Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=2[CH2:50][Cl:51])[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[ClH:51].[ClH:51].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:15][CH2:16]3)[CH2:50][C:49]3[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=3[C:40]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccccc4-c4cc(OC)c(OC)c(OC)c4)c4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dibydrochloride.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH:19]1(CBr)[CH2:21][CH2:20]1>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:11][C:12]2([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]2)[CH2:21][CH2:20]1
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: BrCC1CC1
Agent: CC(C)(C)NC(=O)O
Product: NS(=O)(=O)C1(CC2CC2)CC1

Procedure:
Step 16IId) This compound, 1-cyclopropyl-methylcyclopropylsulfonylamine tert-butylcarbamate, was obtained in 92% yield according to the procedure described in the synthesis of 1-methoxymethylcyclo-propylsulfonylamine tert-butylcarbamate (Step 15IId) except 1.10 equivalents of cyclopropylmethyl bromide were used as electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0 Hz, 2H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[CH2:6]1)=O.O[Li].O>C1COCC1.O>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:8]=2)[CH2:13][CH2:14][NH:5]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)c1)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of N-{3-[3-(2-{[2-(2,2,2-Trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide (191 mg, 0.30 mmol) in THF (4.0 mL) was added a solution of LiOH.H2O (19.8 mg, 0.47 mmol) in H2O (1.5 mL). The mixture was stirred at rt for 30 min. The mixture was partitioned between saturated aq. NaHCO3 and 5:1 CHCl3/isopropanol. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give 191 mg of crude product. Purification by silica gel chromatography (0 to 40% sat. ammonia/MeOH in EtOAc) afforded 163.2 mg of the title compound as a white powder. LCMS ((ES)+ 538.3. 1H NMR (400, DMSO-d6) δ 2.63 (t, 2H, J=5.6), 2.96 (t, 2H, J=5.6), 3.80 (s, 2H), 6.46 (d, 1H, J=5.2), 6.95 (d, 1H, J-=8.4), 7.11 (t, 1H, J=6.4), 7.29 (d, 1H, J=8.0), 7.36 (d, 1H, J=9.2), 7.43-7.57 (m, 5H), 7.93 (d, 2H, J=7.2), 8.09 (s, 1H), 8.21 (d, 1H, J=5.6), 8.49 (d, 1H, J=8.8), 8.82 (d, 1H, J=6.8), 9.41 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(Oc3c(F)cccc3F)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2cc(Oc3c(F)cccc3F)ccc2c1O
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (210 mg) and NBS (133 mg) in MeCN (5 mL) was stirred in an ice/water bath for 2 h; then concentrated, the residue was column purified to give the desired product (156 mg). LC MS ESI: 424 (M+1)+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OCC)(O[CH2:19][CH3:20])(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:19]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:20]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1cccc(C(=O)c2ccccc2)c1

Procedure:
Friedel-Crafts alkylation is carried out with benzophenone and diethyl sulfate in the presence of aluminum chloride to form 3-ethylbenzophenone. It is then subjected to bromination using N-bromosuccinimide to produce 3-(1-bromoethyl)benzophenone, which is then subjected to alkali hydrolysis to obtain 3-(1-hydroxyethyl)benzophenone. This compound is further reacted with carbon monoxide to obtain ketoprofen (Spanish Patent No. 452,500). ##STR4##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.[O:16]1[CH2:19][CH:18]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17]1.C1(N2C=C(C3C=C4C(=CC=3)N(C(=O)C)[C@@H](C)CN4)C=N2)CC1>>[CH3:15][C@H:7]1[CH2:6][NH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:23]3[CH:22]=[N:21][N:20]([CH:18]4[CH2:19][O:16][CH2:17]4)[CH:24]=3)[CH:3]=2)[N:8]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3COC3)c2)OC1(C)C
Agent: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C

Procedure:
(S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the procedure outlined above for (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone. MS (ESI, pos. ion) m/z 313 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[ClH:1].[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:13][NH2:14])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cl
Product: NNc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-(trifluoromethyl)pyridine (25 g) and hydrazine monohydrate (100%) (100 ml) were added to ethanol (60 ml) and stirred at 100° C. for three hours. The reaction solution was concentrated in vacuo, chloroform and water were added to the residue, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was exaporated in vacuo and 4N hydrochloric acid ethanol solution was added to the residue to give 5-trifluoromethylpyridin-2-ylhydrazine hydrochloride (15.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][Al](C)C.O.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.CCCCCC>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)ncc1Br
Temperature: 25 °C
Yield: 35.1 %

Procedure:
5 g of 5-bromo-2,4-dichloropyrimidine was dissolved in 70 mL of tetrahydrofuran, and under stirring at room temperature, 15.8 g of trimethyl aluminum in 15% n-hexane and 1.77 g of tetrakis(triphenyl)phosphine were added, and stirred at 80° C., under nitrogen atmosphere for 7 hours. Under ice cooling, 70 mL of water was added little by little, followed by 46 g of potassium sodium tartrate tetrahydrate, and stirred at room temperature for 1 hour. Then the solution was extracted twice with ethyl acetate, and the resultant organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was evaporated, and purification and isolation by silica gel column chromatography (ethyl acetate:n-hexane=1:8) were followed, to obtain 1.6 g of the title compound as a pale yellow syrup.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[CH:19]1([NH:25][C:26]2[C:31]([NH2:32])=[CH:30][N:29]=[C:28]3[CH:33]=[CH:34][S:35][C:27]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1.C(O)C>[CH:19]1([N:25]2[C:26]3=[C:27]4[S:35][CH:34]=[CH:33][C:28]4=[N:29][CH:30]=[C:31]3[N:32]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1NC1CCCCC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (49 mg, 0.55 mmol) and triethyloxonium tetrafluoroborate (98 mg, 0.51 mmol) in tetrahydrofuran (0.75 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.32 mL) and added to a suspension of N7-cyclohexylthieno[3,2-b]pyridine-6,7-diamine (42 mg, 0.17 mmol) in ethanol (1.1 mL). The reaction mixture was stirred at 80° C. for 1 h. The solvent was removed, and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1 mg, 2%). LCMS calculated for C16H20N3OS (M+H)+: m/z=302.1. Found: 302.1.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[N:6]=[N:5]1>C(O)C.[Pd]>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[N:5]1
Reactant: CC(C)(C)Cn1nnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Cn1nnc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2,2-Dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (8) (4.46 g, 19.04 mmol, 1.0 equiv.) was dissolved in ethanol (50 ml) and flushed with N2, then charged with 10% Pd/C (2.026 g, 1.904 mmol, 0.1 equiv.). The mixture was sparged under an atmosphere of hydrogen (1 atm) and after stirring at room temperature for 5 hrs, the mixture was filtered through a Celite filter. The residue was washed with MeOH several times and the filtrate was concentrated in vacuo to give 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (9). LRMS m/z (M+H) 205.0 found, 205.3 required.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH:25]=2)[CH:19]=1)=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O>CN(C=O)C.C(Cl)Cl>[CH2:45]([N:36]1[CH2:37][CH2:38][CH:33]([N:30]2[C:16]3[N:17]=[C:18]([C:20]4[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH:25]=4)[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]4[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])=[O:13])[C:15]=3[CH:32]=[N:31]2)[CH2:34][CH2:35]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCNCC2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.193 mmol) in DMF (1 mL), K2CO3 (0.032 g, 0.232 mmol) and benzyl bromide (0.04 g, 0.232 mmol) were added. Resulting reaction mixture was stirred at 80° C. for 12 h. On completion of reaction, water was added to it and extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by prep HPLC to provide the desired compound (21.3% yield). LCMS: 608.45 (M+1)+; HPLC: 94.92% (@ 254 nm) (Rt; 4.640); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 9.70 (bs, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.54-7.52 (m, 5H), 6.85 (s, 1H), 5.90 (s, 1H), 5.17 (m, 1H), 4.40 (m, 4H), 3.55 (d, 2H, J=12 Hz), 3.41-3.35 (m, 2H), 2.83 (m, 2H), 2.32-2.41 (m, 2H), 2.23 (s, 3H), 2.22-2.13 (m, 2H), 2.12 (s, 3H), 1.57 (s, 6H), 1.47 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(C(C)C)CC)(C)C.[Br:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>CN1C(=O)CCC1.O>[Br:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzonitrile (A) (5 g, 27.4 mmol) and diisopropyl-ethylamine (4.24 g, 32 mmol) in NMP (40 mL) was added 3-bromoaniline (B) (4.71 g, 27.4 mmol) and the reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was cooled to RT and diluted with water. The solid was filtered off, washed several times with water to remove excess 3-bromoaniline, dried under vacuum to give compound C (5.8 g, 66%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[C:5]([Cl:11])=[C:4]([Br:12])[C:3]=1[Cl:13].Br[C:15]1[C:23]2[N:22]=N[NH:20][C:19]=2C(Cl)=CC=1Cl.Cl[C:27]1C=C(Cl)C2NN=NC=2C=1>>[NH2:22][C:23]([CH3:15])([CH2:27][N:8]1[N:7]=[C:6]2[C:5]([Cl:11])=[C:4]([Br:12])[C:3]([Cl:13])=[C:2]([Br:1])[C:10]2=[N:9]1)[C:19]#[N:20]
Reactant: Clc1c(Br)c(Cl)c2[nH]nnc2c1Br
Reactant: Clc1cc(Cl)c2[nH]nnc2c1Br
Reactant: Clc1cc(Cl)c2[nH]nnc2c1
Product: CC(N)(C#N)Cn1nc2c(Cl)c(Br)c(Cl)c(Br)c2n1

Procedure:
2-Amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 4,6-dibromo-5,7-dichloro-1H-benzotriazole that was prepared along with 4-bromo-5,7-dichloro-1H-benzotriazole described in Example 55 using a procedure similar to that described in Example 53 except using 5,7-dichloro-1H-benzotriazole described in Example 15.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][NH:36][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: NCCc1ccccn1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 10 g (28 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with 2-(2-pyridyl)ethylamine in the presence of HOBT and DIC, 13 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 155° C. The product was suspended in 300 ml of methanol and treated with 20 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in EA. The product was extracted into the aqueous phase 2 times using 2 M hydrochloric acid. The aqueous phase was then rendered alkaline with potassium carbonate and extracted 2 times with EA. After washing with water, drying and concentrating, 7.3 g of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH2:29][O:30][CH:31]1[N:40](C(OCC)=O)[C:39]2[C:34](=CC=CC=2)[CH:33]=[CH:32]1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:8]([CH:22]([CH3:27])[CH3:23])[CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:39][N:40]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Yield: 46.7 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.10 g) isopropyl-2-(pyridin-2-yloxy)-ethylamine (0.18 g) and EEDQ (0.136 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 18 h. The solvent was evaporated and the residue was purified by flash chromatography on silica eluting with dichloromethane/methanol (98:2 then 96:4) to give the title compound as a pale yellow oil (0.033 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[O:16])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CCc2oc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]-N-[4-(ethoxycarbonyl)phenyl]propionamide (0.70 g), potassium hydroxide (0.26 g), ethanol (20 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 5 hrs and further stirred at 50° C. for 3 hrs. The reaction mixture was poured into water and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a colorless powder. Recrystallization from chloroform-ethanol gave 4-({3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]propanoyl}amino)benzoic acid as colorless prism crystals (0.51 g, 75%). melting point: 243–244° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH:3][CH:2]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br/[C:37](/[C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:53][CH2:52]2)=[C:47]([O:54][CH3:55])[N:46]=1)=[CH:38]\[C@@H:39]1[NH:43][C:42](=[O:44])[CH2:41][CH2:40]1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:51]1([C:48]2[CH:49]=[CH:50][C:45](/[C:37](/[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:38]/[C@@H:39]3[NH:43][C:42](=[O:44])[CH2:41][CH2:40]3)=[N:46][C:47]=2[O:54][CH3:55])[CH2:52][CH2:53]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccncc2)ccc1C1CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Pyridyltributyltin (218 mg), tris(dibenzylideneacetone)dipalladium (27 mg) and tri(2-furyl)phosphine (42 mg) were added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-24 (100 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 90° C. for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(pyridin-4-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (42 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][OH:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:28]([O:30][C:16](=[O:17])[CH3:15])[CH3:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred mixture of 8-chloro-6-phenyl-1-(2-hydroxyethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.677 g., 0.002 mole), phthalimide (0.324 g., 0.0022 mole), triphenylphosphine (0.576 g., 0.0022 mole) and dry tetrahydrofuran (20 ml.), under nitrogen, is treated with diethyl azodicarboxylate (0.383 g., 0.0022 mole) and stirred at ambient temperature (22°-25° C.) for 24 hours. The mixture is concentrated in vacuo and the residue chromatographed on silica gel (50 g.) with 3% methanol-97% chloroform. The product thus obtained is crystallized from ethyl acetate to give 8-chloro-1-(2-phthalimidoethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine ethyl acetate solvate of melting point 223.5°-226° C.