Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:17]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)c(CBr)c1
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml) was stirred under refluxing conditions for 4 h. TLC (EtOAc:hexane=5:95) showed no starting material. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as a white solid after flash column using EtOAc:hexane=5:95 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.53 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.5, 2.5 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH:41]4[CH2:45][CH2:44][CH2:43][NH:42]4)[C:28]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)=[CH:29][C:23]=3[N:22]=2)=[N:19][CH:20]=1>C(Cl)(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH:41]4[CH2:45][CH2:44][CH2:43][N:42]4[C:1](=[O:3])[CH3:2])[C:28]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:33][CH:32]=4)=[CH:29][C:23]=3[N:22]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccc(Br)cn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.050 ml of acetic anhydride was added to a pyridine (2 ml) solution of 220 mg of 2-(5-bromo-pyridin-2-yl)-5-(4-methanesulfonyl-phenoxy)-6-pyrrolidin-2-yl-1H-benzimidazole, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=50/1/0.1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C1COCC1.CCOC(C)=O>[C:30]([O:29][C:27]([NH:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(N)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1-amino-2-ethoxy-2-oxoethyl)benzoic acid, as described in Example 1, Step B, (0.8 g, 3.58 mmol) and DIPEA (1.377 mL, 7.88 mmol) were suspended in THF (8 mL) and BOC2O (0.915 mL, 3.94 mmol) was added. The solution was stirred at room temperature for 2 days. The reaction mixture was diluted with EtOAc, washed with 2N HCl and brine, dried over MgSO4 and concentrated in vacuo to give the desired product as a colorless gum. 1H NMR (DMSO-d6, 600 MHz) δ 12.95 (br s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 5.25 (d, J=8.4 Hz, 1H), 4.06 (m, 2H), 1.36 (s, 9H), 1.09 (t, J=7.2 Hz, 3H). MS: cal'd 324 (MH+), exp 224 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH:12]=O)=[CH:6][C:5]=1[O:14][CH3:15].[CH2:17]([O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23])[CH3:18]>N1CCCCC1>[CH2:17]([O:19][C:20](=[O:24])[C:21]([C:22]#[N:23])=[CH:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([O:14][CH3:15])[CH:6]=1)[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1c(OC)cc(C=O)cc1OC
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc(OC)c(C(=O)OC)c(OC)c1
Temperature: 120 °C

Procedure:
A mixture of 11.2 g. of 2,6-dimethoxy-4-formyl-benzoic acid methyl ester, 6.3 g. of cyanoacetic acid ethyl ester and three drops of piperidine was heated in an open vessel with stirring to 120°C. and stirred at this temperature for an additional 15 minutes. The residue was recrystallized from ethyl acetate and yielded α-cyano-3,5-dimethoxy-4-methoxycarbonyl-cinnamic acid ethyl ester, having a m.p. of 142°-144°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][C:34]1[N:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36][CH:35]=1.C(N1CCOCC1)C>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:40]([C:37]3[CH:38]=[N:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[O:41])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3)[C@@H](C)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
To a suspension of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (105 mg, 0.338 mmol), EDC (71.2 mg, 0.371 mmol), HOBT.H2O (56.9 mg, 0.371 mmol) and 6-methyl-3-pyridinecarboxylic acid (51.0 mg, 0.372 mmol) in DCM (5 ml) was added N-ethylmorpholine (0.090 ml, 0.710 mmol). The reaction was stirred for 18 h at ambient temperature. To the reaction was added water (3 ml) and the organic layer collected via a hydrophobic frit. The organic layer was reduced in volume to approximately 2 ml then loaded onto a silica SP4 chromatography cartridge. The cartridge was eluted with ethyl acetate then a gradient from 0-10% (20% methanol in dichloromethane) in ethyl. Fractions containing the desired product were combined and reduced in vacuo to yield the title compound as a white solid (55 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH:57]([C:59](O)=[O:60])[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([CH:57]4[CH2:58][N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]4)=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (94 mg, 0.465 mmol) in CH2Cl2 (2 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]1([NH2:47])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([NH:47][C:36]([NH:1][C:2]2[CH:30]=[CH:29][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)=[O:23])=[CH:20][CH:21]=5)[S:15][C:8]=34)=[C:4]([F:31])[CH:3]=2)=[O:42])[CH2:46][CH2:45]1
Reactant: NC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1)NC1CC1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 126 (150 mg, 0.346 mmol) in DCM (7 mL) was added TEA (105 mg, 1.038 mmol) and triphosgene (103 mg, 0.346 mmol) and the reaction mixture was stirred for 30 minutes. Cyclopropylamine (39.5 mg, 0.692 mmol) was added and the mixture was stirred at RT overnight. The mixture was concentrated and re-dissolved in EtOAc then washed with saturated NH4Cl solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatography (10% MeOH in EtOAc) afforded title compound 129 (40 mg, 22% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.51 (m, 1H), 8.13 (s, 1H), 7.93 (d, J=7.82 Hz, 2H), 7.73 (m, 1H), 7.63 (d, J=7.82 Hz, 2H), 7.37 (t, J=8.61 Hz, 1H), 7.18 (m, 1H), 6.61 (m, 1H), 6.56 (s, 1H), 3.47-3.42 (m, 4H), 1.86-1.81 (m, 4H), 2.53 (m, 1H), 0.64 (m, 2H), 0.411 (m, 2H). MS (m/z)=517.533 (M+H)
Reaction SMILES: CCCCCCCCCC[CH2:11][CH2:12][O:13]S([O-])(=O)=O.[Na+].[OH:19][CH2:20][CH:21](CO)O.C(S)[C@@H](O)[C@H](O)CS.C1C=CC2S(=O)(=O)OC(C3C=C(Br)C(O)=C(Br)C=3)(C3C=C(Br)C(O)=C(Br)C=3)C=2C=1.[CH2:62]([OH:69])[C:63]([NH2:68])([CH2:66][OH:67])[CH2:64][OH:65]>>[CH2:21]([N:68]([C:63]([CH2:66][OH:67])([CH2:64][OH:65])[CH2:62][OH:69])[CH2:11][CH2:12][OH:13])[CH2:20][OH:19]
Reactant: NC(CO)(CO)CO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: OCC(O)CO
Agent: O=S1(=O)OC(c2cc(Br)c(O)c(Br)c2)(c2cc(Br)c(O)c(Br)c2)c2ccccc21
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Na+]
Product: OCCN(CCO)C(CO)(CO)CO
Reaction time: 0.03 h
Yield: 10 %

Procedure:
Protein samples were prepared for SDS-PAGE by diluting 1:1 with 2× denaturing buffer (40 μg/ml SDS, 20% glycerol, 30 μg/ml DTT and 10 μg/ml bromophenol blue in 125 mM Tris, pH 6.8) and boiling for 2 min. Pre-cast Nu-PAGE 10% Bis-Tris protein gels were obtained from Invitrogen. Each lane was loaded with a maximum of 10 μl of sample and run for 50 min at 200V. After electrophoresis was complete, the gel was stained with Invitrogen SafeStain (1 hour in staining solution, then washed overnight with water).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:17]([CH2:18][C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:16]([NH:15][CH3:10])=[O:21]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C)c1ccccc1Cl
Product: CN(C(=O)CCC#Cc1ccccn1)c1ccccc1Cl
Product: CNC(=O)C(CC#Cc1ccccn1)c1ccccc1Cl

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (157 mg, 1.00 mmol) and pent-4-ynoic acid (2-chloro-phenyl)-methyl-amide (220 mg, 1.00 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (66 μmol 7%) of N-(2-chlorophenyl-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:27][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CCCCCCC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CCCCCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol), cyclooctylamine (0.762 g, 6 mmol) and ethanol (15 mL) were stirred at reflux under nitrogen for 20 hours 1N NaOH (2 mL) was added and solvent was evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as white powder after crystallization from acetonitrile-methanol (0.623 g, 87%); m.p. 171°-173° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10].[C:14]([O:18][C:19](ON=C(C(OCC)=O)C(OCC)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O.C(O)(C)(C)C>[C:14]([O:18][C:19]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(=NOC(=O)OC(C)(C)C)C(=O)OCC
Reactant: C[C@H](N)C(=O)O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Triethylamine (1.68 ml.) was added to a suspension of L-alanine (0.89 g.) in a mixture of water (5 ml.) and tert-butyl alcohol (5 ml.) to give homogeneous solution. To the solution was added diethyl 2-tert-butoxycarbonyloxyiminomalonate (4.0 g.) and the mixture was stirred for 1 hour at room temperature. tert-Butyl alcohol was distilled off from the reaction mixture under reduced pressure and to the residue were added ether and a 5% sodium bicarbonate aqueous solution, after which the mixture was adjusted to pH 7 with a citric acid aqueous solution. The aqueous layer was separated and ethyl acetate was added thereto, and the mixture was adjusted to pH 3 with a citric acid aqueous solution. The mixture was shaken enough and the ethyl acetate layer was separated, washed with water and dried. The solution was concentrated under reduced pressure and the residue was recrystallized from a mixture of ether and petroleum ether to give N-tert-butoxycarbonyl-L-alanine (1.59 g.), mp 82° to 84° C.
Reaction SMILES: [NH:1]([C:14]([O:16]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22]C(ON1C(=O)CCC1=O)=O>>[NH:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][C:14]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:16]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 60.9 %

Procedure:
By using 6.41 g of Boc-Leu-Gly-OH and 6.04 g of Boc-Gly-OSu, and the same procedure as in Reference Example 31 was repaeted to obtain 4.67 g (yield: 61.4%) of the above-mentioned objective product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1ccccc1C
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:25])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Fifty-three grams (0.25 mole) of 3,4-dinitrobenzoic acid, 500 ml. of benzene, 65 g. (0.51 mole) of oxalyl chloride and 1 ml. of pyridine were reacted according to Example 2 (A), first paragraph, to provide 3,4-dinitrobenzoyl chloride as a crude oil.
Reaction SMILES: [CH:1]1([CH:6](Cl)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(C(C)=O)C(C)C>[CH:1]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: ClC(c1ccccc1)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)C2CCCC2)CC1
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Into 35 ml of methyl isobutyl ketone were dissolved 2.92 g of cyclopentyl-phenylmethyl chloride, 2.80 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 1.94 g of N,N-diisopropylethylamine, and the resultant solution was heated under reflux with stirring for 72 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gel column chromatography to give 0.88 g of oily 4-(cyclopentyl-phenylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N1CCOCC1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)ccc1C(=O)N1CCOCC1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-[4-bromo-2-(isopropylsulfonyl)benzoyl]morpholine (Intermediate 261), the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:32])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: C=CCOCC1(c2cccc(C)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2cccc(C)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2,5-dioxo-4-(3-methylphenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile (829 mg) in DMF (1.5 mL) is added potassium carbonate (320 mg) and methyliodide (480 μL). The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over MgSO4 and concentrated to give the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:21])=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammonia as an off white solid (75%). MS 275 (MH+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:17](Cl)(Cl)=[S:18].Cl.[NH2:22][CH2:23][C@H:24]([NH:32]C(OC(C)(C)C)=O)[C:25]([O:27]C(C)(C)C)=[O:26]>C1COCC1.O>[NH2:32][C@@H:24]([CH2:23][NH:22][C:17](=[S:18])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:3]=1)[C:25]([OH:27])=[O:26]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CNC(=S)Nc1cccc(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.5 %

Procedure:
35 mg (0.2 mmol) of 3-aminobenzenesulfonic acid and 57 mg (0.68 mmol) of sodium hydrogen carbonate were added to a mixed solvent of 2.0 ml of water and 0.5 ml of THF, and stirred at room temperature for 15 minutes. 20 μl (0.26 mmol) of thiophosgene was added and stirred at room temperature for another 40 minutes. Subsequently, 60 mg (0.2 mmol) of tert-butyl (2S)-3-amino-2-{[(tert-butoxy)carbonyl]amino}propanoate hydrochloride was added and stirred overnight. Following extraction with ethyl acetate, the solvent was distilled away, and 4.0 ml of trifluoroacetic acid was added to the residue, and the resultant was stirred at room temperature for 5 hours. After distilling the solvent away, purification step A was used to obtain 3.5 mg of the title compound.