N:35]=[CH:34][C:33]=1[NH:45][C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[CH:6]=[N:7][C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[CH:21][C:22]=1[F:30]
Reactant: CC(C)(c1cc(Br)c(N)cn1)C(F)(F)F
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)C(F)(F)F)cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.073 mmol) in pyridine (5 mL) was added 4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (20.64 mg, 0.073 mmol) and T3P® (EA solvate) (0.5 mL, 0.073 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated and purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a light yellow solid of N-(4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.038 mmol, 51.7% yield): 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.33 (d, J=9.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 3.93 (s, 2H), 3.82 (s, 3H), 1.63 (s, 6H), 1.40 (t, J=7.0 Hz, 3H). ES-LCMS m/z 678.0 (M+H+2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:19]S(C)=O>>[CH3:19][N:16]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=1)[CH2:15]2
Reactant: CS(C)=O
Reactant: FC(F)(F)c1ccc(C2=CC3CCC(C2)N3)cc1
Product: CN1C2C=C(c3ccc(C(F)(F)F)cc3)CC1CC2
Temperature: 130 °C

Procedure:
(±)-3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-ene in the form of a free amine (1 mg) was dissolved in anhydrous dimethyl sulphoxide (DMSO; 300 ml), and then reacted with [11C]-methyl iodide and heated for 5 min at 130° C. The resulting N-[11C]-methyl labelled [11C]-compound was subsequently purified by HPLC. Removal of the HPLC solvent was achieved by heating the [11C]-labelled (±)8-methyl-3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-ene containing fraction under reduced pressure. The labelled product was then formulated in saline or water (10 ml) and passed over a 0.22 mm membrane filter into a sterile vial.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][O:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(COCCO)OCC
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(COCCOS(C)(=O)=O)OCC
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of 2-diethylphosphonomethoxy-1-ethanol (40.7 g, 192 mmol) in 500 mL of CH2Cl2 was cooled to 0° C. and then triethylamine (29.1 g, 288 mmol) was added in one portion, followed by addition of methanesulfonyl chloride (26.4 g, 230 mmol) dropwise over 20 min. The reaction mixture was kept at 0° C. for 0.5 hours and then poured into water. The aqueous phase was extracted with two portions of CH2 Cl2 and the combined organic phases dried over MgSO4, filtered and concentrated to afford 54.4 g (98%) of 1-methanesulfonyloxy-2-(diethylphosphonomethoxy)ethane as a clear, pale orange oil. The mesylate could be employed without purification or purified by column chromatography on silica gel (5% methanol in CH2 Cl2).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.C1C2C(=CC=CC=2)CC1N[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24]>>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:6]2
Reactant: NC1Cc2ccc(Br)cc2C1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Agent: Br
Product: CC(C)S(=O)(=O)NC1Cc2ccc(Br)cc2C1

Procedure:
The title compound was prepared from 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001, 343, No. 5, pp 461-472) by a similar process to the preparation of Intermediate 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CCN(C)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCC2CNCC21

Procedure:
9 g (45.4 mmol) of ethyl 2-methyl-2,7-diazabicyclo [3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate, extracted ten times using 50 ml of chloroform each time, dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: B(Br)(Br)[Br:2].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH2:28][CH2:27][CH2:26][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[BrH:2].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]3[CH2:28][CH2:27][CH2:26][N:16]3[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCC3)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1ccc(-c2nc3n(c2-c2ccc(O)cc2)CCC3)cc1

Procedure:
A solution of 46.5 g (0.19 mol) of boron tribromide in about 240 ml of dry methylene chloride was added dropwise with stirring over a 90 minute period to a solution of 35.0 g (0.11 mol) of 2,3-di(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole in 600 ml of dry methylene chloride maintained at -75° under a nitrogen atmosphere. The solution was then decanted and the remaining solid material was slurried with methylene chloride and water, collected by filtration and dried to give 2,3-di-(4-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole hydrobromide.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][N:21]=1>C(OCC)(=O)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[N:21]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Yield: 98.1 %

Procedure:
3,4-Dihydro-2H-pyran (0.232 mL, 2.54 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added to a solution of 3-bromo-1H-indazole (0.250 g, 1.269 mmol) in ethyl acetate (12.0 ml), and the mixture was heated at reflux for 48 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column. gradient elution with 0-25% ethyl acetate-hexane) to afford 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.350 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 281, 283 [M+H]+.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.[CH3:13][O:14][C:15]1[C:16]([NH:21][C:22]([NH:24]C(OCC)=O)=S)=[N:17][CH:18]=[CH:19][CH:20]=1>C(O)C.CO>[CH3:13][O:14][C:15]1[C:16]2[N:17]([N:6]=[C:22]([NH2:24])[N:21]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)NC(=S)Nc1ncccc1OC
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: COc1cccn2nc(N)nc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 21.8 g (313.7 mmol) hydroxylamine hydrochloride and 32.2 ml (188.2 mmol) N-ethyldiisopropylamine in a mixture of 130 ml methanol ethanol 1:1 was added 16 g (62.7 mmol) N-(3-methoxy-2-pyridinyl)-N′-carboethoxy-thiourea and stirred for 2 h at room temperature and subsequently for 3 h at 60° C. The volatiles were removed under reduced pressure and the residue was triturated with 100 ml water. The collected precipitate was washed with 25 ml methanol/diethyl ether 4:1 and afterwards with 25 ml diethyl ether. After drying under high vacuum 8 g (78%, 48.7 mmol) of the title compound was collected as off-white crystals.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1.Br[CH2:16]C1OCC(O)C(O)CO1.CC(C=C)=O>>[Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH:13]=[CH2:16])[O:9]2)[CH2:5][O:4]1
Reactant: OC1COC(CBr)OCC1O
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Agent: C=CC(C)=O
Product: C=CC1(C)OC2COC(CBr)OCC2O1
Yield: 54 %

Procedure:
4-Bromomethyl-9-methyl-9-vinyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane starting from 220 mmol (50 g) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane and from 1.36 mol (95.5 g) of methylvinyl ketone, fractional distillation giving 33.2 g of 4-bromomethyl-9-methyl-9-vinyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane (54% yield) with a boiling point from 94° to 101° C. (0.2 mbar).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:12]1[CH:13]=[CH:14][C:8]2[C:7](=[O:16])[NH:6][C:5]3[CH:17]=[C:18]([O:19][CH3:20])[C:2]([CH:23]=[CH:22][C:21]([O:25][CH3:26])=[O:24])=[CH:3][C:4]=3[NH:10][C:9]=2[CH:11]=1
Reactant: C=CC(=O)OC
Reactant: COc1cc2c(cc1Br)Nc1cc(Cl)ccc1C(=O)N2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cc2c(cc1OC)NC(=O)c1ccc(Cl)cc1N2
Yield: 83.6 %

Procedure:
A mixture of Example 223G (71 mg, 0.2 mmol), methyl acrylate (64 mg, 0.8 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol) and 1 mL Et3N in 3 mL of DMF was heated at 110° C. overnight. The reaction mixture was diluted with EtOAc when it was still warm, and poured onto water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was triturated with 20 mL of 1:1 EtOH/Aceton to give 60 mg of the title compound. MS (DCI) m/e 359 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.91 (s, 1H), 7.86-7.75 (m, 2H), 7.25 (s, 1H), 7.03 (d, J=1.53 Hz, 1H), 6.93 (dd, J=8.59, 1.84 Hz, 1H), 6.75 (s, 1H), 6.35 (d, J=15.96 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]3[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:24]=1.C(=O)([O-])[OH:26].[Na+]>O1CCOCC1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:24]=[C:3]([CH2:2][OH:26])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=C([O-])O
Reactant: Fc1ccccc1C1=NCc2nc(CCl)cn2-c2ccc(I)cc21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 1.2 g of 2-chloromethyl-6-(2-fluorophenyl)-8-iodo-4H-imidazo [1,2-a][1,4]benzodiazepine in 20 ml of dioxan was treated with a solution of 0.4 g of sodium hydrogen carbonate in 10 ml of water and the mixture was stirred at 80° C. for 2 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethanol. There was obtained 0.6 g of amorphous 6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol which was converted into the crystalline hydrochloride (m.p. 274-276° C.),