Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]3=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:11]3[N:10]=[C:9]([C:20]3[CH:21]=[N:22][C:23]([NH:30]C(=O)C(C)(C)C)=[CH:24][C:25]=3[C:26]([F:29])([F:28])[F:27])[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].C(O)(=O)C>C(O)C>[NH2:30][C:23]1[N:22]=[CH:21][C:20]([C:9]2[N:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:12]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:11]3[N:10]=2)=[C:25]([C:26]([F:29])([F:28])[F:27])[CH:24]=1
Reactant: COC(=O)c1cc2c(N3CCOCC3)nc(-c3cnc(NC(=O)C(C)(C)C)cc3C(F)(F)F)nn2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)c(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cn1

Procedure:
Compound 22a (300 mg, 0.59 mmol) was suspended in 10 mL of ethanol. 1.5 mL of 2 M potassium hydroxide solution was added and refluxed for 1 hour. The reaction is substantially completed. 2 mL of acetic acid was added. Most of the solvent was distilled off under reduced pressure to precipitate solids. The precipitated solids were filtered to give compound 23a. White solid (224 mg, 92.6%). m.p. 244-245° C. 1H NMR (300 MHz, DMSO-d6): δ 12.54 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.34 (s, 1H), 6.83 (s, 3H), 4.00 (t, J=4.0 Hz, 4H), 3.73 (t, J=4.0 Hz, 4H). LC-MS: 409 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=1)[CH:9]=[C:8]2[CH:27]=[O:28].[N+:29]([CH2:31]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:30].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=1)[CH:9]=[C:8]2[C:27]1[O:28][CH:31]=[N:29][CH:30]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COCCOc1ccn2c(-c3cc(C=O)c4cccc(OC)c4n3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(OC)c4n3)cnc2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To 8-Methoxy-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline-4-carbaldehyde (210 mg, 0.556 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (130 mg, 0.668 mmol) in MeOH (5 mL) was added K2CO3 (154 mg, 1.11 mmol), followed by heating to reflux for 3 hours. The reaction was then cooled to ambient temperature, concentrated and purified by flash column chromatography (EtOAc/MeOH 10:1) providing the desired product (73%). MS APCI (+) m/z 417.2 (M+1) detected.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[C:19]1(C)C=CC=CC=1>>[C:4]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2][CH2:19][O:12]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: Cc1ccccc1
Product: O=C(c1ccccc1)C1(c2ccccc2)COCO1

Procedure:
About 273 grams of crude, wet α-methylolbenzoin prepared as described in Example I was refluxed under a Dean-Stark trap with 0.50 liters toluene for about two hours to remove about 50 ml. water. The reaction mixture was allowed to cool and 35 grams paraformaldehyde and 10 grams p-toluenesulfonic acid were added. The reaction mixture was heated for 45 minutes under controlled conditions such that the solvent refluxed below the trap and no water was collected. The temperature of the reaction mixture was then increased and about 16 ml. water was collected over a three-hour period. The mixture was allowed to cool and then saturated with ammonia gas. The resulting salt precipitate was removed by filtration and benzene solvent removed under vacuum from the residual yellow solution containing the solid reaction product. The crude solid reaction product was recrystallized from 1.6 l. of boiling hexane. 156 grams of recrystallized produce having m.p. of 66°-66.5° C was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].Cl>ClCCl>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane, triethylamine (2.6 mL, 18.5 mmol) and 2-methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added, and the mixture was stirred at 70° C. for 18 hr. To the mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 v/v-50/50 v/v) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:28][CH:29]([CH2:39][CH3:40])[C@@H:30]([C:32]1[N:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=1)[OH:31]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:28][C@H:29]([C:30]([C:32]2[N:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=2)=[O:31])[CH2:39][CH3:40])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC2CCCCC2)no1

Procedure:
It is similarly prepared according to general procedure given for example 8 above but using (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:3]1
Reactant: C=C1CC(=O)O1
Reactant: OC1CCCNC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC(O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of 36.10 g (0.36 mol) of 3-hydroxypiperidine in 300 ml tetrahydrofuran was added dropwise to a solution of 30 g of diketene (0.36 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 53.53 g (0.29 mol, 81% yield) of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Temperature: 80 °C
Yield: 49.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (2.49 g, 10 mmol) in DMF (20 mL) was added 3-amino-phenyl boronic acid (1.51 g, 11 mmol), Pd(PPh3)4 (90 mg, 0.30 mmol), potassium carbonate (1.52 g, 11 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (50 mL×3). The combined organics were concentrated under reduced pressure to give crude product, which was washed with EtOAc to give pure 3′-amino-N-methylbiphenyl-4-sulfonamide (C-3) (1.3 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.95-7.01 (m, 2H), 6.73-6.77 (m, 1H), 2.54 (s, 3H). MS (ESI) m/e (M+H+) 263.0.
Reaction SMILES: [CH2:1]([Si:11]([Cl:14])([Cl:13])Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[Cl:14][Si:11]([Cl:13])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: CCCCCCCCCC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCC[Si](Cl)(Cl)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Tetrahydrofuran (82 mL) and n-decyltrichlorosilane (Tokyo Chemical Industry Co., Ltd., 14.5 g, 52.6 mmol) were placed in a 500 mL four-necked flask in a nitrogen atmosphere, and cooled to 0° C. n-decyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 58 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target dichlorodi-n-decylsilane (Compound E21) (150° C./0.1-0.2 Torr, 13.1 g, yield 65%).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.Cl>C(O)CCC.O1CCOCC1>[F:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([C:14]4[N:15]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[S:12][CH:13]=4)=[CH:17][CH:18]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cs1)C(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in n-butanol (5 ml), 2-chloro-6-fluorobenzo[d]thiazole (202 mg) was added and the reaction mixture was heated at 70° C. and stirred for 10 minutes. 4M HCl in dioxane (0.131 gm) was added and the reaction mixture was stirred for 16 hours at 90° C. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 130 mg (29%). 1H NMR (CDCl3; 300 MHz): δ 7.97 (d, 2H), 7.83 (d, 1H), 7.67 (s, 1H), 7.64 (m, 4H), 7.38 (dd, 1H), 7.13 (td, 1H), 4.77 (q, 1H), 3.80 (s, 3H), 2.37 (m, 1H), 0.97 (dd, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CCN(Cc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
(3R)-1-Benzyl-3-hydroxypyrrolidine (500 μl) and imidazole (466 mg) were dissolved in N,N-dimethyl-formamide (15 ml), tert-butyldiphenylsilyl chloride (1.57 ml) was added under ice cooling, and the mixture was stirred at room temperature for 9 days. After the solvent was distilled off under reduced pressure, and dichloromethane and water were added to the residue to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.27 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:8][C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of phenylmethanol (10.7 g, 98.95 mmol, 1.05 equiv) in N,N-dimethylformamide (100 mL). This was followed by the addition of sodium hydride (3.9 g, 162.50 mmol, 1.20 equiv, 70%) in several batches at 0° C. The mixture was stirred for 25 min at 0° C. To this was added a solution of methyl 2-fluoro-3-nitrobenzoate (18.8 g, 94.41 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The mixture was diluted with 700 mL of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 20 g (74%) of methyl 2-(benzyloxy)-3-nitrobenzoate as yellow oil. MS (ESI) m/z 288 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[F:11][C:5]1[CH:4]=[N:3][CH:2]=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cncc(F)c1
Yield: 64.1 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (3.00 g, 0.0143 mol), anhydrous sodium acetate (3.516 g, 0.0429 mol), and 10% palladium-on-carbon (0.300 g) in methanol (50 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) for 18 hours. The reaction was vacuum filtered through a 0.45μ PTFE membrane and the catalyst thoroughly washed with methanol (25 mL). The filtrate was concentrated by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (100 mL) and water (30 mL), the aqueous pH adjusted to 3 with 6N aqueous hydrochloric acid, and the layers separated. The organic phase was washed with water (2×30 mL) and brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This afforded the title compound as a white solid (1.293 g, 64%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH3:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[N:32]=[CH:33][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=2)[CH:35]=1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)cn1
Yield: 56.6 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 4-methylimidazole (0.25 g) and dimethylformamide (25 ml), the title compound (0.66 g) was obtained as an amorphous solid. MS, m/z: 437.2 (M+H)+, 873.2 (2M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:27])([F:26])[F:25])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:28]O.P(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:28][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:25])([F:27])[F:26])[O:10][N:9]=2)=[CH:7][C:2]=1[F:1]
Reactant: OCc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1cc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)ccc1CBr
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of (2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1.95 mL, 0.740 mmol) in dichloromethane (8 mL) at 0° C. was added phosphorus tribromide (1.0M in dichloromethane) (0.740 mL, 0.740 mmol). After 5 minutes, the ice bath was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, washed with brine, and dried over anhydrous sodium sulfate. The residue was triturated with methanol with sonication, filtered, and washed with methanol. Analysis of the white solid by HPLC and LCMS indicated that there was no significant amount of the desired product present. The filtrate was concentrated under reduced pressure, and the compound was loaded with a minimum amount of dichloromethane on a fritted funnel containing a layer of CELITE® topped with a layer of silica gel. The plug column was eluted with dichloromethane to give 3-(4-(bromomethyl)-3-fluorophenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (0.173 g, 0.370 mmol, 50% yield) as a white solid. The compound had an HPLC ret. time=3.72 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=468.0 and 470.0.
Reaction SMILES: [H-].[Na+].O.[N:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[CH3:22]I>CN(C)C=O>[CH3:22][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([N:4]=[O:5])[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]1=2
Reactant: CI
Reactant: O=NN1c2ccccc2NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)c2ccccc2N(N=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 50% oil dispersion) was added in small portions to a water cooled solution of 10,11-dihydro-5-nitrosodibenzo[b,e][1,4]diazepin11(5H)-one (13.5 g) in dimethylformamide (200 ml) such that the temperature did not exceed 20° C. After the addition was complete the mixture was stirred at room temperature for 30 minutes and then treated with methyl iodide (7.0 g) added in one lot. The resulting mixture, after being stirred at room temperature for 2 hours, was poured into an excess of ice and water, and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue, which contained some dimethylformamide, was repeatedly triturated with water until it turned to a crystalline solid. It was filtered off, washed with water and air-dried to yield the title compound, m.p. 95°-98°.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[S:7](=[O:9])(=[O:8])[C:6]2([CH3:22])[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:23])[N:4]=[C:3]1[N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C:6]3([CH3:22])[S:7](=[O:8])(=[O:9])[C:2]([CH3:39])([CH3:1])[C:3]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[N:4][C@:5]3([CH3:23])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2(C)S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCCC2(C)S(=O)(=O)C1(C)C

Procedure:
A solution of tert-butyl N-[(11bR)-3,3,4a,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (0.076 g, 0.13 mmol) in EtOAc (0.9 ml) and EtOH (0.5 ml) was stirred under hydrogen balloon in the presence of palladium, 10% wt. on activated carbon (0.036 g, 0.033 mmol) for 15 h. The mixture was filtered through the plug of Celite, filter cake was washed with ethyl acetate. The combined filtrate was concentrated to afford crude tert-butyl N-[(11bR)-10-amino-3,3,4a,11b-tetramethyl-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate as mixture of trans and cis diasteromers (˜1:3 ratio) which was used without further purification. m/z (ESI) 560.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH2:15]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.CN(C)C=O>C(N(CC)CC)C>[CH:19]1([C:22]([N:12]2[CH2:13][CH2:14][CH2:15][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:18][CH2:17][CH2:16][CH:10]3[CH2:11]2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc(C23CCCNCC2CCC3)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C23CCCC2CN(C(=O)C2CC2)CCC3)c1

Procedure:
A solution of 1.1 g. of 5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine and 1.3 g. of cyclopropylformyl chloride in 20 ml. of N,N-dimethylformamide containing 1.4 g. of triethylamine was stirred at 25° C. for eight hours. The reaction mixture then was added to 200 ml. of water, and the aqueous solution was extracted several times with diethyl ether. The ethereal extracts were combined, and the solvent was removed therefrom by evaporation under reduced pressure to provide 2-cyclopropylformyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. The product so formed was dissolved in 70 ml. of tetrahydrofuran containing 1 g. of lithium aluminum hydride, and the reaction mixture was heated at reflux and stirred for three hours. The reaction mixture was then cooled to 25° C. and diluted by the dropwise addition of 30 ml. of ethyl acetate. The tetrahydrofuran solution was decanted, diluted with diethyl ether, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine as an oil. The oil so formed was dissolved in 50 ml. of diethyl ether through which was bubbled hydrogen chloride gas, thus forming the hydrochloride salt of the above-named compound, which precipitated out of solution. The precipitate was collected by filtration and recrystallized from 25 ml. of diisopropyl ether and 100 ml. of ethyl acetate to afford 0.75 g. of ethyl acetate to afford 0.75 g. of 2-cyclopropylmethyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine hydrochloride. M.P. 154°-156° C.