Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH2:26])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 55.7 %

Procedure:
To a suspension of 4-((t-butoxycarbonylamino)methyl)benzoic acid (6.08 g, 24.2 mmol) in DMF was added o-phenylene diamine (2.9 g, 29 mmol), EDCI (9.3 g, 48.4 mmol) and HOBt (3.8 g, 24.2 mmol). TEA (11.8 mL, 84.8 mmol) was added drop wise with constant stirring to the above reaction mixture, which was stirred at room temperature overnight. Subsequently, the reaction mixture was evaporated to half its volume; the resulting solution was dissolved in ethyl acetate, washed successively with saturated NaHCO3 (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the pure compound (4.6 g, 56% yield).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C@H:39]([NH2:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C@H:39]([NH:46][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:19]([CH:20]=[C:3]([C:1]#[N:2])[CH2:4][CH2:5]2)=[CH:6][CH2:7]4)=[O:30])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:37]=1
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and (S)-2-(4-methylphenyl)-1-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 77%.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11]OC1=O)([CH3:4])([CH3:3])[CH3:2].[BrH:14].ClCCl>C(O)(=O)C>[BrH:14].[BrH:14].[C:1]([N:5]1[CH2:6][CH2:7][NH:8][CH2:12][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCCN1CCOC1=O
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)N1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To crude 3-[2-(tert-butylamino)ethyl]oxazolidin-2-one (1.18 g, 6.33 mmol) was added acetic acid (8.8 mL) and then 45% hydrobromic acid in acetic acid (19.5 mL). The reaction solution was stirred at room temperature for 3 d, poured into dichloromethane (250 mL), and filtered to give 1.87 g of a brown solid. The solid was heated at reflux in n-butanol for 2 d and the reaction mixture concentrated in vacuo. The residual solid was slurried in 3:1 diethyl ether:dichloromethane and filtered. The filtered solid was heated in ethanol, cooled to room temperature, and filtered to give 0.57 g (30%) of a white solid.
Reaction SMILES: [CH:1]([C:7]1[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cccc(N)c1
Yield: 90.5 %

Procedure:
The 3-(1-hexenyl)nitrobenzene (11.0 g, 0.054 m) was dissolved in absolute ethanol (500 ml), treated with 1.1 g of 10% palladium on charcoal catalyst and hydrogenated on a Parr apparatus at about 45 psi for 21/2 hours. Hydrogen uptake had ceased. The reaction mixture was filtered to remove catalyst, concentrated under vacuum, and then resulting oil purified by Kuglrohr distillation (BP 75°-85° C. at 0.05 mm Hg) to yield 3-hexylaniline (8.6 g, 90% yield) as a clear colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[C:12]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH:13]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)C1=CCCC1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1cc(C2=CCCC2)nc2c1CCC2
Temperature: 140 °C
Yield: 65 %

Procedure:
Following general procedure F except the reaction was heated to 140° C. under microwave irradiation for 2 h, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.157 g, 0.84 mmol) was reacted with cyclopent-1-en-1-ylboronic acid (0.112 g, 1.0 mmol) to afford the title compound (0.120 g, 65%) as a white solid. MW=219.71. 1H NMR (CDCl3, 500 MHz) δ 7.06 (s, 1H), 6.62-6.57 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.77-2.70 (m, 2H), 2.58-2.52 (m, 2H), 2.13 (quin, J=7.5 Hz, 2H), 2.08-2.00 (m, 2H); APCI MS m/z 220 [M+H]+.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([Br:11])[N:10]=1)=O>CO>[Br:11][C:9]1[N:10]=[C:6]([C:4]([NH2:1])=[O:3])[N:7]([CH3:12])[CH:8]=1
Reactant: COC(=O)c1nc(Br)cn1C
Reactant: N
Solvent: CO
Product: Cn1cc(Br)nc1C(N)=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To the saturated solution of ammonia in MeOH was added 165 mg of 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid methyl ester and the resulting mixture was stirred at 20° C. for 16 h. The solution was evaporated to give 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (154 mg, yield 100%). LC-MS calcd for C5H6BrN3O (m/e) 202.97, obsd 204 and 206 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:21])=[N:17][N+]([O-])=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[CH:6]([OH:22])=[O:5].[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:21])=[NH:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution of the compound (190 mg) obtained in Example 33 in 4.4% formic acid-methanol (10 ml) was added dropwise to a suspension of palladium-black (200 mg) in 4.4% formic acid-methanol (10 ml) at room temperature and stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=8:2) to give 71 mg of the titled compound (yield, 37%).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N.O>CN(C)C=O>[O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([NH2:28])=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Ammonia (1 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate that formed was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed with 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11 g (83% yield) of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:11]O>OS(O)(=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(C)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 70° C. The solid material dissolves and stirring is continued at 70° C. for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR=0.39 min, [M+1]+=152.05. This material is dissolved in 7 N NH3 in methanol (25 mL) and the mixture is stirred in a sealed vial for 20 h at 60° C. before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. To a solution of this material in DCM (25 mL), pyridine (5.24 g, 54.0 mmol) is added. The mixture is cooled to 0° C. before trifluoroacetic anhydride (8.10 g, 38.6 mmol) is added portionwise. Stirring is continued at 0° C. for 2 h before the reaction is quenched with water. The mixture is diluted with DCM and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 4:1 to give 2-methyl-isonicotinonitrile (330 mg); LC-MS: tR=0.55 min, [M+1]+=119.13.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].Cl.[N:15]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][CH:11]=1)[NH:1][N:15]=[C:4]2[CH2:5][C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(Cl)cc1C=CC(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1n[nH]c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a suspension of 2 -amino-5-chlorocinnamic acid (3.0 g) in water (35 ml), there is added conc. hydrochloric acid (11 ml). To the resulting solution cooled with ice, a solution of sodium nitrite (1.0 g) in water (2 ml) is dropwise added while stirring, and stirring is continued for 30 minutes. Anhydrous sodium sulfite (5.0 g) is portionwise added thereto. After stirring at room temperature for 1 hour, the resulting mixture is admixed with water (100 ml) and heated on an oil bath for 0.5 to 1 hour while refluxing. The reaction mixture is filtered. The collected material is washed with hot water. The washing water is combined with the filtrate and concentrated. The residue is crystallized from hot water to give 5-chloro-1H-indazole-3-acetic acid (0.7 g) as white needles melting at 205° C (decomp.)
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:44](=[O:46])[CH3:45])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 0.312 g of 3ξ-hydroxy-7β-phenylacetylamino-cepham-4ξ-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0° C. and after addition of 50 ml of toluene is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; a silica gel plate of 100 cm length is used and development is carried out with a 1:1 mixture of toluene and ethyl acetate. 3ξ-Acetoxy-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester of Rf=0.47 is obtained, melting at 162-164° C. after crystallisation from a mixture of methylene chloride and pentane; [α]D20 =+55°±1° (c=0.492 in chloroform); ultraviolet absorption spectrum (in 95% strength ethanol): λmax =253 mμ (ε=700), 258 mμ (ε=820) and 265 mμ (ε=660): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.66μ, 5.77μ, 5.97μ, 6.28μ and 6.71μ.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([NH:52][C@H:53]2[CH2:58][CH2:57][C@@H:56]([NH2:59])[CH2:55][CH2:54]2)=[N:50][CH:51]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:59][C@H:56]2[CH2:55][CH2:54][C@@H:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH3:45])=[CH:51][N:50]=3)[CH2:58][CH2:57]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(N[C@H]2CC[C@@H](N)CC2)nc1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a round bottomed flask was added 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (0.267 g, 1.333 mmol, 00388), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.659 g, 1.733 mmol, GenScript) and triethylamine (0.743 ml, 5.33 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (4.44 ml). cis-N1-(5-Methylpyridin-2-yl)cyclohexane-1,4-diamine (0.3709 g, 1.333 mmol) was added and the reaction was allowed to stir at room temperature for 4 h. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane to give the title compound (105.0 mg, 0.271 mmol, 20.3% yield). Product peak was found at 1.438 min (m+1=388.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.67 (m, 12 H) 1.75 (d, J=4.89 Hz, 2 H) 2.08 (s, 3 H) 3.68 (br. s., 1 H) 3.76 (br. s., 1 H) 6.50 (d, J=8.41 Hz, 1 H) 7.14-7.28 (m, 2 H) 7.76 (s, 1 H) 8.42 (d, J=2.54 Hz, 1 H) 8.65 (d, J=2.54 Hz, 1 H)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]([NH2:16])=[S:15].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:16][C:14]1[S:15][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:13]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C

Procedure:
Slurry 4-cyanophenacyl bromide (40 g, 179 mmol), thiourea (13.6 g, 181 mmol) and sodium bicarbonate (15.3 g, 181 mmol) in absolute ethanol (560 mL). Stir the mixture at reflux for 20 h under a nitrogen atmosphere. Cool the slurry to room temperature, filter, wash the solids with ethanol (100 mL), water (3×75 mL) and hexane (3×75 mL). Collect the yellow solid, add water (200 mL) and stir the slurry for 30 min at room temperate. Filter and wash the solid with hexane (excess). Slurry the solid in EtOAc (50 mL) and concentrate in vacuo twice to remove residual water. Collect the desired intermediate as a light yellow solid (36 g, 99%). MS (ES+) m/z: 202.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:27][CH2:26][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
N-[[2-chloro-4-[5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl]methyl]phthalimide (0.75 g) in ethanol (10 mL) was added hydrazine monohydrate (1.07 g). The mixture was heated to reflux for 1 hour and then cooled to room temperature. The resulting mixture was filtered and concentrated under reduced pressure. The residue was dissolved in chloroform (10 mL) and filtered, and the filtrate was washed with water (10 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with methanol-ethyl:acetate (1:9) to afford the title compound as a pale yellow resin (0.51 g).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:9].[CH2:25]=O>C(O)(=O)C>[F:6][C:7]([F:23])([F:24])[C:8]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:25]1)=[O:9]
Reactant: O=C(NCCc1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(C(F)(F)F)cc2C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
10.0 ml of concentrated sulfuric acid were slowly added dropwise to a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2-(4-trifluoromethylphenyl)ethylamine [prepared from 2-(4-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at −5° C.] in 7.5 ml of glacial acetic acid, and, while cooling in ice, 2 ml of formalin solution were added dropwise. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of ice-water and extracted with dichloromethane, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated and were converted into 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by heating under reflux in ethanol/3N HCl (1:1) and alkaline workup.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9]3=[C:10]([CH:20]=1)[C:11]([CH3:19])=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:8]3[CH2:7][CH2:6]2.[BH4-].[Na+].O>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9]3=[C:10]([CH:20]=1)[CH:11]([CH3:19])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:8]3[CH2:7][CH2:6]2
Reactant: CC1=Nc2ccccc2N2CCc3cc(Cl)cc1c32
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1Nc2ccccc2N2CCc3cc(Cl)cc1c32

Procedure:
To a well stirred mixture of 45.0 g of 4-chloro-6-methyl-1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride, in 450 ml of absolute ethanol, cooled to 0° C. under N2, is added sodium borohydride in portions until the initial purple color is discharged. The mixture is stirred 1 hour longer at 0° C., then 2 hours at room temperature. Then water is added in portions to destroy excess reagent and to maximize precipitation of product. The latter is filtered, washed well with water and dried to yield 4-chloro-6-methyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 167°-170° C.
Reaction SMILES: C1(C([NH:20][C:21]2([CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:36][C:37]5[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=5[N:39]=4)=[CH:31][CH:30]=3)[CH2:25][CH2:24][CH2:23][CH2:22]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:44]>C(O)C.C(Cl)Cl>[ClH:44].[NH2:20][C:21]1([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(C(NC2(COCc3ccc(-c4nc5ccccc5o4)cc3)CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: NC1(COCc2ccc(-c3nc4ccccc4o3)cc2)CCCC1
Reaction time: 72 h

Procedure:
To a solution of 1-triphenylmethylamino-(4-[benzoxazol-2-yl]benzyloxymethyl)cyclopentane (1.24 g; 2.20 mmol) of 1-triphenylmethylamino-(4-[benzoxazol -2-yl]benzyloxymethyl)cyclopentane in ethanol/CH2Cl2 is added ethanolic HCl until ph≅2. This is then stirred for 72 hrs., concentrated to about one-half the volume and the white precipitate which forms is filtered to obtain 1-amino-[4-(benzoxazol-2-yl)benzyloxymethyl]cyclopentane hydrochloride (m.p. >250° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96 mg, 74%).