Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29]I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C:12]([O:14][CH3:15])=[O:13])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: ICCCC/C=C(/c1ccccc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCC/C=C(/c1ccccc1)c1cccnc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Methyl p-methylphenylsulfonylacetate (0.43 g, 2 mmole) was dissolved in dimethylformamide, and after the solution was cooled to 0° C. under argon, sodium hydride (0.1 g) was added, followed by stirring for 10 minutes. A solution of (Z)-6-phenyl-6-(3-pyridyl)-1-iodo-5-hexene (0.8 g) in dimethylformamide (4 ml) was added to the reaction solution, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, water (30 ml) was added, and the product was extracted with ethyl acetate. Working up in the usual procedure, the resulting product was chromatographed on silica gel, and development was effected with isopropyl ether:ethyl acetate (1:1) to yield methyl (Z)-8-phenyl-8-(3-pyridyl)-2-(p-methylphenylsulfonyl)-7-octenoate (1-c) (0.6 g, 61%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:15]=[CH:14][C:13]3[N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH:10]([CH2:22][Cl:23])[C:9]=3[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:30]([O-])([O-:32])=[O:31].[K+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:15]([N+:30]([O-:32])=[O:31])=[CH:14][C:13]3[N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:11][CH:10]([CH2:22][Cl:23])[C:9]=3[C:8]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc2ccc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
Solid 174 (57 mg, 0.16 mmol) was dissolved in cone. H2SO4 (5 mL) at 0° C., then treated dropwise with a cold (0° C.) solution of KNO3 (16 mg, 0.16 mmol) in cone. H2SO4 (0.5 mL). After 15 min, the mixture was poured into ice water and extracted with CH2Cl2 (×6). The combined organic extracts were washed with water (×2), brine and dried. Chromatography eluting with petroleum ether/EtOAc (7:3) gave 8-acetyl-1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (175) (25 mg, 39%) as an orange powder: mp (petroleum ether/EtOAc) 196-198° C.; 1H NMR (CDCl3) δ 9.23 (s, 1H), 8.58 (d, J=9.1 Hz, 1H, 8.49 (d, J=1.3 Hz, 1H), 8.17 (dd, J=9.1, 1.6 Hz, 1H), 4.73 (d, J=11.5 Hz, 1H), 4.56 (dd, J=11.4, 8.8 Hz, 1H), 4.47-4.39 (m, 1H), 3.98 (dd, J=11.6, 3.6 Hz, 1H), 3.77 (dd, J=11.6, 7.8 Hz, 1H), 2.78 (s, 3H). Anal. (C17H12ClF3N2O4) C, H, N.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([NH2:17])=[O:16])=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]#[N:34])[CH:31]=2)[NH:26][CH:25]=1>>[C:33]([C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15](=[O:16])[NH2:17])=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5]1)#[N:34]
Reactant: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1

Procedure:
5-(1-piperazinyl)benzofuran-2-carboxamide or a corresponding salt is reacted with 3-(4-chlorobutyl)-5-cyanoindole to give 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine and optionally then converted into its acid addition salt.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([NH2:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 80 %

Procedure:
By using 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 80%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.21 g, 57% yield), mp=88–90° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−24.8° (c=1, EtOH).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH:9]=1.[CH3:20]I>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]2[N:11]([CH3:20])[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:9]=1
Reactant: CI
Reactant: Fc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cc(Br)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
NaH 60% suspension in mineral oil (0.61 g, 25.5 mmol) was added to a solution of 2-(5-Bromo-2-fluoro-phenyl)-1H-benzoimidazole (3.70 g, 12.76 mmol) in dry THF (100 mL) and the reaction was stirred at room temperature 30 minutes before adding methyl iodide (1.19 mL, 19.1 mmol). Reaction was left stirring for 2 h, then quenched with water (20 mL) The solution was concentrated, then AcOEt (30 mL) was added. The organic solution was separated, washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 3.80 g of desired compound. (97%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]3[NH:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(CCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.5 %

Procedure:
2-(Chloromethyl)benzimidazole (448 mg, 2.64 mmol) and potassium carbonate (729 mg, 5.28 mmol) were added to a solution of 4-(2-phenylethyl)piperidine (500 mg, 2.64 mmol) in dry DMF (20 ml) under a nitrogen atmosphere and the mixture stirred at room temperature for 20 hours. The reaction was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water (25 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a brown oil which was triturated with toluene and recrystallised from methanol to give the title compound as a sandy solid (97.3 mg, 12%), m.p. 170° C.; (Found: C, 78.38; H, 7.79; N, 12.93. C21H25N3.0.1 H2O requires C, 78.51; H, 7.91; N, 13.08%); δH (DMSO-d6) 1.22 (3H, m, piperidinyl H and CH2CH2Ph), 1.50 (2H, m, piperidinyl CH2), 1.67 (2H, m, piperidinyl CH2), 2.01 (2H, m, piperidinyl CH2), 2.56-2.60 (2H, m, piperidinyl CH2), 2.83 (2H, d, J 10.8Hz, CH2 -Ph), 3.67 (2H, s, N-CH2Ar), 7.12-7.19 (5H, m, ArH), 7.24-7.28 (2H, m, ArH), 7.42 (1H, d, J 7.3 Hz, ArH), 7.53 (1H, d, 3 7.3Hz, ArH), and 12.20 (1H, brs, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=2[S:6][C:5]=1[S:18][CH3:19])([OH:3])=[O:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:2][C:1]([C:4]2[C:9](=[O:10])[C:8]3[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=3[S:6][C:5]=2[S:18][CH3:19])=[O:3])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1sc2c(F)c(F)c(F)cc2c(=O)c1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC(=O)c2c(SC)sc3c(F)c(F)c(F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a suspension of 50 mg (0.163 mmol) of the compound of Example 112 in 0.2 ml of chloroform were added 30.7 mg (0.196 mmol) of p-methoxybenzyl chloride, 16.5 mg (0.163 mmol) of triethylamine and 29.4 mg (0.196 mmol) of sodium iodide, and the mixture was stirred for 5 hours at room temperature, which was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water and with saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (CHCl3) to obtain 22.5 mg (0.0528 mmol) of title compound (yield 32%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])#[N:10]>Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:9]#[N:10])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: O
Product: N#Cc1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
2,4-Dichloropyrimidine (149 mg, 1 mmol), 2-cyanoaniline (118 mg, 1 mmol) and 2 drops conc. HCl were dissolved in water (20 ml). The reaction mixture was stirred at ambient temperature for 18 hours. The resulting precipitate was filtered off and dried under vacuum to give the title product as a colourless solid (84 mg, 36%). NMR (300 MHz) 6.79 (d, 1H), 7.42 (m, 1H), 7.62 (m, 1H), 7.75 (m, 1H), 7.89 (m, 1H), 8.24 (d, 1H), 10.23 (br, 1H); m/z: (ES+) 231.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[H-].[Na+].Br[CH2:30][C:31](OC(C)(C)C)=[O:32].CC(C[AlH]CC(C)C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][O:26][CH2:30][CH2:31][OH:32])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(COCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.28 mmol) of 1-9 in 3 mL of DMF at 0° C. was added 20 mg of NaH (0.6 mmol of a 60% suspension in oil), followed by 80 μL (0.6 mmol) of tert-butyl bromoacetate. After stirring for 2 h at 0° C., the reaction was quenched with a saturated NH4Cl solution, and extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide a colorless oil. This residue was dissolved in 10 mL of CH2Cl2, cooled to −78° C., and 900 μL of a 1M DIBAL-H solution in CH2Cl2 was added dropwise. After stirring for 45 min, the reaction was quenched with 500 μL of acetone, the cooling bath was removed, 15 mL of a 0.5 M tartaric acid solution was added, and the biphasic mixture was stirred for 1 h. The layers were separated, the organic was washed with water, dried over Na2SO4, and concentrated: The residue was then dissolved in 5 mL of THF and 1 mL of MeOH, and a small amount of NaBH4 was added. After stirring for 15 min, the reaction was quenched with 1M HCl, extracted twice with EtOAc, washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide 2-2 as a sticky white taffy. Data for 2-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.4 (s, 1H), 4.8-4.6 (m, 3H), 4.2 (d, 1H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 2H), 2.85 (s, 6H) ppm. HRMS (ES) calc'd M+H for C22H24F2N2O3: 403.1828. Found: 403.1824.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[CH3:12][S:13]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:39])[F:38])[CH:32]=3)=[C:27]([CH3:40])[NH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:38])[F:39])[CH:32]=3)=[C:27]([CH3:40])[N:26]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=3[F:11])[CH:25]=2)=[O:23])=[CH:41][CH:42]=1)(=[O:15])=[O:14]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1F

Procedure:
Example 41 is prepared as described for example 2.1, substituting benzyl bromide with 4-bromomethyl-3-fluoro-benzonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=580; Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]1([C@@H:48]([NH2:50])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([NH:50][C@H:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:49])=[O:17])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Reactant: C[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(-c2ccc3[nH]ncc3c2)on1)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example 71A), was dissolved in N,N-dimethylformamide (1.0 mL) followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (0.5 mL). Then a solution of (S)-1-phenylethanamine (22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6 mL) was added, followed by diisopropylethylamine (56 μL, 0.32 mmol) dissolved in N,N-dimethylformamide (0.2 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m, 1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.40-7.45 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H), 9.28 (d, 1H). MS (ESI+) m/z 333 (M+H)+; (ESI−) m/z 331 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:24])=[O:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH2Cl2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (100 mL×2) and the combined organic phase was dried over MgSO4 and concentrated to give the crude product (10 g, 98%). This crude product was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([O:17][CH3:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:20]O>>[CH3:20][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[O:17][CH3:18]
Reactant: CO
Reactant: COc1cc(C2CCCCC2)ccc1CC(=O)O
Agent: Cl
Product: COC(=O)Cc1ccc(C2CCCCC2)cc1OC
Reaction time: 18 h

Procedure:
A solution of 20 g of (4-cyclohexyl-2-methoxyphenyl)-acetic acid in 200 ml of dry methanol is saturated with HCl gas at 0°. After standing at 22° for 18 hours, it is evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>ClCCl>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 g, 0.10 mol) and pyridine (10 ml) were mixed together in dichloromethane (200 ml) in a reaction flask. Cyclopropane carboxylic acid chloride (9.1 ml, 0.10 mol) was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and the temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 5% sodium hydroxide (200 ml) and water (100 ml). The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 g, after drying. The product was identified by infrared (IR) and nuclear magnetic spectroscopy (NMR) analysis as the title compound, having a melting pont of 130°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-methoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Product: CC1CCN(CCc2ccc(NC(=O)C#Cc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine. Yield: 0.21 g (45.3% of theory); C24H23Cl2F3N2O (M=483.36); calc.: molecular ion peak (M+H)+: 483/485/487; found: molecular ion peak (M+H)+: 483/485/487; Rf value: 0.65 (Alox, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15])[CH3:2].[BrH:17].BrBr>CC(O)=O>[Br:17][CH2:15][C:14]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: CCc1c(C(C)=O)cnn1-c1ccccc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1c(C(=O)CBr)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5.40 g (25.3 mmol) of 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone in HOAc (30 mL) was added HBr in HOAc (30 mL). Bromine (1.42 ml, 27.7 mmol) was added dropwise and the mixture was stirred at rt for 45 minutes and was poured into ice water (500 mL). The liquid was decanted and remaining residue was washed with water, then dissolved in CH2Cl2 (500 mL) and washed with sat NaHCO3, dried over MgSO4, and concentrated to give 7.20 g of 2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[OH:20][CH2:21][CH2:22][N:23]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:25][CH2:26][NH2:27]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][OH:30])[CH2:22][CH2:21][OH:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Reactant: NCCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: OCCN(CCO)CCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 78.3 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 3-[bis(2-hydroxy-ethyl)amino]-propylamine (0.51 g) in toluene (25 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a yellow plate like crystals (0.55 g); mp 88-90° C.