Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(#N)C>[Cl:15][C:7]1[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)n2nccc2n1
Yield: 71 %

Procedure:
In a round bottom flask equipped with a magnetic stirbar, 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.0 eq, 10.43 g, 57.24 mmol) was suspended in acetonitrile (100 ml). Phosphorus oxychloride (4.0 eq, 21 ml, 229.4 mmol) and triethylamine (1.05 eq, 8.4 ml, 60.27 mmol) were added and the mixture stirred at reflux for 3.5 hours, at which time LCMS indicated completion of the reaction. The mixture was cooled down and slowly poured into crushed ice (final total volume of about 600 ml). The solid was filtered, washed with water and dried in a vacuum oven to afford 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine as a tan solid (8.15 g, 71% yield). LCMS (ES): >97% pure, m/z 201 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26]>C[O-].[Na+]>[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH:31][C:19](=[O:20])[CH2:18][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)NCCN
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)NCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Yield: 66.8 %

Procedure:
A solution of 10.7 g (0.035 mol) of ethyl 4,5-diphenylpyrazole-1-acetate of example 1 in 10.9 g (0.094 mol) of 2-[(1,1-dimethylethyl)amino]ethanamine was heated with about 50 mg of sodium methoxide at about 150° C. for two hours. The excess amine was stripped off under vacuum and the residue was triturated in acetonitrile. The solid product was filtered off and recrystallized from isopropyl acetate to yield 8.8 g of white crystals, mp 115°-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14]([O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1)=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: C1CCOC1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (0-5° C.) solution of 30.0 g (0.180 mol) of 2-amino-3-methoxybenzoic acid (Aldrich Chemicals) in 500 mL of tetrahydrofuran was added 17.8 g (0.0600 mol) of triphosgene. A precipitate formed upon addition. The ice bath was removed after 15 minutes, and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into 1000 mL of water and stirred for thirty minutes. The product (mp 267-268° C.) was filtered and amounted to 32.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCc1cccnc1
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
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added pyridin-3-ylmethanamine (33 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 57 as a solid (37 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:15]3[C:16](=[O:30])[N:17](CC4C=CC(OC)=CC=4OC)[CH2:18][C:14]=3[C:13]([F:31])=[C:12]([NH:32][C@@H:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]3[NH:39]C(=O)OC(C)(C)C)[N:11]=2)=[CH:2]1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>CS(C)=O.CCOC(C)=O.C1COCC1>[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].[NH2:39][C@H:34]1[CH2:35][CH2:36][CH2:37][CH2:38][C@H:33]1[NH:32][C:12]1[N:11]=[C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)[C:15]2[C:16](=[O:30])[NH:17][CH2:18][C:14]=2[C:13]=1[F:31]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4coc5ccccc45)c3C2=O)c(OC)c1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2coc3ccccc23)c2c(c1F)CNC2=O
Temperature: 125 °C
Yield: 20 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-(benzofuran-3-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (75 mg, 0.119 mmol) and TFA (2 mL) was placed in a vial and heated at 125° C. for 3 h. The solvent was subsequently removed in vacuo to give a residue which was dispersed in DMSO and MeOH (1/1), passed through a microfiltration frit, and purified via preparative HPLC. The fractions were collected and the solvent removed in vacuo to give a TFA salt of the title compound as a gray solid (9.2 mg, 20%). 1H NMR (500 MHz, CD3OD) δ ppm 1.67 (br s, 3H), 1.79-2.05 (m, 5H), 3.98 (br s, 1H), 4.50 (s, 2H), 4.69 (br s, 1H), 7.28-7.47 (m, 2H), 7.56 (d, J=7.81 Hz, 1H), 8.31 (d, J=6.83 Hz, 1H), 9.08 (s, 1H). [M+H] calc'd for C21H21FN4O2, 381. found, 381.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.CCO>[CH:40]1([C:39]2[C:20]([N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=3[CH:38]=2)[CH2:42][CH2:41]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)cc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)cc3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 97.7 %

Procedure:
A solution of 6-(N-(4-(benzyloxy)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.174 g, 0.298 mmol) in 3:1 THF/EtOH (20 mL) was subjected to hydrogenation at 40 psi in the presence of 5% palladium on charcoal (20 mg). After 3 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through Celite and the filtrate concentrated to dryness at reduced pressure. The residue was triturated with DCM/hexane. The resulting solid was collected by filtration and dried in vacuo to afford the title compound (144 mg, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (br. s., 1H) 8.44 (q, J=4.4 Hz, 1H) 8.13 (s, 1H) 7.97 (dd, J=8.9, 5.4 Hz, 2H) 7.46 (d, J=8.9 Hz, 2H) 7.40 (t, J=8.9 Hz, 2H) 7.12 (s, 1H) 6.77 (d, J=8.9 Hz, 2H) 3.27 (s, 3H) 2.83 (d, J=4.6 Hz, 3H) 2.28-2.39 (m, 1H) 0.76-1.11 (m, 3H) 0.47 (br. s., 1H). LCMS (m/z, ES+)=495 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5- dimethyl-8-(2-methylphenyl)-2-naphthalenyl)ethynyl]- benzoate (Compound 3) 80.0 mg (0.190 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.89(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.46 (2H, s), 7.29-7.14 (4H, m), 6.59 (1H, s), 5.90 (1H, t, J=4.7 Hz), 2.39 (2H, m), 2.60 (3H, s), 1.39 (3H, s), 1.29 (3H, s).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[Cl:23].[CH3:24][S:25]SC.Cl>O1CCCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([S:25][CH3:24])[C:15]=1[Cl:23]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1c(C(=O)O)ccc(Br)c1Cl
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexane; 8.8 ml) was added to a stirred cooled solution of di-isopropylamine (2.22 g) in dry tetrahydrofuran, maintaining the temperature below -40° C. The mixture was stirred for 0.5 hours then a solution of 4-bromo-3-chlorobenzoic acid (2.36 g) in dry tetrahydrofuran was added. The mixture was stirred at -40° C. for 6 hours. Dimethyl disulphide (2.82 g) was added and the mixture was stirred at -40° C. for 1 hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-3-chloro-2-methylsulphenylbenzoic acid (0.98 g) as a solid, m.p. 128°-130° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH3:7])[C:10]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CCOC(CN)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(CNC(=O)c1cccc(OC)c1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Oxalyl chloride (34 mL, 0.395 mol) was added to a solution of 3-methoxy-2-nitrobenzoic acid (60 g, 0.305 mol) in dry dichloromethane (600 mL), followed by N,N-dimethylformamide (0.6 mL, 7.8 mmol), which initiates mild gas evolution. The mixture was stirred at room temperature for two hours, then concentrated under vacuum to remove volatiles. The crude acid chloride was dissolved in dry dichloromethane (150 mL) then added dropwise to a cooled (5° C.) solution of aminoacetaldehyde diethylacetal (48 mL, 0.33 mol) and triethylamine (52 mL, 0.374 mol) in dry dichloromethane (250 mL). The mixture was stirred at room temperature for two hours, then washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and concentrated to give N-(2,2-diethoxyethyl)-3-methoxy-2-nitrobenzamide (296a, 92 g, 97% yield) as a yellow solid. MS: 335 [M+1].
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:12][C:10]([CH3:13])([CH3:11])[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:28]
Reactant: CC(C)(O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.9 %

Procedure:
(4.9 g, 18.2 mmol) 1-(Dibenzylamino)-2-methylpropan-2-ol (CAS 344868-41-3) was dissolved in dichloroethane (50 ml) and ethyl 2-diazoacetate (2.83 ml, 27.3 mmol, 1.5 equiv.) and rhodium(II) acetate dimer (200 mg, 0.455 mmol, 0.025 equiv.) were added carefully at room temperature. The mixture was stirred for 3 hours at 80° C. The reaction mixture was evaporated with isolute and the crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 70:30. The desired (2-dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (1.03 g, 80% purity, 13% yield) was obtained as a colorless liquid, MS: m/e=356.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: NC(CC(=O)O)c1ccc(O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
5.298 g (29.24 mmol) commercial 3-amino-3-(4-hydroxyphenyl)propionic acid were suspended in 136 ml methanol, the mixture cooled to 0° C. and 3.20 ml (43.86 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane and dichloromethane/2-propanol 8:2. The organic part was concentrated to give 5.09 g (80%) 3-amino-3-(4-hydroxyphenyl)propionic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])F.Cl.[OH-].[Na+].[CH2:25](O)C>[Fe]>[F:21][C:18]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:2]=1)[NH2:8])([F:20])[CH3:25]
Reactant: CCO
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: CC(F)(F)c1cccc(N)c1

Procedure:
Dissolve the nitro compound obtained in Step 1 (870 mg, 4.8 mmol) in ethanol (10 mL), add iron powder (1.3 g, 23.3 mmol), concentrated aqueous HCl (37%, 2.7 mL), stir the reaction at room temperature for 2 hrs. After the reaction, carefully neutralize the mixture with NaOH solution. Filter off the solid, pour the filtrate to ice water (50 mL), extract with EtOAc (15 mL×3), combine the organic layers, wash with brine (100 mL) and dry over anhydrous Na2SO4. Concentrate under reduced pressure to get the crude product (760 mg) which is used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10](F)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.COB(OC)OC.C(#N)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Reactant: C1CCNCC1
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCCC3)c(OC)c21
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 2.83 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.70 g of piperidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 15 ml of acetonitrile was refluxed with heating for 4.5 hours. The reaction solution was cooled to room temperature, 30 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 2.20 g of the objective compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1[C:13]2[C:12]([OH:14])=[CH:11][C:10]([F:15])=[CH:9][C:8]=2[N:7]([CH2:16][CH3:17])[CH:6]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[CH2:16]([N:7]1[C:8]2[C:13](=[C:12]([O:14][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[C:10]([F:15])[CH:9]=2)[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])=[CH:6]1)[CH3:17]
Reactant: Brc1ccccc1
Reactant: CCn1cc(CCN(C)C)c2c(O)cc(F)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1cc(CCN(C)C)c2c(Oc3ccccc3)cc(F)cc21
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A mixture of 1-9b (80 mg, 0.32 mmol), bromobenzene (100 mg, 0.64 mmol), K2CO3 (110 mg, 0.8 mmol) and CuI (152 mg, 0.8 mmol) in 10 mL of dioxane was stirred at reflux overnight. After cooled to room temperature, the volatiles were evaporated under vacuum and the resulting residue was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The organic layers were combined, washed with brine (2×30 mL), dried over MgSO4 and evaporated. The resulting brown residue was purified by preparative HPLC (acid condition, water/CH3CN, 25-30% CH3CN in 7.5 min, RT=6.5 min) to give 32-2 (3 mg, 3%) as a white solid. 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.34 (t, J=8.0 Hz, 2H), 7.13-7.09 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.85 (d, J=11.2 Hz, 1H), 6.10 (d, J=11.2 Hz 1H), 4.05 (q, 2H), 3.33-3.28 (m, 2H), 3.11-3.07 (m, 2H), 2.74 (s, 6H), 1.33 (t, J=7.2 Hz, 3H). LRMS: calc 326.2 and found: 327.1 [M+1].
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([OH:16])[C:10]=2[N:9]=[C:8]1[CH3:26].[OH-].[Na+]>O>[CH3:26][C:8]1[N:7]([CH3:6])[C:11]2[CH:12]=[CH:13][C:14]3[CH2:17][CH2:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:16][C:15]=3[C:10]=2[N:9]=1
Reactant: Cc1nc2c(O)c(CC=Cc3ccccc3)ccc2n1C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c3c(ccc2n1C)CCC(c1ccccc1)O3
Temperature: 90 °C
Yield: 9.8 %

Procedure:
A suspension of 5 ml phosphoric acid (85%) and 260 mg (0.9 mmol) 1,2-dimethyl-5-(3phenyl-allyl)-1H-benzimidazol-4-ol was heated at 90° C. for 90 min. After cooling to room temperature, the reaction mixture was poured into water (400 ml), neutralized with 6N sodium hydroxide solution and extracted with dichloromethane (4×300 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=2:1) to afford 24.5 mg (10%) of the title compound as a white solid. m. p. 161°-164° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-piperidin-4-yl-morpholine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O3 [(M+H)+] 692.3129, observed 692.3123.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([O:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][C:15]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:14]1[C:15]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH2:2])=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)c1cccc(-c2ccccn2)c1OCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(-c2ccccn2)c1OCc1ccccc1
Temperature: -3 °C
Reaction time: 1 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.31 g, 3.67 mmol, 3.67 mmol, 2.0 equiv) in THF (15 mL) was cooled to ˜−3° C. and 2.5M n-BuLi in hexanes (1.4 mL, 3.5 mmol, 1.9 equiv) was added dropwise at <2° C. The yellow light suspension was allowed to warm to room temperature and stirred 1 hr. The mixture was cooled to ˜3° C. and a solution of 12 (0.67 g, 1.84 mmol, 1.0 equiv) in THF (5 mL) was added at <5° C. The mixture was allowed to warm to room temperature and stirred 3 hr. TLC (25% EtOAc/heptanes) showed the reaction was complete. The mixture was quenched by addition saturated NH4Cl solution (5 mL). The mixture was partitioned between EtOAc (75 mL) and H2O (5 mL). The organic phase was washed with brine (25 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a yellow-orange oil (crude weight=1.41 g). The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (15 g) packed in hexanes. The column was eluted with hexanes (100 mL), 5% EtOAc/hexanes (200 mL) and 10% EtOAc/hexanes (200 mL). Product fractions were concentrated under reduced pressure and the residue dried under high vacuum for 1 hr to give 0.64 g of 13 as a colorless, viscous oil.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[S:22][C:21]([CH2:23][NH:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[F:2])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccc(Cl)s2)ccc2ccccc12
Yield: 71 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-chlorothiophen-2-carbaldehyde in 71% yield as a slightly white oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:18]1([CH:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Batch size: 2.3 g (15.5 mmol) 3-(3-pyridyl)-acrylic acid, 2.7 g (21.3 mmol) oxalyl chloride and 4.1 g (13.9 mmol) 2-(1-diphenylmethylpiperidine-4-yl)-ethylamine in 60 ml abs. dichlormethane.