Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH2:18]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH:18][CH3:1]
Reactant: O=CO
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of formic acid (7.64 g) and acetic anhydride (16.9 g) was stirred at 60° C. for 2 hr then a solution (100 mL) of 5-methoxy-2-nitroaniline (9.30 g) in tetrahydrofuran was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution (200 mL) of the residue in tetrahydrofuran was added a 1.0M solution (140 mL) of borane-tetrahydrofuran complex in tetrahydrofuran at 0° C., and the mixture was stirred with heating under reflux for 2 hr. Methanol was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. After stirring, 1N hydrochloric acid was added to adjust to pH=2. The reaction mixture was stirred with heating under reflux for 1 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title object compound (6.30 g, 62%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:14][C:13]=2[CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:14][C:13]=2[CH3:21])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)c2sc(S(N)(=O)=O)cc2C)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(S(N)(=O)=O)sc1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
5-(4-methoxyphenylsulfonyl)-4-methylthiophene-2-sulfonamide (9.75 g, 0.028 mol) was suspended in methylene chloride (150 ml) and a 1.0M solution of boron tribromide in methylene chloride (90 ml, 0.09 mol) was added dropwise over 1/2 hour, at 0° C. Then the solution was stirred at ambient temperature for 5 hours. The solution was added to ice and water (500 ml) and ethyl acetate (500 ml) was added. The organic layer was separated, washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl, dried, filtered and concentrated in vacuo. A yellow oil was obtained which crystallized from ethyl acetate-n-butyl chloride. Yield was 67%. The recrystallized white solid melted at 170°-172° C. Purity and structure were confirmed by C, H, N, analyses, HPLC and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][C:11](=[N:13]O)[CH2:10][S:9]2)=[CH:4][CH:3]=1.Cl>CO>[ClH:1].[NH2:13][C:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:9][CH:10]=1
Reactant: ON=C1CSC(c2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Product: Nc1csc(-c2ccc(Cl)cc2)c1

Procedure:
Following the procedure of Example 12, the above oxime (6.14 g, 27.0 mmol) is reacted with HCl and methanol to give 3-amino-5-(4-chlorophenyl)thiophene hydrochloric acid salt.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=CC=C([Cl:20])C=1OC.[Li]CCCC.COB(OC)OC>>[Cl:20][C:4]1[C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=[CH:2][CH:3]=1
Reactant: COc1c(Cl)cccc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1c(Cl)cccc1B(O)O
Yield: 91 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-6-chloroanisole (0.71 g, 3.2 mmol), n-BuLi (2.5M in hexanes; 1.28 mL, 3.2 mmol), and trimethylborate (1.09 mL, 9.6 mmol) to afford 0.55 g (91%) of 3-chloro-2-methoxyphenylboronic acid which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([C:31]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=2)=[O:32])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccccc1
Yield: 27.2 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-phenoxypropionate (666 mg), which is the product of Reference example 4, biphenyl-4-carboxylic acid (400 mg) and carbonyldiimidazole (393 mg) and the reaction mixture was treated to give the title compound (280 mg) as a white powder.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CCCC1>C(#N)C.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][N:23]2[CH2:24][CH2:25][CH2:22][CH2:21]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromophenethyl 4-methylbenzenesulfonate (500 mg, 1.407 mmol) from Example 56A in anhydrous acetonitrile (3 mL) was treated with triethylamine (0.589 mL, 4.22 mmol) and pyrrolidine (0.349 mL, 4.22 mmol). The reaction was stirred 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water, saturated ammonium chloride, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 5% methanol in dichloromethane, to give the title compound. MS DCI(+) m/z 254.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[N:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[CH3:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([N:19]([CH3:20])[CH3:18])=[N:6][C:5](=[O:10])[N:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:17]
Reactant: CSc1nc(=O)n(C2CCCCC2)c(=O)n1C
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)c1nc(=O)n(C2CCCCC2)c(=O)n1C

Procedure:
A suspension of 300 parts of 1-methyl-3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione in 887 parts of toluene is stirred at 25°-30° for three hours with 150 parts of dimethylamine. Toluene is distilled from the reaction until a pot temperature of 125° is attained. The reaction mass is cooled to 50° at which time 480 parts of hexane is added over 0.66 hours. The slurry at 25° is filtered to give 282 parts of crystalline 1-methyl-3-cyclohexyl-6-dimethylamino-s-triazine-2,4(1H,3H)-dione, m.p. 110°-115°.
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([CH3:39])[S:29]([C:32]1[CH:37]=[CH:36][C:35](C)=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[C:32]1([S:29]([N:28]([CH2:39][O:19][C:18]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:20])[CH3:27])(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CCl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(COC(=O)c1[nH]c2ccccc2c1Nc1ccncc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
Under N2 at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.2 g, 7.55 mmol) in a mixture of anhydrous THF and DMF (150:40 mL). Cool to 0° C. and add N-chloromethyl-N-methyl-4-methylbenzenesulfonamide (2.0 g, 9.10 mmol) in anhydrous THF (10 mL) dropwise. After 20 min., add water (100 mL) and then extract with dichloromethane (3×100 mL). Combine the organic layers wash with NaHCO3 (sat), water, brine, dry with Na2SO4 and then concentrate. Purify the residue on an ISCO RediSep 35-gram silicagel cartridge, eluting with 50% heptane/ethyl acetate, ethyl acetate and then 10% methanol/ethyl acetate. Combine product containing fractions and concentrate to an oil. Dissolve the oil in methanol and add ether to obtain the title compound as a white solid (800 mg): MS: 437(M+H), 1H NMR (DMSO-d6) δ 11.52 (1H, s), 8.29 (1H, s), 8.04 (2H, d, J=5.5 Hz), 7.76 (2H, d, J=7.2 Hz), 7.43 (6H, m), 7.03 (1H, m), 6.46 (2H, d, J=6.0 Hz), 5.60 (2H, s), 2.79 (3H, s).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][P:9]([N:14]1[CH:20]2[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:19]2)([O:11][CH2:12][CH3:13])=[O:10])[CH3:7].O>C1COCC1>[CH:1]1([C@@H:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][C@H:20]2[NH:14][P:9]([O:8][CH2:6][CH3:7])([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CC1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a suspension of Cu(I)I (0.15 g, 0.77 mmol) in THF (20 mL) was slowly added 0.50M cyclopropylmagnesium bromide (61.2 mL, 30.6 mmol) in THF at −30° C. After stirring at that temperature for 15 minutes, a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (2.82 g, 7.66 mmol; Example H, Step D) in THF (10 mL) was added at −30° C., and then the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Water (50 mL) was added and extracted with ethyl acetate (2×40 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 4-cyclopropyl-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.84 g, 59%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[N:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C(Cl)Cl>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[N:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2cnnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2cnnn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (470 mg), rhodium(II) acetate (dimer) (22 mg) and methylene chloride (10 mL) was added dropwise ethyl diazoacetate (137 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→20/80 (volume ratio)] to give the title compound as a colorless amorphous compound (203 mg, 37%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43])[CH3:36]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[C:38](=[O:43])[CH2:39]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CCN1CCNCC1=O
Solvent: CN(C)C=O
Product: CCN1CCN(c2nccc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc(Cl)cc5)c4s3)n2)CC1=O
Temperature: 100 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (15.0 mg, 0.029 mmol) in DMF (0.4 mL) was added 1-ethylpiperazin-2-one (7.4 mg, 0.058 mmol). The reaction mixture was heated at 100° C. overnight. Reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C31H35ClN5O4S: 608.2 (M+H+); Found: 608.2 (M+H+).
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#N)=[CH:23][C:22]=1[F:29]>>[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:4])=[CH:23][C:22]=1[F:29]
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Reactant: CN(C)C(C)(C)COc1ccc(C#N)cc1F
Product: CN(C)C(C)(C)COc1ccc(C=O)cc1F

Procedure:
Synthesized from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 18, 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzonitrile (1.4 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (965 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)=[CH:19][CH:18]=1>>[F:27][C:25]1([F:28])[CH2:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([N:10]3[CH2:11][CH2:12][C:8]4([CH2:14][CH2:15][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[C:9]3=[O:13])=[CH:22][CH:21]=2)[CH2:26]1
Reactant: FC1(F)CC(c2ccc(Br)cc2)C1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: O=C1N(c2ccc(C3CC(F)(F)C3)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 336, step 1 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3, 165 mg) and 1-bromo-4-(3,3-difluoro-cyclobutyl)-benzene (193 mg, described above). White solid (270 mg, 70%). MS (m/e): 378.3 [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:19]N1CCC(N)CC1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Reactant: NC1CCN(Cc2ccc(F)c(F)c2)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nnc(NC2CCN(Cc3ccc(F)c(F)c3)CC2)s1
Yield: 24.6 %

Procedure:
A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.3 g, 2.06 mmol) (D6) (prepared by a procedure similar to that described in U.S. Pat. No. 5,736,545), 1-(3,4-difluoro-benzyl)-piperidin-4-ylamine (D7) (0.47 g, 2.06 mmol) and diisopropylethylamine (0.54 ml, 3.09 mmol) in acetonitrile (5 ml) in a sealed tube, was stirred at 80° C. for 1 h., under microwave irradiation. After this period, the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 0-2.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The crude product was precipitated from acetonitrile to yield E19 (0.17 g, 25%) as a solid. C15H15F2N5S requires 335. Found 336 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23].Br[CH2:25][C:26]#[N:27].[H-].[Na+].ClCC#N>C1COCC1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]#[N:27])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccc(C(=O)C2CCN([C@H]3CCNC3=O)CC2)cc1C
Reactant: N#CCBr
Agent: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@H]3CCN(CC#N)C3=O)CC2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of (S)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (6.32 mmol, 2.0 g) and bromoacetonitrile (18.96 mmol, 2.275 g) in THF (60 mL) at 0° C. was added sodium hydride (60%, 18.96 mmol, 0.76 g) and allowed to stir under N2 for 1 hour. Allowed to warm to ambient temperature and chloroacetonitrile (2 mL) was added. After 30 min the reaction was cooled to 0° C. and quenched with saturated ammonium chloride solution. Flash column chromatography (silica) was performed eluting with 3% MeOH/ethyl acetate to 15% MeOH/ethyl acetate and provided the title compound as an red-brown foam (1.6 g, 71.2% yield). Calculated molecular formula=C20H25N3O3=355.4406. found MS (ESI) m/e 356.6 (M+H+); analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.831 min.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([C:33]([F:32])([F:42])[F:43])[CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 3-trifluoromethylbenzylamine (2.2 eq.) in the manner of example 68, m.p.143-145° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C29H23CIF3N3O3: C, 62.88; H, 4.18; N, 7.59. Found: C, 62.87; H, 4.08; N, 7.52.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N(Br)C(=O)C1.[C:17]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1)#[N:18]>O1CCOCC1.O>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[S:32][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:31]=3)[CH2:26][CH2:25]2)=[CH:33][CH:34]=1)#[N:18]
Reactant: CO/C=C/C(=O)OC
Reactant: N#Cc1ccc(CN2CCN(C(N)=S)CC2)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(Cc3ccc(C#N)cc3)CC2)s1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 mL, 2.51 mmol) in 1:1 mixture of dioxane/water (4 mL) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343.1 (M+H)
Reaction SMILES: ClC1C=CC(CCC(C2C=CC=C(F)C=2)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1cccc(F)c1
Agent: O=C(CCc1ccc(Cl)cc1)c1cccc(F)c1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1cccc(F)c1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-chlorophenyl)-1-(3-fluorophenyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(3-fluorophenyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(3-fluorophenyl)pent-2-enoate were obtained as colourless oils.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].S1C2C=CC=CC=2N=C1S[C:24](=[O:40])[C:25]([CH3:39])([O:27][N:28]1C(=O)C2=CC=CC=C2C1=O)[CH3:26]>C(#N)C>[NH2:28][O:27][C:25]([CH3:39])([CH3:26])[C:24]([NH:13][NH:12][S:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)(=[O:10])=[O:11])=[O:40]
Reactant: NNS(=O)(=O)c1ccc(O)c(O)c1
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)Sc1nc2ccccc2s1
Solvent: CC#N
Product: CC(C)(ON)C(=O)NNS(=O)(=O)c1ccc(O)c(O)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 204 mg of 3,4-dihydroxybenzenesulphonic hydrazide and 379 mg of 2-methyl-2-(phthalimidooxy)thiopropionic acid S-(2-benzothiazolyl) ester was heated to 60° C. in 5 ml of acetonitrile for 3 hours. After cooling, any undissolved material was filtered off under suction. The filtrate was freed from solvent in a vacuum and the residue was taken up in 3 ml of ethanol. The suspension was treated with 100 mg of hydrazine hydrate and stirred at 20° C. for 1 hour. A clear solution first resulted, from which a white precipitate separated out. Undissolved material was filtered off and the filtrate was evaporated in a vacuum. The crystalline residue was triturated with 10 ml of 0.1N aqueous hydrochloric acid for 10 minutes and the insoluble material was separated by filtration. The filtrate was adjusted to pH 7 by the addition of 2N aqueous sodium hydroxide solution and chromatographed on MCI gel CHP2OP, with elution being carried out first with 2% aqueous acetic acid and then with water/methanol (9:1, v/v). By evaporation of the product fractions in a vacuum, there was obtained 2-[2-(aminooxy)-2-methylpropionyl]-1-[(3,4-di-hydroxyphenyl)sulphonyl]hydrazine as white crystals of melting point 220° C. (dec.).