Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:17][CH3:18])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12](O)=[O:13])=[O:4].C(Cl)(=O)C(Cl)=O.[NH3:27]>C1COCC1>[F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:17][CH3:18])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:27])=[O:13])=[O:4]
Reactant: COc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(F)(F)F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C(N)=O)cc1CNC(=O)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoic acid (1.0 g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 g of the desired product.
Reaction SMILES: C([O:5][C@H:6]([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=O)CC.[OH-].[Na+].O>C(O)C>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([OH:5])[CH3:17])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: CCC(=O)O[C@H](C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@@H](O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate (step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol (20 ml) was added 2N aqueous NaOH (5 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, extracted with diethyl ether (2×50 ml). The organic layer was washed with brine, dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (1:1) afforded 1.16 g (80%) of title compound as a colorless solid (79% e.e.). Recrystallization from hexane/diethyl ether afforded 717 mg of a colorless needle (99% e.e.).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][Si:13]([C:16]1([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14].Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:22][Si:21]([C:16]1([Si:13]([CH3:12])([CH3:14])[CH3:15])[C:20]([P:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=[CH:17]1)([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
76.6 ml of a 2.5 molar solution of butyllithium in hexane (0.19 moles) were added over 10 min at 0° C. to a solution of compound 1 (40.2 g, 0.19 moles) in 500 ml of ether. When the addition was complete. the bath was removed and the solution was stirred for 1 h at room temperature. After cooling to 0° C., 42.2 g (0.19 moles) of chlorodiphenylphosphine were added over 10 min, after which the bath was removed and the suspension was heated to room temperature. After stirring for 1 hour at room temperature, the ether was removed under vacuum and the product was dissolved in hexane again. After the salts had been filtered off, the hexane was removed under vacuum to leave 69.1 g (yield: 91%) of compound 16 in the form of an oil. 1H NMR (400 MHz, CDCl3): δ=7.45 (m, 4H); 7.35 (m, 6H); 6.8 (m, 1H); 6.65 (m, 1H); 6.6 (m, 1H); 0 (s, 18H); 31P NMR (161.9 MHz, CDCl3): δ=−19.5 ppm.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]=[O:28])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of n-octylbenzene (1.2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid (TFA) was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO3 and extracted with diethyl ether (Et2O) (3×5 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67%). 1H-NMR (CDCl3) 9.96 (s, 1H); 7.77 (d, 2H, J=8.1 Hz); 7.31 (d, 2H, J=8.1 Hz); 2.67 (t, 2H, J=7.9 Hz); 1.6 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz);
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:36][O:37][CH2:38][C:39]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:40]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
A mixture of N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.0 mg, 0.0413 mmol), methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol, Aldrich, Cat. No. M9653) in dimethylsulfoxide (DMSO) (0.5 mL) was stirred at r.t. for 4 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=557.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.C(O)(=O)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
2-Bromothiophene (130.4 g, 0.8 mol) was dissolved in 2-Me-THF (240 ml, 0.3 L/mole) and the resulting mixture cooled to 2° C. NiCl2(dppe) (2.11 g, 4.0 mmol) was added followed by addition, over about 40 min. at ≦30° C., of the 4-fluoro-phenylmagnesium bromide solution prepared as in STEP A above to yield a dark red solution. The solution was then stirred at 22° C. for 1.5 hrs. A solution of acetic acid (91.7 ml, 1.6 mol) in water (240 ml, 0.3 L/mol) was then added and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer was washed with water (80 ml, 0.1 L/mol), then concentrated in vacuo at 75° C. to yield 2-(4-fluorophenyl)thiophene as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 4 (34.29 g, 94.60 mmol) in tetrahydrofuran (234 mL) and methanol (234 mL) was added 1 N aq sodium hydroxide (473 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 3 N aqueous hydrochloric acid was added dropwise to pH 2. The resulting slurry was filtered, and the solid was washed with water (300 mL, then 100 mL). The solid was dried by azeotropic removal of water first with toluene, then heptane (7×100 mL), followed by heating to 70° C. under reduced pressure to afford (+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid (Intermediate 5). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1 H), 8.02 (d, J=8.4 Hz, 2 H), 7.84 (d, J=8.4 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 7.66-7.58 (m, 3 H), 7.40 (t, J=7.6 Hz, 1 H), 5.56 (dd, J=6.0, 8.6 Hz, 1 H), 2.49 (s, 3 H), 2.24-2.10 (m, 1 H), 2.08-1.95 (m, 1 H), 1.66-1.52 (m, 1 H), 1.52-1.39 (m, 1 H), 1.03 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([NH:4][CH:5]([CH:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(NC(C)=O)C(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(NC(C)=O)C(O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A solution of methyl 2-acetamido-3-(4-methoxyphenyl)-3-oxopropanoate (22.7 g, 85.7 mmol) in methanol (500 mL) was cooled to 0° C. and NaBH4 (976 mg, 25.7 mmol) was added in portions. The reaction mixture was stirred for 1 h at 0° C. and then quenched with water (1 L). The resulting mixture was extracted with EtOAc (300 ml×3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether/EtOAc (100 mL, 10:1) to afford methyl 2-acetamido-3-hydroxy-3-(4-methoxyphenyl)propanoate (13.5 g, 59% yield, erythro-form >95%) as a colorless solid.
Reaction SMILES: Cl.[N:2]1([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:2]1([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([O:11][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(C(C(=O)O)N2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(C(=O)O[C@H]2CN3CCC2CC3)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
2-(Piperidin-1-yl)-2-p-tolylacetic acid hydrochloride (242 mg, 0.90 mmol), DCC (370 mg, 1.79 mmol) and HOBT (275 mg, 1.79 mmol) were dissolved in dry THF (10 ml). (R)-quinuclidin-3-ol (342 mg, 2.69 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was recovered, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(piperidin-1-yl)-2-p-tolylacetate (169 mg, 55% yield) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=O)[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[NH2:22][NH2:23]>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=[N:22][NH2:23])[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2CC(=C=O)C(=O)O2)cc(OC)c1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC

Procedure:
11.2 g (0.04 mol) of 4-(3,4,5-trimethoxyphenyl)-carbonyl-γ-butyrolactone and 2 ml (0.04 mol) of hydrazine hydrate are stirred in 60 ml of ethanol at room temperature for 1 hour and the precipitate is filtered off with suction.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:39](O)=[O:40])=[CH:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:39]([C:33]3[C:32]([C:29]4[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=4)=[CH:37][C:36]([CH3:38])=[CH:35][CH:34]=3)=[O:40])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: Cc1ccc(C(=O)O)c(-c2ccc(C(C)C)cc2)c1
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (150 mg), 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (127 mg), HOBt (87 mg), and Et3N (64 mg) in CH2Cl2 (10 mL) was added at room temperature EDCl (124 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the oily residue was crystallized from EtOH to give the title compound (160 mg) as white crystals.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Br:22])=[CH:17][N:16]=2)=[CH:11][CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Br:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([C:12]2[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CC=C(c2ncc(Br)cc2C)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid tert-butyl ester (11.6 g) described in Reference Example 143 (5) in dichloromethane (30 ml) was added trifluoroacetic acid (10 ml) at room temperature, and stirred at 50° C. for 4 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added thereto under ice-cooling, and extracted with 10% methanol/chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with basic silica gel column chromatography (chloroform) to give N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylamine (8.13 g) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCCC1.Cl[C:13]1[C:18]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=1>O>[O:4]1[CH2:5][CH2:6][N:1]([C:13]2[C:18]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-n2cccn2)c1
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (50 μl) was added to a tetrahydrofuran solution (1 ml) containing 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (30 mg), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was thus obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH2:10][C:9]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH:10]=[C:9]2[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCC1=CC(C)(C)Oc2cc(OC)c(Br)cc21

Procedure:
Following General Procedure C, ethylmagnesium bromide (2.0 M in THF, 4.7 mL, 14.08 mmol) was added to a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 800 mg, 2.81 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[Cl:19][C:14]1[CH:13]=[C:12]([C:3]2[N:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=2[C:23]2[CH:24]=[C:25]([F:27])[CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Reactant: OB(O)c1cc(F)cc(Cl)c1
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: COCCOC
Product: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under argon, 100 mg (0.27 mmol) of the compound from Example 4A are provided in 4 ml of 1,2-dimethoxyethane, and 71.7 mg (0.41 mmol) of 3-chloro-5-fluorophenylboronic acid, 1.5 ml (1.37 mmol) of an aqueous sodium bicarbonate solution (10%) and 9.5 mg (8 μmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is stirred at 80° C. overnight. The mixture is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient), and 93.0 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[C:5]=1[O:17][CH2:18][CH3:19])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:11]([C:9]3[O:10][C:6]4[C:5]([O:17][CH2:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:16]=[CH:15][C:7]=4[C:8]=3[CH3:14])=[O:13])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCOc1ccc2c(C)c(C(=O)O)oc2c1OCC
Product: CCOc1ccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)oc2c1OCC

Procedure:
With a procedure similar to the example above, 4-{4-[(6,7-diethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 6,7-diethoxy-3-methyl-benzofuran-2-carboxylic acid and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C29H37N3O6 (m/e) 523, obsd 524 (M+H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: S=C(Cl)Cl
Reactant: C=CCNCCCNc1c(C)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
To an ice-cold solution of the diamine of Step C (4.9 g) and triethylamine (5.8 mL) in chloroform (70 mL) under nitrogen was added thiophosgene (1.6 mL). After 20 minutes at ambient temperature, additional thiophosgene (0.5 mL) was added. After 15 minutes, the reaction was quenched with water and extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title product (3.2 g, 55.6%) as a white solid, m.p. 82-84° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([C:13]2[CH:14]=[C:15]([C:24]([F:27])([F:26])[F:25])[C:16]([O:22][CH3:23])=[C:17]([CH:21]=2)[C:18](O)=[O:19])=[O:12])[CH2:3]1.[S:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:23][O:22][C:16]1[C:15]([C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]([C:11]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:2](=[O:28])(=[O:1])[CH2:3]2)=[O:12])=[CH:21][C:17]=1[C:18]([N:31]1[CH2:32][CH2:33][S:29][CH2:30]1)=[O:19]
Reactant: C1CSCN1
Reactant: COc1c(C(=O)O)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C(=O)N2CCSC2)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-(1,1-dioxo-2,3-dihydro-1,3-benzothiazole-3-carbonyl)-2-methoxy-3-trifluoromethylbenzoic acid (277 mg) was dissolved in dichloromethane (3 mL), thiazolidine (0.10 mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (238 mg) were added to the solution, and then the mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (138 mg) as a colorless oily substance.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH:2]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cnc2c(c1)CCCC2
Yield: 43.5 %

Procedure:
A mixture of 3-quinolinecarboxylic acid (1.73 g, 10.0 mmol) in trifluoroacetic acid (20 ml) with platinum dioxide (200 mg) was shaken in a Parr vessel at 10-15 psi. After 90 minutes the reaction mixture was filtered and the solvent removed in vacuo to yield an oil. The oil was added dropwise onto diethyl ether yielding a white solid which was collected by filtration and then recrystallised from ethyl acetate/hexane to yield the title compound as a white solid (770 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:14]([N:21]=[C:22]=[S:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:22](=[S:23])[NH:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: S=c1[nH]nc(-c2ccc3[nH]cnc3c2)n1Cc1ccccc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and benzylisothiocyanate (0.149 g; 0.13 ml; 1 mmol); Yield: 0.052 g (17%); MS m/z: 308.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.33 (s, 2H); 6.97-6.99 (m, 2H); 7.15-7.22 (m, 3H); 7.44 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.71 (d, 1H, 3J=8.7 Hz), 7.81 (br s, 1H); 8.79 (s, 1H); 14.08 (s, 1H); HPLC (METHOD [A]): rt 10.47 min (100%)