Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([F:15])([F:14])[F:13])=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH:20][C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1>>[N:27]1([C:24]2[N:23]=[CH:22][C:21]([NH:20][C:16]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][C:10]=3[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:26][CH:25]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CNc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1cc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1cc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1 above, 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid and methyl-(6-morpholin-4-yl-pyridin-3-yl)-amine. LCMS calcd for C21H18F3N3O3 (m/e) 417, obsd 418 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.O[CH:45]1[CH2:50][C:49](=O)[NH:48][C:46]1=O.C(NCC)C.[Cl-].[Na+]>CN(C)C=O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:45])=[O:17])/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:1]
Reactant: O=C1CC(O)C(=O)N1
Reactant: COc1cccc(C2=C/C(=C\c3cccc(C(=O)O)c3)CCC2CN(C)C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(/C=C2\C=C(c3cccc(OC)c3)C(CN(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
1.8 g of the Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid base prepared according to example 4 were dissolved in 50 ml analytical grade dimethylformamide, and 2 g DCC and 1.1 g hydroxysuccinimide were added at 0° C. to 15° C. The mixture was stirred at 0° C. for one hour and 2 ml diethylamine were then added dropwise at this temperature. The mixture was stirred at 0° C. for an additional hour and then at room temperature for four days. The reaction mixture was poured on to 300 ml saturated sodium chloride solution and the mixture was then extracted 3 times with 250 ml ethyl acetate each time. The organic phases were washed with 50 ml saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was chromatographed on silica gel with ethyl acetate/methanol=6/5. 0.87 g Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide base was obtained in this way in the form of an orange-yellow oil. To liberate the hydrochloride, the oil was dissolved in 5 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 0.52 g (22.1% of theory) of the title compound 34 was obtained in this way in the form of white crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=4)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C(F)(F)F)c3)nc2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 110 °C

Procedure:
To a reaction vessel charged with N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-(trifluoromethyl)phenyl)acetamide 192-1 (300 mg, 0.62 mmol), 2-methylpyridin-4-ylboronic acid 172-1 (127 mg, 0.93 mmol) and Pd(PPh3)4 (36 m g, 0.03 mmol) was added toluene (6 mL), ethanol (2 mL) and saturated sodium carbonate (2 mL). The reaction mixture was flushed with nitrogen and heated to 110° C. for 10 hours. After the reaction was cooled down to room temperature, it was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 172. MS m/z 498.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.67 (s, 1H), 8.66 (d, 1H), 8.05 (m, 1H), 7.94 (m, 2H), 7.75 (d, 1H), 7.52 (s, 1H), 7.45 (m, 3H), 3.88 (s, 2H), 3.58 (b, 4H), 3.14 (b, 2H), 3.09 (b, 2H), 2.61 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:39](=[O:40])[CH2:38][CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: O=C(Cl)CCc1ccccc1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)CCc3ccccc3)ccc2O1

Procedure:
The titled compound was prepared following the procedure using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-phenylpropanoyl chloride as an oil (77%). HPLC, Rt: 5.9 min (Purity: 97.3%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][OH:15])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)Cl.C1COCC1>[Br:16][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: BrBr
Reactant: OCCCc1cc(-c2ccccc2)n[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 2 h
Yield: 97.9 %

Procedure:
3-(3-Phenyl-1H-pyrazol-5-yl)propan-1-ol (3.0 g, 14.83 mmol) was dissolved in dry DCM (40 mL) and THF (15 mL). The reaction was cooled in an ice bath and Br2 (1.146 mL, 22.25 mmol) pre-dissolved in DCM (10 mL) was added slowly dropwise: via addition funnel. The reaction was stirred for 2 h in an ice bath. The reaction was quenched by the addition of Na2SO3 (20 mL of 10% solution; the reaction went from reddish-brown to clear and some bubbling was observed). The reaction was extracted (100 mL each of H2O and DCM). The aqueous layer was extracted again with DCM (100 mL). The combined organic layer was back extracted again with H2O (200 mL). The organic layer was dried and concentrated to give the title compound (4.08 g) as a yellow solid. LCMS m/z=281.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.83 (m, 2H), 2.61-2.68 (m, 2H), 3.47 (t, J=6.44 Hz, 2H), 7.39 (t, J=7.33 Hz, 1H), 7.47 (t, J=7.45 Hz, 2H), 7.78 (d, J=7.07 Hz, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and phenyl-acetyl chloride (386.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the 2-phenyl-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: Br.[Br:2][C:3]1[NH:4][C:5]2[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:7]3[N:8]([CH2:13][CH2:14][N:15]=3)[C:9](=[O:12])[C:10]=2[N:11]=1.I[CH3:25]>>[Br:2][C:3]1[N:11]([CH3:25])[C:10]2[C:9](=[O:12])[N:8]3[CH2:13][CH2:14][N:15]=[C:7]3[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:5]=2[N:4]=1
Reactant: CI
Reactant: O=C1c2nc(Br)[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Agent: Br
Product: Cn1c(Br)nc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
The product of Procedure 17 is allowed to react with iodomethane under alkaline conditions according to the method of Procedure 67 to give the desired product, m.p. 206°-207°.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH2:31][CH3:32]>>[CH2:30]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:31][CH3:32]
Reactant: CCCBr
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of bromopropane are treated as described in Example 5. The title compound is crystallized in the form of hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([O:23]C)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCC2CCCO2)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-((tetrahydrofuran-2-yl)methoxy)biphenyl-3-carboxylate (130 mg, 0.40 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added lithium hydroxide (50 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidified with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.84 (t, J=1.6 Hz, 1H), 7.54-7.50 (m, 3H), 7.38 (dd, 1H, J=2.8, 1.6 Hz), 7.27 (d, 2H, J=8.0 Hz), 4.34-4.27 (m, 1H), 4.12 (dd, 1H, J=10.0, 3.6 Hz), 4.04 (dd, 1H, J=10.0, 6.4 Hz), 3.97-3.80 (m, 2H), 2.38 (s, 3H), 2.20-1.80 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])S[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].O[O:21][S:22]([O-:24])=O.[K+]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[S:22](=[O:24])(=[O:21])[C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 5-nitro-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl)-pyridine (0.300 g, 1.08 mmol, as prepared in the previous step) in MeOH (15 mL) was cooled to 0° C. and treated with oxone (984 mg, 3.23 mmol based on KHSO5 content) as a solution in water (1.5 mL). The ice bath was removed, and the mixture was allowed to stir at RT for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 25-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=5% EtOAc-hexane for 0-3 min, then 5-15% EtOAc-hexane for 5-30 min) to afford the title product (322 mg, 96%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C14H18N2O4S, 311.1 (M+H), found 311.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:15][O:14][CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:17][CH:18]=3)=[O:23])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: COCCN1CCCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-1-(2-methoxyethyl)-1,2,3,4-tetrahydroquinoline (D13) (72 mg, 0.35 mmol) in DCM (2.5 ml) was added 4-biphenylcarboxylic acid (104 mg, 0.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.53 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) and the reaction stirred at ambient temperature overnight. The mixture was diluted with DCM, washed with 2M sodium hydroxide solution, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 20% EtOAc/60-80° C. petroleum ether gave the title compound as a pale yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.93 (d, 2H), 7.77 (br, 1H), 7.69 (d, 2H), 7.62 (d, 2H), 7.47 (t, 2H), 7.39 (t, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.73 (dd, 1H), 3.63 (t, 2H), 3.49 (t, 2H), 3.37 (s, 3H), 3.36 (t, 2H), 2.73 (t, 2H), 1.91 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30](=[S:32])[NH2:31])[CH:16]=2>CN(C=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30]1[S:32][CH:2]=[C:3]([CH3:4])[N:31]=1)[CH:16]=2
Reactant: CC(=O)CCl
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C(C)C)C2)n1
Yield: 85.1 %

Procedure:
Combine chloroacetone (0.197 g, 2.13 mmol) and (R)-N-(9-(3-fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 22) (0.300 g, 0.708 mmol) and heat at 80° C. in DMF under nitrogen for 2.5 h. Upon cooling, dilute the mixture with water and collect the precipitate by filtration. Slurry the precipitate in hot EtOAc to give 0.278 g of a yellow solid. MS (ES): m/z 462 (M+1); HPLC: Rt=3.33 min (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.ClCCl.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([NH:27][S:24]([C:20]3[S:21][C:22]([Cl:23])=[C:18]([Cl:17])[CH:19]=3)(=[O:25])=[O:26])=[O:15])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:16]
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Reactant: Cc1c[nH]c2c(/C=C/C(=O)O)cc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c[nH]c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
A mixture of (E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)-acrylic acid (772 g, 3.53 mole), 4,5-dichloro-2-thiophenesulfonamide (900 g, 3.88 mole), 4-(dimethylamino)pyridine (861 g, 7.06 mole) and EDCI (1.348 kg, 7.06 mole) in dichloromethane (25.5 L) was stirred at ambient temperature for 14 h. The solution was diluted with 2 M aqueous HCl (16 L), and stirred for 1.5 h, which induced precipitation of the product. The product was collected via vacuum filtration and washed sequentially with water (2×2 L), dichloromethane (2×2 L), and hexanes (2 L) to provide 1.044 kg (71% yield) of the desired title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 6.71 (d, 1H, J=15.6 Hz), 7.22 (dd, 1H, J=10.0, 2.6 Hz), 7.27 (br s, 1H), 7.39 (dd, 1H, J=9.6, 2.6 Hz), 7.95 (s, 1H), 8.15 (dd, 1H, J=15.6, 1.2 Hz), 11.35 (s, 1H).
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:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(C)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a solution of 2,4-dichloropyrimidine (3.8 g, 25.5 mmol) in THF (175 mL) was added Pd(PPh3)2Cl2 (1.8 g, 2.6 mmol), CuI (247 mg, 1.3 mmol), and TEA (10.7 mL, 76.5 mmol) and the mixture was heated to 60° C. A solution of N-(5-ethynyl-2-methylphenyl)-2,2,2-trifluoroacetamide (6.4 g, 28 mmol) in THF (75 mL) was added through an addition funnel over 60 min. After 16 h, the dark reaction was concentrated onto silica gel and purified by column chromatography. Fractions containing product were concentrated and the impurity was triturated with DCM. The remaining liquid was purified again by column chromatography to give the desired product (2.7 g, 31%). 1H NMR (400 MHz, d6-DMSO) δ 11.09 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J=8.0 and 1.6 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 2.24 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O-:10].[Na+].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O:10][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1c(Cl)ccc([O-])c1Cl
Reactant: CCOC(=O)C(C)Br
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(Cl)c(C)c1Cl
Temperature: 25 °C
Yield: 85.2 %

Procedure:
In 100 ml of ethanol was dissolved 10.0 g. (0.05 mole) of sodium 2,4-dichloro-3-methylphenolate. With stirring at room temperature, 9.1 g (0.05 mole) of ethyl 2-bromopropionate was added. The mixture was heated under relfux for 4 hours. The ethanol was distilled off under reduced pressure, and the residue was extracted with 50 ml of diethyl ether. The ethereal layer was washed with 25 ml of a 5% aqueous solution of sodium hydroxide and 25 ml of water, and dried over anyhdrous magnesium sulfate. The dessicant was removed by filtration, and the diethyl ether was distilled off to give 11.8 g of crude ethyl 2-(2,4-dichloro-3-methylphenoxy)propionate. The crude ester (11.8 g) was dissolved in 100 ml of glacial acetic acid. Concentrated hydrochloric acid (25 ml) was added, and the mixture was stirred at 100° C. for 40 minutes. The reaction mixture was cooled, and poured onto 300 ml of ice water. The precipitated crystals were filtered, washed with water, and dried to give 9.2 g of 2-(2,4-dichloro-3-methylphenoxy)-propionic acid. The yield was 73.9% based on the sodium 2,4-dichloro-3-methylphenolate, and the final product had a melting point of 149.5 to 150.5° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:16]([C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[CH2:22][CH:23]([C:25]([OH:27])=[O:26])[NH2:24])([OH:18])=[O:17]>>[C:25]([CH:23]([NH:24][C:25]([CH:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][CH:30]=[C:19]([C:16]([OH:18])=[O:17])[CH:20]=1)=[O:26])[CH2:22][C:21]1[CH:28]=[CH:29][CH:30]=[C:19]([C:16]([OH:18])=[O:17])[CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1cccc(C(=O)O)c1)C(=O)O
Product: O=C(O)c1cccc(CC(NC(=O)C(Cc2cccc(C(=O)O)c2)Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-carboxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[CH2:13]([O:12][CH2:11][CH2:10][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NCCN1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1CCOCc1ccccc1

Procedure:
To a solution of imidazolidin-2-one (500 mg) in DMF (5.0 mL) was added a sodium hydride 60% dispersion in mineral oil (232 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. ((2-Bromoethoxy)methyl)benzene (0.83 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (388 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)(Cl)Cl.ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:23]([F:26])([F:25])[F:24])=[O:32])=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3,4-dihydro-4-oxo-3-quinazolinyl)-3-{p-[(trifluoromethyl)thio]phenyl}urea (1.0 g, 2.63 mmol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.57 g, 80% real, 2.64 mmol) in chloroform, stirred for 3 hours at 0° C., stirred for 32 hours at room temperature, cooled to 0° C., treated with additional 3-chloroperoxybenzoic acid (0.114 g, 0.53 mmol) in chloroform, stirred for 36 hours at room temperature, diluted with dichloromethane, washed sequentially with saturated sodium sulfite solution, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a yellow solid. Chromatography of the solid using silica gel and a 4:1 ethyl acetate/hexanes solution gives the title product as a white solid, 0.50 g, mp 148°-150° C., which is identified by 1HNMR spectral analysis.