Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N:17]=[N:18][NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]#[N:31])#[N:6]>CCOCC>[CH3:1][NH:2][C:3]([N:17]([C:8]1[CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=[CH:12][C:7]=1[C:5]#[N:6])[N:18]=[N:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]#[N:31])=[O:4]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 0.38 g. (6.7 mmol.) of methyl isocyanate in 20 ml. of ether is added dropwise to 1.6 g. (4.2 mmol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 125 ml. of ether. The reaction mixture is stirred at 25° for 12 hours, refluxed for 6 hours, then left to stand at 25° for 48 hours. Removal of the solvent under reduced pressure gives 3-(N-methylcarbamoyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, m.p. 170° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:17]OC(OC)N(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:17]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C1CCNC1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cc(Br)ccc1/C=C/N1CCCC1

Procedure:
A solution of 4-bromo-2-nitrotoluene (100 g, 463 mmol), pyrrolidine (46.2 mL, 565 mmol), and N,N-dimethylformamide dimethylacetal (75.6 mL, 565 mmol) was refluxed for 4 hours at
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:21])[C:17](Br)([F:19])[F:18])[CH3:14]>CS(C)=O.[Cu]>[CH2:13]([O:15][C:16](=[O:21])[C:17]([C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1)([F:19])[F:18])[CH3:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
To a solution of 4-iodo-2-methyl-6-nitroaniline (2.78 g, 10 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (2.03 g, 10 mmol) in anhydrous DMSO (20 mL) was added copper powder (1.28 g, 20 mmol). The mixture was purged with N2 and heated at 60° C. in a sealed vial for 14 h. After being cooled to the room temperature, the reaction mixture was poured into 20% aqueous NH4Cl solution (300 mL). The resulting mixture was basified to pHY=8.5 with saturated aqueous Na2CO3 solution and was extracted with EtOAc (3×100 mL). The organic extract was washed with brine (2×30 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (40:1 hexanes/EtOAc) to afford the title compound (1.79 g, 65%). 1H NMR (CDCl3) δ 1.36 (t, 3H), 2.30 (s, 3H), 4.36 (q, 2H), 6.41 (br s, 2H NH), 7.51 (s, 1H), 8.33 (s, 1H). ESI-MS m/z 275 (MH+), 255 (M-F)+, 297 (M+Na)+, 549 (2M+1)+ and 571 (2M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-])=O)=[C:9]([F:14])[CH:8]=[C:7]([Cl:15])[C:5]=2[N:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:11][C:10]1[C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[C:7]([Cl:15])=[CH:8][C:9]=1[F:14]
Reactant: O=[N+]([O-])c1c(F)cc(Cl)c2nc(Cl)sc12
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1c(F)cc(Cl)c2nc(Cl)sc12

Procedure:
5 g Iron powder was added to 40 ml 5% aqueous acetic acid. The mixture was heated to reflux and a solution of 5 g 2,4-dichloro-6-fluoro-7-nitrobenzothiazole in 40 ml acetic acid and 40 ml ethyl acetate was added. The mixture was heated for 2 hours under reflux and after cooling the mixture was filtered over celite, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and water and dried with magnesium sulfate. Yield: 4.3 g=97% of theory m.p.: 173° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C([O:8][C:9](=[O:26])[CH:10]([C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[F:25])[CH2:11][CH:12]([CH3:14])[CH3:13])C.O.[CH:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[CH:4]1([CH2:5][O:8][C:9](=[O:26])[CH:10]([C:15]2[CH:20]=[C:19]([O:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[F:25])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:2][CH2:3]1
Reactant: [Li]CCCC
Reactant: OCC1CC1
Reactant: CCOC(=O)C(CC(C)C)c1cc(F)c([N+](=O)[O-])cc1F
Solvent: O
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with n-BuLi (2.5M in hexane 7.4 g, 46 mL, 115.6 mmol) at −15° C. under nitrogen, and the reaction mixture was stirred 1 h at 25° C. To the mixture was added 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester (29 g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at 25° C. and the reaction mixture stirred for an additional 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 29.5 g, (81%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 4.07 (t, J=7.7 Hz, 1H), 4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65 (d, J=7.7 Hz, 2H), 0.54 (d, J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25 (d, J=4.4 Hz, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.6, 152.7 (d, 1JCF=243.4 Hz), 148.8, 138.1, 133.3 (d, 2JCF=15.7 Hz), 115.8, 112.6 (d, 2JCF=29.5 Hz), 75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2, 10.0, 9.8, 3.4.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH:23]([NH:26][C:27](=[O:31])[O:28][CH2:29][I:30])([CH3:25])[CH3:24]>C(#N)C>[I-:30].[CH:23]([NH:26][C:27]([O:28][CH2:29][N+:19]1([CH3:22])[CH2:20][CH2:21][N:16]([C:15]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:6][C:5]=3[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)[CH2:17][CH2:18]1)=[O:31])([CH3:25])[CH3:24]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: CC(C)NC(=O)OCI
Solvent: CC#N
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CC[N+](C)(COC(=O)NC(C)C)CC1
Product: [I-]
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirred solution of Olanzapine, (2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine)[4134] (0.025 g, 0.086 mmol, 1.0 eq) in ACN was added iodomethyl isopropylcarbamate [6318] (0.20 g, 0.086 mmol, 1.0 eq) at RT. The reaction mixture was stirred at RT for four to 16 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (5 ml×2) to give the desired product [294], 1-(((isopropylcarbamoyl)oxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (0.013 g, 41%) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:23]([O:25][C:26]([CH2:28][CH2:29][CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:27])[CH3:24].[CH3:50]C(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:50]=[CH:30][CH2:29][CH2:28][C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC=Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-[4-(t-Butoxycarbonyl)piperazin-1-yl]benzaldehyde and [3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide were reacted in THF in the presence of potassium t-butoxide to obtain ethyl 5-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}-4-pentenoate, which was then subjected to catalytic reduction using palladium/carbon to obtain an objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)[CH:20]=[CH:19][C:18]=1[NH2:29]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:29][C:18]1[CH:19]=[CH:20][C:21]([C:23]2[NH:27][C:26]([CH3:28])=[N:25][N:24]=2)=[CH:22][C:17]=1[O:16][CH3:15])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: COc1cc(-c2nnc(C)[nH]2)ccc1N
Solvent: CC#N
Product: COc1cc(-c2nnc(C)[nH]2)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 30 mg of 2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction, stirred with isopropanol and dried under reduced pressure.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[O-:23][Bi](=O)=O.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[O:23]=[C:12]1[C:4]2[C:3]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)=[N:2][NH:1][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=[Bi](=O)[O-]
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(-c2n[nH]c3c2C(=O)c2ccccc2-3)cc1

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate (6.3 g, Example 7), sodium bismuthate (31 g), glacial acetic acid (180 ml) and water (60 ml) was boiled under reflux for about 3.5 hours. A further amount of sodium bismuthate (33 g) was added and the mixture boiled under reflux for about 24 hours, then cooled. The pH of the reaction mixture was adjusted to 8-9 by addition of saturated sodium bicarbonate solution. The reaction mixture was filtered through a celite pad and the residue solid washed with ethyl acetate. The organic layer was separated, dried, filtered and evaporated to give a brown solid. The solid was boiled up in methanol (50 ml), cooled and the solid was filtered off, then dried to give methyl 4-(4-oxo-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate, m.p. dec. 235° C.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[O:34]=[C:35]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:37][C@H:36]1[NH2:52]>O1CCCC1>[O:34]=[C:35]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:37][C@H:36]1[NH:52][C:5]([NH:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:16]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH:15]=1)=[O:11]
Reactant: N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3NC2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 254.2 %

Procedure:
Triphosgene (1.8 g) was added to a solution of tert-butyl 3-aminobenzoate (3.13 g) in anhydrous tetrahydrofuran (200 ml) under ice-cooling, and then triethylamine (7.25 ml) was added five times each 1.45 ml over 15 minutes, and the mixture was stirred at room temperature for 5 minutes. Subsequently (R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (4 g) was added under ice-cooling. The mixture was stirred at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. Ice-water was added to the residue, extracted with methylene chloride,the organic layer was washed with saturated brine. After dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue, crystals were collected by filtration, to thereby obtain 7.38 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:51][C:50]([C@@H:52]4[CH2:56][CH2:55][CH2:54][N:53]4[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][CH:48]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[NH:51][C:50]([C@@H:52]5[CH2:56][CH2:55][CH2:54][N:53]5[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][CH:48]=3)=[CH:45][CH:46]=2)=[CH:32][CH:31]=4)[C@@H:17]2[CH2:18][C@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 41.6 %

Procedure:
Methyl (S)-1-((1R,3S,4S)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (122 mg, 0.24 mmol) and (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (114 mg, 0.26 mmol) were combined in DME (3 mL). Pd(PPh3)4 (28 mg, 0.024 mmol) and K2CO3 (2M H2O, 0.4 mL, 0.79 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (73 mg).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:11]>C(OCC)C>[CH3:3][C@H:4]([CH2:5][CH:6]=[CH2:7])[CH2:9][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CC[C@@H](C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 250-mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with 1.60 g (40.0 mmol) of a 60% dispersion of sodium hydride in mineral oil. The sodium hydride was washed with 3×20 mL of dry hexane and then suspended in 40 mL of dry N,N-dimethylformamide and cooled to 0° C. To the stirred suspension was added 4.32 mL (6.21 g, 36.3 mmol) of benzyl bromide followed by dropwise addition of 3.47 g (34.6 mmol) of ketone 2 (via cannula) dissolved in 10 mL of diethyl ether over 15 min maintaining the reaction temperature at 6° C. or less. The reaction mixture was stirred for 20 minutes at 0° C., then warmed to room temperature. After 12 hours, 10 mL of water was cautiously added and the mixture was transferred to a 250-mL separatory funnel. The aqueous Phase was extracted with 3×100 mL of ethyl acetate. The organic layers were individually washed with 100 mL of brine, combined, dried over sodium sulfate, filtered, concentrated and chromatographed (6 cm×33 cm column, 9:1 hexane:dichloromethane) to afford 5.93 g (89%) of benzyl ether 3 as a clear, colorless liquid: Rf =0.20 (9:1 hexane:dichloromethane). [a]54622 --1.6° (c 2.21, CH2Cl2). IR(film): 3080m, 3070m, 3035m, 3005w, 2980s, 2960s, 2930s, 2910s, 2880s, 2860s, 2975w, 1645m, 1605w, 1495m, 1480w, 1455s, 1445m, 1415w, 1375m, 1365m, 1310w, 1255w, 1205w, 1160w, 1100s, 1040m, 995m, 915s, 745s, 695s, 605m. 1H-NMR: 7.36-7.24 (m, 5H, ArH); 5.85-5.72 (m, 1H, CH=CH2); 5.06-5.00 (m, 2H, CH=CH2); 4.51 (s, 2H, ArCH2O); 3.33 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 3.28 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 2.27-2.19 (m, 1H, CHCH3); 1.98-1.84 (m, 2H, CH2CH=CH2); 0.93 (d, J=6.5, 3H, CHCH3). 13C NMR: 138.7, 136.8, 128.2, 127.4, 127.3, 115.8, 75.2, 72.9, 38.0, 33.3, 16.7. Anal. Calcd. for C13H18O: C, 82.06; H, 9.53. Found: C, 82.08; H, 9.49.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH3:16])([O-:15])=[O:14].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 300 g of cinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-phenylbutanoic acid methyl ester.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23]>CN(C=O)C.[Cu-]=O>[Cl:11][C:12]1[CH:17]=[C:16]([S:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:23])([F:25])[F:24]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-mercaptobenzoic acid (0.308 g), (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.786 g) and copper(I) oxide (0.1 43 g) in DMF (5 ml) was stirred and heated under reflux for 1 hour. More 4-mercaptobenzoic acid (0.308 g) was added and heating was continued for a further 2 hours. The mixture was cooled, filtered, and the filter washed with DMF (5 ml). The filtrates were concentrated by evaporation and the residual solid was extracted with boiling ethyl acetate (2×60 ml). The extracts were absorbed onto deactivated silica (silica deactivated by treatment with 10% water) and purified by chromatography eluting with 5% methanol/ethyl acetate to give the title compound (0.803 g) as a solid. NMR: 1.63 (s, 3H), 7.31 (d, 2H), 7.5 (dd, 1H), 7.68 (d, 1H), 7.89 (d, 2H), 8.22 (d, 1H), 9.8 (brs, 1H); MS (ESP−): 418; EA: found: C, 48.2; H, 3.1; N, 3.2%; C17H13NClF3O4S requires C, 48.6; H, 3.1; N, 3.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([Cl:36])[C:23]=1[CH:24]=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]4[N:19]=[C:24]([C:23]5[C:22]([Cl:21])=[CH:29][C:28]([N:30]6[CH2:31][CH2:32][O:33][CH2:34][CH2:35]6)=[CH:27][C:26]=5[Cl:36])[NH:20][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cc(N6CCOCC6)cc5Cl)[nH]c4c3)o2)cc1
Reaction time: 18 h

Procedure:
To a 50 ml rbf was added 0.2250 g (0.785 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine, 0.2041 g (0.785 mmol) of 2,6-Dichloro-4-morpholin-4-yl-benzaldehyde, and 5 mL of DMSO. To this dark brown solution was added 0.0190 g (0.118 mmol) of FeCl3. It was allowed to stir open to air for 18 h. The crude was then extracted with EtOAc, and the combined extracts were washed with water, brine and dried with Na2SO4. The volatiles were removed in vacuo and the concentrate was purified on silica gel (ACN/DCM, 1:9 to 10:0) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (d, J=5.05 Hz, 4H) 3.71-3.77 (m, 4H) 7.17 (s, 2H) 7.70-7.75 (m, 2H) 7.90 (d, J=8.72 Hz, 1H) 7.99-8.07 (m, 1H) 8.19 (d, J=8.21 Hz, 2H) 8.27 (br. s., 1H) 8.47 (s, 1H) 13.17 (d, J=8.97 Hz, 1H). MS (m/z) 528.0 M (+1), tR=1.41, Meth 10
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Br)(Br)[Br:25].N1C=CC=CC=1>CCOCC>[Br:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 116.7 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (1.0 g), phosphorus tribromide (0.70 g) and pyridine (0.05 g) in dry ether was stirred at 0° C. for 15 hours. The reaction mixture was quenched with water and extracted with ether. The organic extracts were dried (anhydrous magnesium sulphate), filtered and the solvent evaporated yielding 4-[bromo-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 299, 1.18 g) as a yellow oil: NMR: (CDCl3) 1.1(4H,m) 1.9(1H,m) 6.9(1H,s) 7.9(1H,m) 8.0(1H,s) 8.15(2H,m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].Cl>CC(O)C.C1COCC1>[C:11]1([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of tyramine (3.0 g, 22 mmol) in 2-propanol (100 mL) and THF (50 mL) was added 4-phenylcyclohexanone 1 (3.8 g, 22 mmol) and 3 Å molecular sieves. After 2 hours, sodium borohydride (1.2 g, 31 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with MeOH, filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 CH2Cl2:MeOH) gave the free base which was converted to an HCl salt. Recrystallization from MeOH/Et2O gave the trans-isomer trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (0.98 g, 14%): mp 238-241° C.; IR (KBr): 2940, 1517, cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.99 (br d, 1H), 7.30-7.15 (m, 5H), 7.07 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.10-3.07 (m, 3H), 2.89-2.86 (m, 2H), 2.53-2.50 (m, 1H), 2.20 (d, J=20 Hz, 2H), 1.88 (d, J=20 Hz, 2H), 1.59-1.46 (m, 4H); CI—MS (methane) (m/z): 296 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C20H25NO, 296.2014; found, 296.2015; HPLC: method A, 5.83 minutes (100%); method B, 10.56 minutes (96.5%); Analysis Calcd for C20H25NO.HCl.0.25H2O: C, 71.41; H, 7.94; N, 4.16. Found: C, 71.29; H, 7.66; N, 4.12.