Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[N:3]=[CH:2]1.[CH2:10](Cl)[C:11]1[O:15]C=[CH:13][CH:12]=1.[CH3:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19]>>[CH:21]1([N:20]([CH3:22])[C:18]([C:17]2[O:15][C:11]([CH2:10][N:9]3[CH:8]=[CH:7][C:6]4=[N:3][CH:2]=[N:1][C:5]4=[CH:4]3)=[CH:12][CH:13]=2)=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: ClCc1ccco1
Reactant: CC(=O)N(C)C
Reactant: c1cnc2nc[nH]c2c1
Product: CN(C(=O)c1ccc(Cn2ccc3ncnc-3c2)o1)C1CCCCC1
Temperature: 75 °C
Reaction time: 60 h
Yield: 65 %

Procedure:
To a stirred solution of imidazopyridine (150 mg, 1.25 mmol) in dimethylacetamide (30 mL) under argon, furfuryl chloride (product of Example H) (320 mg. 1.25 mmol) was added in one portion. The reaction temperature was slowly raised to 75° C. and was stirred for 60 hr. The reaction flask was cooled to room temperature and the solvent was removed under reduced pressure at <45° C. The residue obtained was triturated with excess of dry ether and filtered. The crude product (410 mg) was chromatographed (silica gel, CH2Cl2 :MeOH:NH4OH::90:10:1) to give the title compound (265 mg, 65%) as white solid, mp 189-90° C., 1H NMR (CDCl3) 1H NMR (CDCl3) 0.85 -1.9(m, 13H), 3.6-3.8 & 4.3-4.45(m, 1H), 5.62 (s, 2H), 6.62 (brs, 1H), 6.82 (brs, 1H), 7.73 (dd, J=7 Hz, 1H), 7.85 (dd, J=3,7 Hz, 1H), 8.57 (s, 1H), 8.8 ppm (s, 1H), Anal calcd. for C19H22N4O2 0.5H2O: C, 65.70,H,6.62, N, 16.11. Found: C, 65.65, H, 6.71, N, 16.06.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13]>C1COCC1>[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: COC(=O)C(C)(C)C(F)(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)CC#N)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a mixture of acetonitrile (3.32 mL, 97 mmol) in THF (300 mL) cooled to −78° C. was added n-BuLi (56.4 mL, 141 mmol). The mixture was stirred at −30° C. for 30 min. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (15 g, 88 mmol) dropwise. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with NH4Cl (aq) and extracted with DCM/MeOH (10:1). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (5 g, 27.9 mmol, 31.7% yield): 1H NMR (400 MHz, CDCl3) δ: 3.75 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17]C1C=CC(C)=C(C=1)N.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:17])[CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cl)cc1N
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: Cc1ccc(Cl)cc1NC(=O)OC(C)(C)C
Yield: 77 %

Procedure:
N-tert-Butoxycarbonyl-4-chloro-2-methylaniline. By the procedure in Example 1, Part C, 28.3 g (0.2 mole) of 5-chloro-2-methylaniline was reacted with 48.1 g (0.22 mol) of di-tert-butyl dicarbonate to give 37.1 g (77% yield) of N-tert-butoxycarbonyl-5-chloro-2-methylaniline melting at 100°-102° C., after crystallizing from hexane.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27](O)=[O:28])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[O:28])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: NCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)NCCc1ccccn1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 7 mg (0.05 5 mmol) of 2-aminoethylpyridine, 11 mg (0.05 5 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[S:54]([N:57]1[CH2:62][CH2:61][NH:60][C@@H:59]([CH3:63])[CH2:58]1)(=[O:56])=[O:55])[C:49]#[N:50]>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:60]2[CH2:61][CH2:62][N:57]([S:54]([C:53]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[CH3:45])(=[O:56])=[O:55])[CH2:58][C@@H:59]2[CH3:63])=[O:35])=[CH:28][CH:27]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(Cl)nc2C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (425 mg, 1.12 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (160 mg, 0.93 mmol) in DMF (3 ml) and the mixture was treated with DIPEA (0.407 ml, 2.33 mmol). This mixture was stirred for ca. 10 min at ambient temperature. 3-Methyl-4-{[(3S)-3-methyl-1-piperazinyl]sulfonyl}benzonitrile (may be prepared as described in Description 11) (313 mg, 1.12 mmol) was added as a solution in DMF (2 ml) and stirring was continued for ca. 1 hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound as a pale cream foam (376 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[NH2:14][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1
Reactant: N
Solvent: C1CCOC1
Product: Nc1cc(F)cc(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
200 ml of tetrahydrofuran and 50 g of 2,4,6-trifluorobenzotrifluoride were initially introduced into a stainless steel autoclave and it was pressurized using 30 ml of liquid ammonia. Subsequently, the mixture was heated at 120° C. for 6 hours with stirring. After cooling and releasing the pressure, the reaction mixture was subjected to a fractional distillation. 15 g of 2-amino-4,6-difluoro-benzotrifluoride were obtained at a boiling point of 57° to 58° C. at 12 mbar. After a small intermediate run, 32 g of 2,6-difluoro-4-amino-benzotrifluoride passed over at a boiling point of 103° to 105° C. at 16 mbar. The melting point of the 2,6-difluoro-4-amino-benzotrifluoride obtained was 66° C.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)C1
Reactant: O=C=Nc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)Nc2ccccc2)C1

Procedure:
5-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (0.87 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.33 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.63 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(5-(3-phenylureido)pentyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[NH:9][CH:8]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:5][CH2:4][OH:3])=[CH:8][NH:9]2
Reactant: CCOC(=O)C(=O)c1c[nH]c2cccc(Cl)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCc1c[nH]c2cccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-3-(1H)-indoleglyoxylic acid ethyl ester (7.04 g, 30.0 mmol) in dry THF (0.4 L), at 0° C. under argon was added portionwise LiAlH4 (5.4 g, 135.2 mmol). The suspension was stirred at 0° C. for 20 min and at reflux for 3.5 h, cooled to 0° C., and water (17.6 mL) was added. It was stirred for 10 min, and then diluted with EtOAc. The reaction mixture was filtered. The solid was washed with EtOAc. The combined EtOAc portions were washed with water and brine, dried, filtered, and concentrated to give the title compound: TLC Rf=0.38 (9:1 CH2Cl2/Me2CO); MS (ESI−) m/z 194.0; 13C NMR (75 MHz, CDCl3) δ 138.02, 126.42, 124.21, 124.12, 122.70, 120.61, 112.63, 110.06, 63.59, 29.78.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[N:30]=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH:45]=2)O1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C.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>[N:30]1[C:22]([C:21]2[N:20]=[C:19]([C:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=3)[CH:18]=[N:17][C:16]=2[N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:23][N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nc2ccccn2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccn4n3)n2)CC1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-3-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-bromopyrazin-2-ylcarbamate (92 mg, 0.1872 mmol) was dissolved in DMF (1.5 mL) and treated with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (86.83 mg, 0.2808 mmol), PdCl2(PPh3)2 (13.14 mg, 0.01872 mmol) and K2CO3 (280.8 μL of 2 M, 0.5616 mmol). The mixture was allowed to heat at 100° C. for 1 hour and then allowed to cool to ambient temperature. The reaction was treated with EtOAc/water, the organics separated, washed with water (2×) followed by brine (2×), dried (MgSO4), filtered and concentrated to a brown oil. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petrol) to afford the title compound as a white solid (77 mg, 69% Yield). MS (ES+) 594.0
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>ClCCl>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:24][O:25][CH3:26])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)c1ccc(O)c(C)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1ccc(OCOC)c(C)c1O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture composed of 1-(2,4-dihydroxy-3-methylphenyl)propan-1-one (5.00 g, 27.8 mmol) and dichloromethane (80 mL), diisopropylethylamine (5.26 mL, 30.5 mmol) was added under cooling with ice, and then a solution of chloro(methoxy)methane (2.30 mL, 30.5 mmol) in dichloromethane (20 mL) was added dropwise to the mixture over 20 minutes. After the completion of dropwise addition, the mixture was brought back to room temperature and stirred overnight. Dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=90/10→70/30) to obtain 5.73 g of the title compound (yield: 92%).
Reaction SMILES: N1N=C(C2C=CC=CC=2C(N2CC3CN(C(OC(C)(C)C)=O)CC3C2)=O)NC=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][NH:41][CH2:42]3)[CH2:38]2)[N:31]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[CH3:60][C:61]1[N:65]=[C:64]([C:66]2[CH:74]=[CH:73][CH:72]=[CH:71][C:67]=2[C:68](O)=[O:69])[O:63][N:62]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][N:41]([C:68]([C:67]4[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=4[C:64]4[O:63][N:62]=[C:61]([CH3:60])[N:65]=4)=[O:69])[CH2:42]3)[CH2:38]2)[N:31]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4nc(C)no4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting Intermediate 23 for Intermediate 15 and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C22H24N6O2, 404.48; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H), 7.62 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.53 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 6.28 (s, 1H), 3.99-3.88 (m, 2H), 3.80-3.75 (m, 1H), 3.74-3.65 (m, 2H), 3.53-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.12-3.04 (m, 2H), 3.01-2.93 (m, 1H), 2.42 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([F:11])[C:9]=1[F:10].[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>CN(C=O)C>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=[C:22]([O:13][CH2:12][C:6]3[CH:5]=[C:4]([F:3])[C:9]([F:10])=[C:8]([F:11])[CH:7]=3)[CH:32]=[C:26]12.[C:16]([OH:18])([C:15]([F:20])([F:19])[F:14])=[O:17]
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaH (38.3 mg, 0.956 mmol) in DMF (2 mL) was added (3,4,5-trifluorophenyl)methanol (65 mg, 0.401 mmol) at rt. The reaction mixture was stirred for 5 mins at rt, and then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one trifluoroacetic acid salt (100 mg, 0.319 mmol) was added. The reaction mixture was stirred for another 1 h at rt, quenched with water and then filtered to give clear solution. The solution was purified by MDAP (0.3% TFA in water/MeCN) to afford the title compound as its TFA salt (16 mg, 0.036 mmol, 11.42%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: OCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCCCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A mixture of 5.0 g of 4-(trifluoromethoxy)phenol, 5.87 g of 8-bromo-1-octanol, and 7.76 g of K2CO3 in 56 ml of anhydrous dimethylformamide is stirred and heated at 80° C. for 16 hours. The reaction mixture is poured into dilute HCl solution and the mixture is extracted three times with ethyl acetate. The combined extracts are washed with brine and dried over MgSO4. After filtration and concentration, the crude product is purified by flash chromatography on silica gel, eluting with a 4:1 hexane/ethyl acetate mixture to give the title compound 8-(4-(trifluoromethoxy)-phenoxy)-1-octanol.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C@@H:17]2[CH2:22][O:21][C@@H:20]([CH2:23][CH2:24][CH2:25][OH:26])[O:19][CH2:18]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:4][S:1]([O:26][CH2:25][CH2:24][CH2:23][C@H:20]1[O:21][CH2:22][C@H:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([Cl:6])=[CH:8][CH:9]=2)[CH2:18][O:19]1)(=[O:3])=[O:2]
Reactant: OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.256 g (2.23 mmol) of mesyl chloride in 2 ml of dichloromethane is added, dropwise, to a solution of 0.530 g (1.72 mmol) of trans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]-1-propanol prepared in step 5.1 and of 0.48 ml (3.45 mmol) of triethylamine in 8 ml of dichloromethane cooled to 0° C. under an inert atmosphere. The reaction mixture is stirred at 0° C. for 1 hour. 25 ml of water and 50 ml of dichloromethane are added. The mixture is separated off after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over magnesium sulfate and concentration is carried out under vacuum, to obtain 0.66 g of product in the form of a white solid used without modification in the following step.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:20]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31](I)[C:25]=2[CH:24]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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:20]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH3:19])[C:25]=2[CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc2c(I)cccc2s1
Reactant: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-propoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene (see Example 14, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16].C(Cl)Cl.[CH3:23][O-:24].[Na+].CO>C(OCC)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:14](=[O:18])[C:15]([O:24][CH3:23])=[O:16]
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a solution of 5-trifluoromethylindole (2.0 g, 10.8 mmol) in diethyl ether (30 mL) at 4° C. was added a 2.0 M solution of oxalyl chloride in methylene chloride (5.5 mL, 11.0 mmol). The resulting solution was allowed to warm to room temperature. After 90 min, the solution was cooled to −78° C. To this solution was added 25% (w/w) solution of sodium methoxide in methanol (5.0 mL, 21.9 mmol). The resulting solution was allowed to warm to room temperature. After one hour, the solution was filtered to give the title compound (1.24 g, 43%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.66 (m, 1H), 8.45 (s, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[C:14](O)(=[O:18])[CH2:15][CH:16]=[CH2:17]>ClCCl>[N:5]1([C:14](=[O:18])[CH2:15][CH:16]=[CH2:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: C=CCC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sulfurous dichloride (6.91 g, 58.1 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (27.7 g, 232 mmol) in anhydrous dichloromethane (100 mL) at room temperature under argon atmosphere. The mixture was stirred for 30 min and but-3-enoic acid (5.0 g, 58.1 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and washed with 2.0 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as white solid (5.12 g). LCMS m/z=188.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.24 (d, J=6.57 Hz, 2H), 5.28-5.42 (m, 2H), 6.04-6.19 (m, 1H), 7.61 (t, J=7.71 Hz, 1H), 7.78 (t, J=7.71 Hz, 1H), 8.24 (dd, J=10.61, 8.34 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.C(=O)C1C=C[C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[C:38]1(C)[CH:43]=CC(C=O)=C[CH:39]=1>>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:5]([CH2:6][N:1]2[CH2:43][CH2:38][CH2:39][CH:7]([CH2:8][O:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[NH:20][C:19]5[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=5[N:17]=4)=[CH:14][CH:15]=3)[CH2:2]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: Cc1ccc(C=O)cc1
Product: COc1ccc(CN2CCCC(COc3ccc(-c4nc5cc(C(N)=O)ccc5[nH]4)cc3)C2)cc1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting 2-[4-(piperidin-3-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide and p-anisaldehyde for p-tolualdehyde. HPLC (Method C): Rt=4.42. MS (ESI+): mass calcd. for C28H30N4O3, 470.58; m/z found, 471.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.14 (s, 1H), 8.01 (d, J=8.8 Hz, 2H), 7.86 (dd, J=1.5, 8.7 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.21-4.19 (m, 2H), 4.07-4.04 (m, 1H), 3.95-3.92 (m, 1H), 3.74(s, 3H), 3.61-3.56 (m, 1H), 3.44-3.40 (m, 1H), 2.00-1.89 (m, 2H), 1.79-1.67 (m, 1H), 1.45-1.35 m, 1H).