Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:15][C:16]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:15][C:16]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: Cl
Product: Cc1ccc(C)c(C(=O)NCCC23CC4CC(CC(C4)C2)C3)c1
Yield: 86.2 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (0.131 g) and 2.5-dimethylbenzoic acid (0.099 g) to give the title compound as a white solid (0.163 g).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:25][CH:24]=1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)cc1
Yield: 20 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 4-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 20% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O([Si](C)(C)C)[Si](C)(C)C.ClCCCl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCCl
Product: N#Cc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A solution of 2-chloro-3-nitrobenzamide (1.02 g, 4.9 mmol) in P2O5/(TMS)2O/1,2-dichloroethane (30 mL) was heated at 85° C. for 18 hours. After it was cooled to 25° C., the solution was filtered through a plug of silica gel (60 mL), eluting with 5% methanol/CHCl3 (400 mL). The combined washes were concentrated under reduced pressure to give 2-chloro-3-nitrobenzonitrile as an off-white solid (0.66 g, 74%).
Reaction SMILES: [F:1][CH2:2][C:3]1([S:6]([NH:9][C:10]([C@@:12]23[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][C@@H:21]([CH3:28])[CH2:20][C@@H:19]([CH3:29])[C@H:18]([NH:30]C(=O)OC(C)(C)C)[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([O:42][C:43]4[CH:52]=[N:51][C:50]5[C:45](=[CH:46][C:47]([O:53][CH3:54])=[CH:48][CH:49]=5)[N:44]=4)[CH2:41][C@H:15]2[C:14](=[O:55])[NH:13]3)=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[ClH:56]>O1CCOCC1>[ClH:56].[NH2:30][C@@H:18]1[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([O:42][C:43]3[CH:52]=[N:51][C:50]4[C:45](=[CH:46][C:47]([O:53][CH3:54])=[CH:48][CH:49]=4)[N:44]=3)[CH2:41][C@H:15]2[C:14](=[O:55])[NH:13][C@:12]2([C:10]([NH:9][S:6]([C:3]3([CH2:2][F:1])[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:11])[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][C@@H:21]([CH3:28])[CH2:20][C@H:19]1[CH3:29]
Reactant: COc1ccc2ncc(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5C=CCC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc2c1
Agent: COc1ccc2ncc(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5/C=C\CC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc2c1
Agent: COc1ccc2ncc(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5/C=C\CC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2ncc(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5C=CCC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)nc2c1

Procedure:
A solution of tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxyquinoxalin-2-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (120 mg, 0.15 mmol) in 4M HCl in dioxane (10 ml 4 M solution) was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to get crude compound (100 mg, 95%) as brown solid. The crude compound was washed with diethyl ether and taken to the next step without further purification. 1H NMR (400 MHz, CD3OD): δ ppm 9.19 (s, 1H) 8.26-8.34 (m, 2H) 7.90 (d, J=8.78 Hz, 2H) 7.26-7.34 (m, 3H) 6.02 (br. s., 1H) 5.58-5.67 (m, 1H) 5.04 (t, J=9.54 Hz, 1H) 4.59-4.71 (m, 2H) 4.33-4.53 (m, 1H) 4.12-4.26 (m, 2H) 3.98 (s, 3H) 3.73-3.81 (m, 2H) 3.66-3.71 (m, 2H) 2.77-2.97 (m, 2H) 2.42-2.75 (m, 3H) 1.91-2.11 (m, 2H) 1.67-1.78 (m, 2H) 1.44-1.62 (m, 2H) 1.21-1.42 (m, 5H) 1.01-1.15 (m, 5H) 0.92 (br. s., 1H): MS: MS m/z 687.4 (M+−36).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[C:68]([O:70][CH3:71])[CH:69]=1)[C:64](Cl)=[O:65]>>[CH3:71][O:70][C:68]1[CH:67]=[C:63]([CH:62]=[C:61]([O:60][CH3:59])[CH:69]=1)[C:64]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:65]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(OC)cc(OC)c4)cc3)cc2C1=O

Procedure:
The compound of example 179 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,5-dimethoxy benzoyl chloride. The compound of example 179 was used directly without isolation for the preparation of compound of example 180.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=3Br)[CH:7]=[CH:6][C:5]=12.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=3[C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)=[CH:43][CH:44]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc3nonc3c2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 56.9 %

Procedure:
A solution of 5-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 0.645 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.256 g, 0.709 mmol), and Cs2CO3 (1.0 g, 3.220 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.105 g, 0.129 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction mixture was refluxed for 12 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (170 mg, 57%) as a yellow color solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1 H), 8.39 (s, 1 H), 8.07-8.00 (m, 3 H), 7.81 (t, J=8.4 Hz, 1 H), 7.70 (d, J=8.2 Hz, 1 H), 7.64 (t, J=8.2 Hz, 1 H), 7.48 (d, J=8.5 Hz, 2 H), 7.25 (d, J=8.3 Hz, 2 H), 7.12 (d, J=8.4 Hz, 2 H), 5.39 (s, 2 H), 1.49 (s, 6H). MS: [M+H]: m/z=464.2. HPLC: 93%, Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:30]3[CH:31]=[CH:32][C:33]4[N:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:22]5[C:27]([C:28]=4[CH:29]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
Into a 500 mL three-neck flask were put 6.5 g (26 mmol) of 4-bromodiphenylamine, 7.5 g (26 mmol) of 9-phenyl-9H-carbazole-3-boronic acid, and 400 mg (1.3 mmol) of tri(o-tolyl)phosphine. The atmosphere in the flask was replaced with nitrogen. To the mixture were added 100 mL of toluene, 50 mL of ethanol, and 14 mL (0.2 mol/L) of potassium carbonate aqueous solution. Under reduced pressure, this mixture was degassed while being stirred. After the degassing, 67 mg (30 mmol) of palladium(II) acetate was added to the mixture. This mixture was refluxed at 100° C. for 10 hours. After the reflux, an aqueous layer of this mixture was extracted with toluene, and the extract was combined with an organic layer and then washed with a saturated saline solution. The organic layer was dried with magnesium sulfate. After the drying, this mixture was subjected to gravity filtration. The obtained filtrate was condensed to give an oily light brown substance. This oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of hexane:toluene=4:6). A white solid obtained after the purification was recrystallized with dichloromethane/hexane to give 4.9 g of a white solid, which was the object of the synthesis, in a yield of 45%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Br:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
2,6-Dibromophenol (29.30 g, 116 mmol) and benzyl bromide (33.14 g, 194 mmol) were dissolved in 2-butanone (300 mL). Potassium carbonate (29.47 g, 213 mmol) was added, and the mixture was stirred for 1.5 hr at reflux temperature. The reaction mixture was cooled to room temperature, filtered, and evaporated to dryness. The remaining viscous oil was subjected to silicagel column chromatography, flushing with n-pentane to remove benzyl bromide, then DCM/n-pentane=1:1 to elute the product, yielding the product as a white crystalline solid (39.32 g, 99%). 1H-NMR (CDCl3): δ=7.61 (dd, 2H), 7.54 (d, 2H), 7.41 (m, 3H), 6.90 (t, 1H), 5.04, (s, 2H) ppm.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29]>>[CH3:31][S:28]([CH2:27][CH2:26][NH:25][C:15]([C:12]1[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[N:14][CH:13]=1)=[O:17])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Product: CS(=O)(=O)CCNC(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 75 %

Procedure:
Prepared in 75% yield (170 mg) as described in general procedure (H) from 2-(3,3-dicyclohexylureido)thiazole-5-carboxylic acid (175 mg, 0.5 mmol) and 2-aminoethylmethylsulfone (HCl salt, 80 mg, 0.5 mmol).
Reaction SMILES: [Cl-].C([Al+]CC)C.C[O:8][C:9]([C:11]1[CH:15]=[C:14]([Br:16])[N:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[CH:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1)=O>>[Br:16][C:14]1[N:13]([CH:17]([CH3:18])[CH3:19])[C:12]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[N:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=3)[C:9](=[O:8])[C:11]=2[CH:15]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cn1
Agent: CC[Al+]CC
Agent: [Cl-]
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1ccc(F)c(Cl)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but diethylaluminium chloride (1.8M in toluene) was used instead of trimethylaluminium chloride, and 5-bromo-2-[(3-chloro-4-fluoro-phenylamino)-(5-chloro-pyridin-2-yl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BL1) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a yellow solid. ESI-MS: tR=1.30 min, [M+H]+ 482/484/486 (LC-MS 1).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:8][CH2:7]1
Reactant: NCC#CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC/C=C/CN1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
A solution of 1-amino-4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-2-butyne (25.8 g) and tetrahydrofuran (40 ml) was added dropwise over 45 mins to a suspension of lithium aluminum hydride (6.05 g) and tetrahydrofuran (500 ml), while the reaction temperature was maintained below 5° C. After the addition was complete, the reaction mixture was stirred at room temperature for 14.5 hrs and at 45° C. for 3.5 hrs. The reaction mixture was cooled to 0° C. and quenched by sequential addition of water (6 ml) 15% aqueous sodium hydroxide solution (6 ml), and water (18 ml). The mixture was filtered through a bed of celite, washed with dichloromethane (200 ml), and the filtrate was concentrated. Purification of the residue by distillation gave 25.0 g (96%) of product, bp 135° C., (0.03 mm).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>CO>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Solvent: CO
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Yield: 95.1 %

Procedure:
43.4 g (0.267 mol) of bromine was added dropwise to a solution of 50.5 g (0.267 mol) of 2′,4′-dichloroacetophenone in 100 g of methanol at a reaction temperature of 45 to 50° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 120 g of toluene and was then washed with water (100 ml×3 times). Thereafter, the toluene was distilled off under reduced pressure, giving 68.0 g (0.254 mol) of crude brown oily 2-bromo-2′,4′-dichloroacetophenone.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CN(C)C=O.CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one were suspended in 600 ml of dimethylformamide. The mixture obtained was heated with stirring to 100° C., whereupon a solution of 122 g (1mole) of p-hydroxybenzaldehyde in 400 ml of methanol was added. The dissolution of both compounds was complete. The dye started crystallizing after some 30 min. The heating was stopped after 2 h and the reaction mixture was allowed to cool down to room temperature. The dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:14]([OH:16])=[O:15])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,10-decanedicarboxylic acid, benzyl bromide and potassium carbonate in N,N-dimethylformamide was stirred at room temperature for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and diluted hydrochloric acid, and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C[Si]([N:30]=[C:31]=[O:32])(C)C>>[NH:2]([CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])[C:31]([NH2:30])=[O:32]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NC(N)=O)c1

Procedure:
Following the method of Example 16, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and trimethylsilyl isocyanate gave the title compound after recrystallisation from ethyl acetate/petroleum ether, m.p. 154°-156° C. (dec.). 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.52 (1H, d, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.16 (1H, t. J=8 Hz), 7.08 (1H, t, J=8 Hz), 6.97 (1H, s), 6.88 (2H, s), 6.77 (1H, s), 5.21 (1H, d, J=8 Hz), 5.01 (2H, s), 4.85 (1H, m), 4.34 (2H, s), 3.28 (2H, J=5 Hz), 2.30 (6H, s).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=O)=O)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[SH:2][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(-c3ccc(S(=O)(=O)Cl)cc3)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Sc1ccc(-c2ccc(-c3ccc(S)cc3)cc2)cc1
Temperature: 0 °C
Yield: 51 %

Procedure:
4,4″-dichlorosulfonyl1,1′:4′,1″-terphenyl (8.576 g, 20 mmol) synthesized in process 1-a is dissolved in tetrahydrofuran (THF) solvent (300 ml), add lithium aluminium hydride (8.586 g, 200 mmol, 10 eq.) and refluxed for 3 hours. The obtained reacted mixture is poured into ice water, and adjusted the pH to 1 or less by adding concentrated hydrochloric acid. Deposited impurity is removed by suction filtration, then washed by methylene chloride completely. After that, the filtrate is extracted by acid-base extraction (CH2Cl2, NaOH, HCl), the organic phase is dried up using magnesium sulfate and recrystalyzed. Thus, light yellowish crystal of 4,4″-dimercapto-1,1′:4′,1″-terphenyl (3.003 g, 10.2 mmol, 51%) is obtained (compound G).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:12]1)[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:51]1[N:52]=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:57]([C:54]1[N:55]=[CH:56][C:51]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C@H:7]([N:11]2[CH2:14][C:13]4([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]4)[CH2:12]2)[CH2:6][CH2:5]3)=[N:52][CH:53]=1)#[N:58]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Reactant: N#Cc1cnc(Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C#N)cn4)ccc31)C2
Temperature: 110 °C
Yield: 59.5 %

Procedure:
To a solution of tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 700 mg, 1.66 mmol) in anhydrous dioxane (10 mL) was added bis(pinacolato)diboron (473 mg, 1.86 mmol) and potassium acetate (659 mg, 6.71 mmol). The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (62 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated to 110° C. under nitrogen for 5 hours. TLC indicated the complete consumption of the starting material (3-1a). The reaction was cooled to room temperature and 5-chloropyrazine-2-carbonitrile (278 mg, 1.99 mmol), Pd(dppf)Cl2 (62 mg, 0.07 mmol) and 5.81 mL of 2M aqueous K2CO3 solution (de-oxygenated with a stream of nitrogen for 15 minutes prior to addition) were added. The reaction was purged with nitrogen (3×) and was heated for 20 hours at 110° C. The reaction was cooled and concentrated in vacuo. The residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution. The organics layer was washed with 50 mL of brine, dried (Na2SO4) and concentrated to give crude product as black semi-solid. The crude product was purified via silca gel chromatography using a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) system, eluting with 0-100% EtOAc:heptanes to give the title compound as a brown solid (440 mg, 59%). MS (ES+) 446.3 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.56-1.64 (m, 4H), 1.81-1.92 (m, 1H), 2.06 (dd, 1H), 2.77-2.87 (m, 1H), 2.92-3.04 (m, 3H), 3.12 (d, 2H), 3.24-3.28 (m, 4H), 3.86 (dd, 1H), 7.41 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 1H), 8.09 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][O:27][C:28]4=[O:32])=[CH:3][C:4]=3[N+:24]([O-:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3[N+](=O)[O-])CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 72.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-nitrophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.5 g) described in Preparation Example 63 and oxazolidin-2-one (0.3115 g), the title compound (1.105 g) was obtained.