Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1(Br)C(=O)C2C(=CC(O[Si](C(C)C)(C(C)C)C(C)C)=C(C)C=2)OC1.[CH3:26][C:27]1[C:28]([Br:51])=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[O:33][CH2:32][C:31](Br)(Br)[C:30]2=[O:50].[F:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2([OH:65])[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:55][CH:54]=1.C(N(CC)CC)C>C(#N)C>[Br:51][C:28]1[C:27]([CH3:26])=[C:36]([O:37][Si:38]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:43])[CH3:44])[CH:45]([CH3:47])[CH3:46])[CH:35]=[C:34]2[C:29]=1[C:30](=[O:50])[C:31]([N:62]1[CH2:61][CH2:60][C:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)([OH:65])[CH2:64][CH2:63]1)=[CH:32][O:33]2
Reactant: Cc1c(O[Si](C(C)C)(C(C)C)C(C)C)cc2c(c1Br)C(=O)C(Br)(Br)CO2
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Agent: Cc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)OCC(Br)(Br)C2=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(O[Si](C(C)C)(C(C)C)C(C)C)cc2occ(N3CCC(O)(c4ccc(F)cc4)CC3)c(=O)c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-dibromo-6-methyl-7-triisopropylsilyloxychroman-4-one and 6-methyl-3,3,5-tribromo-7-triisopropylsilyloxychroman-4-one (the compounds of Preparation 34, 1.0 g), 4-(4-fluorophenyl)-4-hydroxypiperidine (0.79 g, 4.05 mmol) and triethylamine (0.60 mL, 4.30 mmol) in acetonitrile (30 mL) was stirred 30 min at ambient temperature. The precipitate which formed was collected by filtration to afford 0.188 g of 5-bromo-6-methyl-7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one. The filtrate was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 20% ethyl acetate/hexane (100 mL), 0.115 g of 6-methyl -7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one as a light yellow solid which had mp 193-195° C.; 20% ethyl acetate/hexane (100 mL) and 40% ethyl acetate/hexane (100 mL), 0.07 g of a mixture; 40% ethyl acetate/hexane (100 mL) and 60% ethyl acetate/hexane (400 mL), 0.30 g of 6-methyl-7-hydroxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][N:14]([CH3:20])[CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(C23CNCC2C3)c2ccccc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CC2CC2(c2ccc(F)c3ccccc23)C1

Procedure:
A stirred solution/suspension of 1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (215 mg, 0.95 mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde (0.5 mL, 9.5 mmol), then with sodium triacetoxyborohydride (1.25 g, 4.75 mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride containing a little 2-propanol (2×10 mL). The combined organic solution was dried (MgSO4) and concentrated in vacuo to afford 1-(4-fluoronaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (150 mg, 65%, essentially pure without chromatography). This was dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with ether, collected, and dried in vacuo to afford 3-methyl-1-(4-fluoronaphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane, hydrochloride (150 mg, 82%) as a white solid. MS (M+1) 242.1. 1H NMR (DMSO-d6) δ 0.91-1.01 (m, 1H) 2.01-2.09 (m, 1H) 2.13-2.24 (m, 1H) 2.72-2.84 (m, J=4.69 Hz, 3H) 3.16-3.30 (m, 1H) 3.72 (q, J=5.60 Hz, 2H) 3.93 (dd, J=11.23, 5.17 Hz, 1H) 7.31 (dd, J=10.74, 8.01 Hz, 1H) 7.48-7.79 (m, 3H) 8.07 (d, J=8.20 Hz, 1H) 8.20 (d, J=8.40 Hz, 1H). 13C (DMSO-d6) δ 14.51, 22.36, 29.97, 56.72, 60.47, 109.90, 121.34, 123.61, 125.04, 127.43, 128.50, 131.39, 134.24 157.08.
Reaction SMILES: [Li].ClC1C=CC(C)=CC=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[N:20][N:21]=2)=[CH:13][CH:12]=1.C([Li])CCCCC.C([O:32][B:33](OC(C)C)[O:34]C(C)C)(C)C>O1CCCC1.O.C(O)(=O)C>[O:18]1[CH:19]=[N:20][N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:11]([B:33]([OH:34])[OH:32])=[CH:12][CH:13]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2nnco2)cc1
Agent: [Li]
Agent: [Li]CCCCCC
Solvent: Cc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: -35 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
Lithium granules (8.2 g) and tetrahydrofuran (670 g) were charged to a reactor under an argon atmosphere and the mixture cooled to −35° C. 4-Chlorotoluene (74.3 g) was added at −35° C. and the mixture was held at this temperature for 6 hours. The resultant solution was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (124.4 g) in tetrahydrofuran (800 g) at −65° C. After 30 mins a solution of n-hexyllithium (33% w/w in hexanes) (240 ml) was then added at −65° C. After a further 30 min triisopropylborate (230.8 g) was then added maintaining the reaction mixture at −65° C. The reaction mixture was allowed to warm to −35° C. and drowned out into a solution of acetic acid (91.5 g) in water (688 g). The resultant solid was isolated, washed with THF and water, and dried to yield the title compound (92.2 g, 88%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Br.[N:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[ClH:29].[C:30]1([C:36]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:44]3[C@H:40]([CH2:41][NH:42][CH2:43]3)[C@@H:39]([OH:45])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>ClCCl.CC(C)=O.C(OCC)C.C(N(CC)CC)C>[ClH:29].[C:46]1([C:36]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:44]3[C@H:40]([CH2:41][N:42]([C:26](=[O:28])[CH2:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH2:43]3)[C@@H:39]([OH:45])[CH2:38][CH2:37]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 1 h
Yield: 12.9 %

Procedure:
0.42 cm3 of triethylamine and 0.49 g of carbonyldiimidazole are added to a solution, cooled to +4° C., of 0.86 g of (2-pyrrolidinophenyl)acetic acid hydrobromide in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 1 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.42 cm3 of triethylamine in 10 cm3 of dry dichloromethane is added. The reaction mixture is stirred at room temperature for 24 hours and then then washed twice with 10 cm3 of water and then with an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The product, which is obtained in the form of a base, is converted to the hydrochloride by dissolving in a minimum amount of acetone and treating with a solution of hydrochloric acid in ethyl ether and adding ethyl ether. The solid obtained is triturated in ethyl ether and then dried. 0.2 g of (3aR,4S,7aR)-7,7-diphenyl-2-[(2-pyrrolidinophenyl)acetyl]-4-perhydroisoindolol hydrochloride is obtained in the form of a beige solid.
Reaction SMILES: [OH-].[Na+].C([C:11]1[S:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:13](=[O:23])[CH:12]=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([N:14]2[C:13](=[O:23])[CH:12]=[CH:11][S:15]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(-n2sc(C(=O)c3ccccc3)cc2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(-n2sccc2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
Aqueous sodium hydroxide (4 mL, 10%) was added to the solution of 5-benzoyl-2-p-tolylisothiazol-3-one 29 (203 mg, 0.678 mmol) in benzene (9 mL), and the mixture was stirred for 3 d at room temperature. The reaction mixture was added water (20 mL) and extracted with ethyl acetate. The combined organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) and gave the compound 30 (77 mg, 59%). 1H-1-NMR (CDCl3, 300 MHz) δ 2.38 (s, 3H), 6.32 (d, J=6.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 8.14 (d, J=6.6 Hz, 1H). HRMS: calculated for C10H10NOS (M+H)+192.0483. Found 192.0494.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC[C@H](NCc1ccccc1)C(=O)O
Solvent: O
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Yield: 98.9 %

Procedure:
N-Benzyl-glutamic acid (35 g) was dissolved in 300 ml of water and refluxed for 15 hours. The solution was extracted with methylene chloride, washed with brine, dried over sodium sulfate and concentrated to yield 32 g of N-benzyl-5-oxo-proline. The acid (55.25 mmoles, 12.1 g) was dissolved in 15 ml of DMF and 30 ml acetonitrile. The solution was cooled to -25° C. Oxalyl chloride (5.0 ml) in 10 ml acetonitrile was added. The solution was stirred vigorously for 30 minutes. A solution of t-butanol (135 mmoles, 10.0 g) and pyridine (13.2 g) in 10 ml acetonitrile was added over 30 minutes and then warmed to 0° C. Brine and ethyl acetate were added. The organic phase was diluted and washed with water, dried and concentrated to yield 10.7 g of N-benzyl-5-oxo-L-proline t-butyl ester. (MS)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[I:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(I)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(F)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 11.8 %

Procedure:
A solution of 4-fluoro-2-iodo-6-methyl-benzoic acid (8.87 g, 31.8 mmol) in acetone (80 mL) was treated with anhydrous K2CO3 (6.91 g, 50 mmol) followed by methyl iodide (2.72 mL, 40 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography of the resulting material using 10% ethyl acetate in hexanes afforded 4-fluoro-2-iodo-6-methyl-benzoic acid methyl ester (1.1 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10](Br)=[O:11]>>[C:2]1([NH:1][C:10](=[O:11])[CH2:9][Br:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Product: O=C(CBr)Nc1ccccc1

Procedure:
Aniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=O)=[N:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C.[Cl-].[NH4+]>[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH2:1])=[N:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reaction time: 0.5 h

Procedure:
Methyl(triphenyl)phosphonium bromide (774 mg, 2.166 mmol) was suspended in diethyl ether (5 ml) and potassium tert-butoxide (1.78 M in THF, 1.3 ml, 2.314 mmol) was added at 0° C. dropwise, the suspension was stirred 30 min at same temperature. A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (500 mg, 1.444 mmol) in diethyl ether (1 ml) was added dropwise at 0° C. and the mixture was stirred from 0° C. to 5° C. for 1 h 20 min. The mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 8% EtOAc in Hexane) to afford ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]cyclohexanecarboxylate as a light yellow oil. MS ESI calc'd. for C14H8BrNO2S [M+H]+ 344, 346. found 344, 346.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26](Cl)([CH3:28])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:26]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (219 mg, 0.62 mmol) in THF (10 ml) was treated with AcCl (53 μl, 0.75 mmol) and stirred at room temperature for 1 hour. More AcCl (200 μl) was added and stirred for a further hour. Sat. NaHCO3 solution was added and the layers separated. The organic extract was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (247 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h
Yield: 79.1 %

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (1.06 g, 6.26 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (1.00 g, 7.51 mmol) in DMSO (25 mL). K2CO3 (1.73 g, 12.52 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. Then the reaction mixture was cool down to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc (4:6) and then with EtOAc, 100% to get the title compound (1.40 g). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.16 (d, J=9 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.Br[CH2:13][CH:14](OC)OC>CCO.C(Cl)Cl.[Fe]>[CH3:1][C:2]1[N:3]2[CH:13]=[CH:14][N:11]=[C:4]2[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COC(CBr)OC
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(N)ccc2nccn12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
2-Methyl-3-nitro-6-amino pyridine (63 mg, 0.41 mmol) was suspended in 1.3 mL EtOH containing 0.3 mL conc. HCl. 2-Bromo-1,1-dimethoxy-ethane (73 μL, 0.62 mmol) was added and the resulting mixture was refluxed for 8 h, at which point additional 2-bromo-1,1-dimethoxy-ethane (0.1 mL, 0.85 mmol) was added. The mixture was stirred at reflux overnight, cooled and diluted with CH2Cl2. The organics were washed with sat. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 4 mL AcOH/EtOAc (1:1) and the resulting solution was heated to 75° C. Iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and the mixture was stirred for 20 min. Additional iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and stirring was continued for 30 min. The mixture was cooled to room tempearture and concentrated. The resulting residue was purified by silica gel silica gel flash chomatography with 20% MeOH in CH2Cl2 to give compound 843A (51 mg, 85%) as a yellow-brown solid. HPLC: 72% at 0.18 min and 28% at 0.27 min (retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 147.85 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([N:30]1[CH2:33][CH:32](OC(C2C=CC(Cl)=CC=2)C2C=CC=CC=2Cl)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([N:30]1[CH2:33][CH:32]([O:14][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][CH:15]=2)[CH2:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2Cl)cc1
Reactant: OC(c1ccc(Br)cc1)c1ccc(Br)cc1
Product: Brc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Br)cc2)cc1

Procedure:
This material was prepared from 4,4′-dibromobenzhydrol (84) using the procedure described for compound (8) (6.15 g, 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH:29]3[C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)C1NCC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-carbonyldiimidazole (0.59 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45) and collecting 15 cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified using isopropyl ether to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone (0.6 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (1 cc) and adding a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.COCCNC.[CH3:56][C:57]([OH:61])([C:59]#[CH:60])[CH3:58]>>[OH:61][C:57]([CH3:58])([CH3:56])[C:59]#[C:60][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: COCCN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: CNCCOC
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: COCCN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-(((2-methoxyethyl)(methyl)amino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 2-methoxy-N-methylethanamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (20 mg, 20%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 158) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.81 (t, J=7.0 Hz, 3 H), 1.12 (m, 4 H), 1.30 (m, 14 H), 2.27 (m, 2 H), 3.24 (m, 1 H), 3.41 (m, 1 H), 4.32 (d, J=4.0 Hz, 2 H), 6.95 (m, 1 H), 7.06 (m, 1 H), 7.25 (m, 1 H). mp 106-107° C. Rf 0.30 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:10][CH:11]=C)([CH3:9])[C:5]([O:7][CH3:8])=[O:6].CSC.C[OH:18]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:9])([CH2:10][CH:11]=[O:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: C=CCC(C)(C(=O)OC)C(=O)OC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)C(C)(CC=O)C(=O)OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 31A (1.1 gm, 5.9 mmol) was dissolved in CH2Cl2)/MeOH 10:1 (15 mL) and cooled to −78° C. To the solution was bubbled O3 over 20 minutes. The reaction solution was purged with N2 for a further 10 minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 31B as an oil.