Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.Cl.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:30]=1)[CH2:28][NH2:29].C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH2:28][NH:29][C:18](=[O:19])[CH2:17][N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:30]=1
Reactant: NCc1cc(Br)ccc1F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.144 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 93A, 36.0 mg (0.150 mmol) of 5-bromo-2-fluorobenzylamine hydrochloride, 22.1 mg (0.163 mmol) of HOBt and 17.6 mg (0.136 mmol) of N,N-diisopropyl-ethylamine are placed in 1.5 ml of dimethylformamide and treated with 33.9 mg (0.177 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then diluted with 15 ml of water and extracted with ethyl acetate. After evaporation of the organic phase, the crude product is purified by preparative HPLC [Method 13]. 21 mg (32% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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]>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2c(F)cccc2F)cc([N+](=O)[O-])c1
Yield: 94 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (20 g, 77 mmol) in 1,2-dimethoxyethane (250 ml) was degassed by N2 bubbling for 5 min. 2,6-Difluorophenylboronic acid (14.6 g, 92.4 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (6.28 g, 7.7 mmol, 0.1 eq.) and aqueous sodium carbonate (24.49 g, 231 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to give the product in 94% yield (21.2 g). LC-MS (ESI): Calculated mass: 292.24; Observed mass: 293.1 [M+H]+ (rt: 1.49 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 118.8 %

Procedure:
2,5-dibromonitrobenzene (12.0 g, 42.7 mmol) was dissolved in dimethylformamide (DMF, 80 ml), Cu (6.0 g, 93.94 mmol) was added thereto, and then the reaction mixture was reacted at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, the insoluble material was filtered off and the filtrate was concentrated. The resultant product was recrystallized in ethanol to obtain 4,4′-dibromo-2,2′-dinitrobiphenyl (10.2 g, 60%). MS [M+] 354.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:12]2[CH:17]=[CH:16][C:15]([C:2]3[CH:3]=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[C:14]([F:21])[CH:13]=2)=[C:14]([F:21])[CH:13]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: Brc1cnc2[nH]ccc2c1
Product: Fc1cc(Br)ccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1
Temperature: 90 °C

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate HF heating at 90° Celsius for 16 hours and using 5-bromo-1H-pyrrolo[2,3-b]pyridine and 4-bromo-2-fluorobenzeneboronic acid. MS (ESI): mass calcd. for C19H11BrF2N2, 384.01; m/z found, 385.0, 387.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 12.29 (s, 1H), 8.47 (s, 2H), 7.60-7.50 (m, 2H), 7.50-7.34 (m, 5H), 6.73 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH2:16]O)[CH:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CC(CO)C(N)C1)=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(O)CCCC.C(O)C.O>[C:22]([O:21][C:19]([N:18]1[CH2:16][CH:14]2[CH:13]1[CH2:12][NH:11][CH2:15]2)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1CO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NC1CN(C(=O)OCc2ccccc2)CC1CO
Agent: O=C([O-])O
Solvent: CCCCCO
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CNCC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
3-tert-Butoxycarbonylamino-4-hydroxymethyl-pyrrolidine-1-carboxylic acid benzyl ester. To a 3 L round-bottomed flask, was added the filtered reaction mixture of 3-amino-4-hydroxymethyl-pyrrolidine-1-carboxylic acid benzyl ester in pentanol/ethanol mixture. To the mixture sodium bicarbonate (30.8 g, 367 mmol), H2O (655 mL), and Boc anhydride (38 g, 174.1 mmol) were added. The mixture was stirred under N2(g) for 15 h at room temperature. The biphasic mixture was then separated and the organics were washed with brine (655 mL). The organics were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The material was warmed to 98° C. in toluene/heptanes (280 mL each) and then filtered. The filtrate was slowly cooled to room temperature and stirred for 20 h. The resulting solids were filtered and washed with heptanes to provide the title compound (39.5 g, 64% over two steps). 1H-NMR (CD3OD, 400 MHz): 7.31 (m, 5H), 5.11 (s, 2H), 4.20 (m, 1H), 3.50-3.70 (m, 4H), 3.34-3.42 (m, 1H), 3.18-3.29 (m, 1H), 2.49 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)Cl.[CH3:18][C:19]1([CH3:52])[NH:24][CH2:23][CH2:22][N:21]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:50])[F:49])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:30]=[C:29]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)[N:28]=3)[CH2:20]1>C(Cl)Cl.CO>[C:8]([N:24]1[CH2:23][CH2:22][N:21]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:49])[F:50])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[N:30]=[C:29]([C:40]2[CH:45]=[N:44][C:43]([NH2:46])=[N:42][CH:41]=2)[N:28]=3)[CH2:20][C:19]1([CH3:52])[CH3:18])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Triethylamine (72.8 μl, 0.52 mmol) and acetic anhydride (24.6 μl, 0.26 mmol) were added to a methylene chloride solution (3.0 ml) of 5-[8-(3,3-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (107.2 mg, 0.22 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 2 hours followed by the addition of acetic anhydride (4.1 μl, 0.04 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (102.6 mg, 88%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 40.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(trifluoromethyl)benzylamine (available from Aldrich Chemical Company, Inc.; 108 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-trifluoromethyl-benzylcarbamoyl)-biphenyl-2-carboxylic acid (53 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.20 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.2, 1.9 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.56-7.72 (m, 5H), 7.51 (d, J=8.3 Hz, 2H), 4.60 (d, J=5.8 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCOc1ccc(C=O)cc1
Product: CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([O:18][CH:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[NH4+:38].O.ClCCl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]2[O:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:38]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [NH4+]
Reactant: COc1cccc(CC2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 2-oxo-1,2-diphenylethyl 2-[(3-methoxy-phenyl)methyl]cyclohexanecarboxylate (440 mg) and ammonium acetate (593 mg) in acetic acid (2.4 ml) was refluxed for 3 hours and cooled to room temperature, and a mixture of water and dichloromethane was added thereto. The organic layer was washed with water and sodium bicarbonate aqueous solution, dried over magnesium sulfate, and evaporated in vacuo to afford 2-[2-[(3-methoxyphenyl)methyl]cyclohexyl]-4,5-diphenyloxazole (394 mg).
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in imethoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%). 1H-NMR (CDCl3) δ 6.89 (m, 1H, —CH2CH:CHCOOEt), 5.77 (d, 1H, —CH2CH:CHCOOEt), 4.16 (q, 2H, —COOCH2CH3), 2.15 and 1.98 (1H each and a multiplet, —CH2CH:CHCOOEt), 1.48 (m, 1H, C2H5(CH3)CHCH2), 1.30–1.10 (m), and 0.83.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C#N
Reactant: BrCCCCBr
Product: COc1cc(OCCCCBr)ccc1C#N

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxy-2-methoxy-benzonitrile and 1,4-dibromobutane.
Reaction SMILES: [OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:3]([NH:5][C@@H:6]([CH2:19][CH2:20][CH2:21][CH3:22])/[CH:7]=[CH:8]/[C:9]([O:11]CC1C=CC=CC=1)=[O:10])=[O:4].N#N>CCO.[Pd]>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:3]([NH:5][C@@H:6]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:4]
Reactant: CCCCCCCCCCC(O)C(=O)N[C@H](/C=C/C(=O)OCc1ccccc1)CCCC
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CCCCCCCCCCC(O)C(=O)N[C@@H](CCCC)CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of benzyl (E,4S)-4-[(2-hydroxydodecanoyl)amino]oct-2-enoate (0.445 g, 1 mmol) in EtOH (2.5 mL), through which N2 had been passed for 5 min, 10% Pd/C catalyst (0.042 g) was added. The reaction mixture was stirred under H2 for 5 h at room temperature. The catalyst was removed by filtration through a pad of Celite and the filtrate was evaporated under reduced pressure. The product was purified by column chromatography (CHCl3/MeOH 9/1). Yield 0.28 g (70%); mp 53-55° C.; [α]D−2.4 (c 0.75 CHCl3); 1H NMR δ 6.82 (1H, m, NH), 4.18 (1H, m, CHNH), 3.91 (1H, m, CHOH), 2.39 (2H, t, J=6.3 Hz, CH2COOH), 1.95-1.12 (26H, m, 13×CH2), 0.88 (3H, t, J=6.0 Hz, CH3); Anal. Calcd. for C20H39NO4: C, 67.19; H, 10.99; N, 3.92. Found: C, 67.05; H, 11.18; N, 3.63.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(C)(C)CCO
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
A solution of 3-methoxy-3-methylbutan-1-ol (2.50 g, 21.16 mmol) in DCM (30 mL) was treated with p-toluene sulfonyl chloride (5.00 g, 26.2 mmol) followed by TEA (4.28 g, 42.3 mmol) and stirred at RT for 3 h. The mixture was washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 3-methoxy-3-methylbutyl 4-methylbenzenesulfonate (2.84 g, 49%). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J=8.2 Hz, 2 H), 7.45 (d, J=8.1 Hz, 2 H), 4.03 (t, J=7.2 Hz, 2 H), 2.96 (s, 3 H), 2.38 (s, 3 H), 1.75 (t, J=7.2 Hz, 2 H), 1.01 (s, 6 H); MS (ESI) m/z: 295.0 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36](=[O:37])[O:38][CH2:39][CH3:40])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 2 ml of dimethylformamide, 178 mg of ethyl chloroformate and 271 mg of potassium carbonate were added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was evaporated, and the resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (2:8) as the eluent to give 169 mg of ethyl N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH3:13]
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Solvent: CO
Product: CCc1c(Br)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.0 g, 8.37 mmol) and PdC (400 mg) in 50 mL of MeOH was stirred at rt. under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated. The resulting oil was purified by column chromatography to give 5-bromo-4-ethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: C(OC(=O)C1C=CC(S)=CC=1)C.[H-].[Na+].CS(OCC[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)(=O)=O.CCOCC>CN(C)C=O>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:23]2[NH:24][C:25]3[C:30]([CH:22]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:32]=1
Reactant: CS(=O)(=O)OCCc1c(-c2cccnc2)[nH]c2ccccc12
Agent: CCOC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester (prepared according to the procedure found in J. Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50% sodium hydride (dispersion in mineral oil) in 30 ml of dimethylformamide. This mixture is stirred at room temperature for 0.5 hour under nitrogen atmosphere, and added dropwise to a solution of 9.78 g of 3-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-indole in 60 ml of dimethylformamide at -10°. This mixture is stirred at room temperature overnight and poured into 1 liter of ice-water. This is extraced several times with ether. The ether extract is washed with water, dried over MgSO4 and evaporated in vacuo to give 3-[2-(4-ethoxycarbonylphenylthio)-ethyl]-2-(3-pyridyl-indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=2)[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc2c(O)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Product: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Temperature: 85 °C

Procedure:
8-Chloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinolin-4-ol (2.16 g, 5.8 mmol) was dissolved in POCl3 (20 mL) under an atmosphere of nitrogen. The reaction was heated to 85° C. for 4 hours. The reaction was cooled to 0° C. and quenched with water. A saturated solution of sodium bicarbonate in water was used to neutralize the reaction. The reaction was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and was concentrated. 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline (1.87 g, 82%) was purified by silica gel chromatography.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].[K+].O>CN(C=O)C.[Cu]I>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:26]([F:28])([F:27])[F:25])[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)F)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 19.9 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (1.84 g), (trifluoromethyl)trimethylsilane (1.14 g), copper(I) iodide (1.52 g), potassium fluoride (0.28 g) were stirred in DMF (8 ml) at 100° C. for 8 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous solution of sodium chloride. After drying the organic layer with sodium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitro-benzyl)-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (0.32 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[CH3:36][N:35]([CH3:37])[C:33]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([CH:14]([N:5]([CH3:6])[C:4]3[CH:7]=[C:8]([F:11])[C:9]([F:10])=[C:2]([F:1])[CH:3]=3)[CH3:15])[CH:17]=1)[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])=[O:34]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1cc(F)c(F)c(F)c1
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)c(F)c(F)c1
Yield: 35.6 %

Procedure:
3,4,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(3,4,5-trifluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (54.0 mg, 36.1%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.54 (d, 3H), 2.62 (s, 3H), 2.91 (bs, 3H), 3.00 (bs, 3H), 3.24-3.31 (m partially hidden by H2O, 2H), 3.33-3.42 (m partially hidden by H2O, 2H), 3.45-3.52 (m, 2H), 3.52-3.60 (m, 2H), 5.55 q, 1H), 5.56 (s, 1H), 6.73 (d, 1H), 6.75 (d, 1H), 7.67 (d, 1H), 7.89 (d, 1H).